Prostate Cancer: Advancements in the Pathogenesis, Diagnosis and Personalized Therapy [2024 ed.] 3031517113, 9783031517112

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Gordana Kocic Jovan Hadzi-Djokic Tatjana Simic   Editors

Prostate Cancer

Advancements in the Pathogenesis, Diagnosis and Personalized Therapy

Prostate Cancer

Gordana Kocic  •  Jovan Hadzi-Djokic Tatjana Simic Editors

Prostate Cancer Advancements in the Pathogenesis, Diagnosis and Personalized Therapy

Editors Gordana Kocic Department of Biochemistry Medical Faculty University of Nis Nis, Serbia

Jovan Hadzi-Djokic Serbian Academy of Science and Arts Belgrade, Serbia

Tatjana Simic Faculty of Medicine University of Belgrade Belgrade, Serbia

ISBN 978-3-031-51711-2    ISBN 978-3-031-51712-9 (eBook) https://doi.org/10.1007/978-3-031-51712-9 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Paper in this product is recyclable.

Preface

Prostate cancer represents one of the most common malignant diseases in men and is continually on the rise worldwide. This monograph is designed to provide medical professionals interested in clinical and basic medical research in oncology and urology with a comprehensive understanding of this complex disease, its pathogenesis, and the latest therapeutic approaches. Over the years, the scientific community has invested immense efforts in researching prostate cancer, its causes, genetic factors, molecular mechanisms, various forms of therapy with specific emphasis on personalized therapy. While the current science made significant progress, there is still much to discover and understand. The first part of the book (Recent Advances in Prostate Cancer Etiology and Pathogenesis) is dedicated to understanding prostate cancer itself—its epidemiology, risk factors, as well as its molecular, epigenetic, and exposomic influences, genetic basis, metabolic reprogramming, and tumor microenvironment–tumor interaction. The second part (An Integrative Approach in Prostate Cancer Diagnostics) discusses the histopathological and molecular tumor markers in assessment of prostate cancer aggressivity, early detection, and differentiating between theranostic, surrogate, and diagnostic markers. Understanding these aspects is crucial for prostate cancer early detection and prevention. The third part of the book (Current Treatment Options and Monitoring of Prostate Cancer) focuses on the therapeutic approach. Here, the details about surgical interventions, robot-assisted laparoscopic radical prostatectomy radiotherapy, hormone therapy, immunotherapy, stereotactic radiotherapy as well as pharmacogenomics and precision therapy should be found. There is the opportunity to find out more about clinical trials and their role in the development of new drugs and treatments. This monograph is presented in an understandable and accessible manner, to be a reference source for academic, residency, and postgraduate (PhD) medical profession and all those who wish to delve deeper into prostate cancer. Editors hope that this book serves as a valuable source of information for doctors, medical researchers, Medical doctors on Specialization and Sub-specialization training in Urology, Pathology, Oncology, Clinical Biochemistry, Laboratory Medicine, Diagnostic

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Preface

Radiology, Oncologic Radiology, and related cancer research disciplines. Through understanding its complexity, we can hope for better approaches to prevention, diagnostics, and treatment, as well as providing better support to patients and their families. Nis, Serbia Belgrade, Serbia  Belgrade, Serbia 

Gordana Kocic Jovan Hadzi-Djokic Tatjana Simic

Contents

Part I Recent Advances in Prostate Cancer Etiology and Pathogenesis 1

Prostate Cancer: Epidemiology, Etiology, Pathogenesis, and Risk Factors��������������������������������������������������������������������������������������    3 Tomislav Pejčić

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 Genetic Susceptibility to Prostate Cancer ��������������������������������������������   21 Tatjana Simic, Marija Matic, and Djurdja Jerotic

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 Basic Insights into Tumor Microenvironment in Prostate Cancer������   43 Sanja Mijatović and Danijela Maksimović-Ivanić

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Oxidative Stress, Redox Signaling, and Apoptosis in Prostate Cancer Development and Progression ��������������������������������������������������   73 Andrej Veljkovic

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Epigenomics, Transcriptomics, and Translational Control in Prostate Cancer������������������������������������������������������������������������������������   89 Gordana Kocic

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 Metabolic Reprogramming As a Prostate Cancer Hallmark��������������  123 Milica Zeković

Part II An Integrative Approach in Prostate Cancer Diagnostics 7

Diagnostic, Prognostic and Theranostic Potential of miRNAs in Prostate Cancer������������������������������������������������������������������������������������  147 Ana Savic-Radojevic and Marija Pljesa-Ercegovac

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 Diagnostic Approaches of Prostate Cancer: When Is a Biopsy Required?��������������������������������������������������������������������������������������������������  169 Bogomir Milojević

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Contents

Histopathological and Molecular Markers in the Assessment of Prostate Cancer Aggressivity��������������������������������������������������������������  179 Ljubinka Jankovic Velickovic

10 Tumor  Markers in Early Detection and Monitoring of Prostate Cancer: Recent Advances������������������������������������������������������������������������  207 Vesna Coric and Tatjana Djukic 11 Biological  Markers of Therapeutic Response in Prostate Cancer������  221 Uroš Bumbaširević and Miloš Petrović Part III Current Treatment Options and Monitoring of Prostate Cancer 12 Surgical  Treatment of Prostate Cancer��������������������������������������������������  245 Vladimir Vasić 13 Robot-Assisted  Laparoscopic Radical Prostatectomy��������������������������  255 Ranko Miocinovic and Amit R. Patel 14 The  Use of Apheresis in Personalized Cell-­Mediated Treatment of Prostate Cancer������������������������������������������������������������������������������������  263 Bela Balint, Mirjana Pavlovic, and Milena Todorovic 15 Hormone  Therapy for Advanced Prostate Cancer ������������������������������  295 Jovan Hadzi-Djokic 16 Perspectives  of Immunotherapy in Prostate Cancer����������������������������  325 Timur Cerić 17 Pharmacogenomics  and Precision Therapy in Prostate Cancer: Challenges and Perspectives ������������������������������������������������������������������  335 Nikola Stefanović 18 Stereotactic  Radiotherapy in the Treatment of Prostate Cancer��������  379 Biljana Seha 19 Treatment  of Castration-Resistant Prostate Cancer����������������������������  389 Zoran Todorović

About the Editors

Gordana Kocic, MD, PhD  is a Full Professor of Biochemistry at Medical Faculty University of Nis (Serbia). She is a specialist in medical biochemistry and a subspecialist in three areas of clinical biochemistry: immunoassays, biochemical oncology, and biochemical endocrinology. She is a full member of the Medical Department of the Medical Academy of the Serbian Medical Association, a member of the Scientific Council University of Nis, and the Secretary of the Branch of the Academy of the Serbian Medical Association in Niš (Serbia). Professor Gordana Kocic’s research has been published in 162 scientific papers in journals from the Journal Citation Report—SCI list, a significant amount of which are in the Q1 category; she is one of authors of textbooks: Biochemistry (Medical Faculty, University of Niš), Clinical Biochemistry (Medical Faculty University of Nis), and Selected Chapters in Urology (Institute for textbooks Belgrade); monographs: “Biochemistry of Free Radicals” and “Oxidative Modification of Biomolecules”; six chapters in monographs of national impact. She presented her scientific achievements published as supplements to prestigious journals. Four registrable patents provide as documentation of innovation activities. The prizes she received are: for PhD thesis, the best scientific articles awarded by the Serbian Medical Society branch Nis, the award for scientific achievement, “Best technological innovation for 2010,” by Chamber of Commerce Republic Serbia’s. As a Principal Investigator of the projects of the Ministry of Education and Science Republic of Serbia and Fund of Science Republic of Serbia (No 7750154 (NPATPETTMPCB)) and in the NETCHEM project, she has been overseeing and organizing a number of project research activities. She collaborated on two international bilateral projects with Slovenia and TEMPUS projects, Erasmus Plus project, the ERAWEB WB joint mobility program, and the SANU Branch projects. Jovan Hadzi-Djokic, MD, PhD  is a Full Professor of Urology spent almost his entire clinical and academic practice at University Clinical Center Medical Faculty Belgrade (Serbia), being the Director of the Institute of Urology and Nephrology of the Clinical Center of Serbia, a consultant for urology at the Institute of Oncology and Radiology of Serbia, at the Clinic for Gynecology and Obstetrics of the Clinical ix

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About the Editors

Center of Serbia. He has been a Member of the Serbian Academy of Sciences and Arts since 2003. He trained at the Foch Hospital (Centre Medico Chirurgicale) in Paris (France) and at the University Urology Clinic in Florence (Italy). During his surgical career, he introduced new operative techniques into routine urological practice, which made it highly respectable within the framework of European and world urology as a scientific discipline. Recognized as a renowned professor, urology expert, and scientist, Academician Prof. Jovan Hadzi-Đokic enjoys a reputation in many professional associations throughout the world, as a member of the editorial boards of numerous journals. He published more than 500 professional-­scientific papers, 11 monographs, and textbooks in the field of urology: Tumors of the urinary bladder (1995), Angiographic atlas of urological diseases (1995), Urinary stoma (1996), Urgent urology (1997), Urological gynecology (2000), Minimal invasion treatment of urinary obstruction (2000), Localized prostate cancer (2005), Urinary diversions (2009), Urinary incontinence (2009), Erectile dysfunction (2012), Prostate (2014), and Hormones and Prostata (2022). He wrote more than 60 chapters in textbooks and monographs edited by other authors. His scientific opus is characterized by a large number of publications and papers in top international journals related to urology. He is a full member of the Serbian Medical Association, the Serbian Urological Association, the European Association of Urology, and the Societe General d’Urologie. He is an honorary member of the Association of Urologists of Romania. He gave more than 80 invited lectures in Serbia and abroad. For his professional engagement, professional leadership, and scientific contributions, he received several awards from various health institutions, organizations, and Serbian Government, as well as the October Award of the City of Belgrade for the book Urinary Bladder Tumors. He has been a winner of medal “Karadjordje star of third degree,” which has been awarded by the President of Republic of Serbia for special merits and successes in representing the state and its citizens. As especially admirable person, he was awarded by honorary citizenship from two cities Republic of Serbia. Tatjana Simic, MD, PhD  is a Full Professor of Medical and Clinical Biochemistry at the Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, Serbia and a Corresponding member of Serbian Academy of Sciences and Arts. She obtained her PhD in Biochemistry at Faculty of Medicine, University of Belgrade in 1998. She is a Specialist in Clinical Biochemistry and Specialist in Laboratory Medicine. She is a Coordinator of PhD module “Tumor biology and redox medicine” (2016–present), Manager of the Center of excellence for Redox Medicine (2022–present), President of Serbian Proteomic Association (2023–present), and President of the Board for Accreditation of Research institutions of Republic of Serbia (2021–present). She coordinated multiple research projects and participated in numerous collaborative projects. From the very beginning of her scientific career, she has been involved in the research of the role that free radicals and altered mechanisms of antioxidant defense play in disturbed redox homeostasis in various malignant and non-malignant diseases. Regarding her research in the field of urological oncology, her group demonstrated the significance

About the Editors

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of polymorphisms in genes encoding antioxidant enzymes in susceptibility to urinary tract tumors and their chemoresistance. She supervised ten PhD candidates. She is an author and coauthor in more than 120 scientific articles referred on SCOPUS, and her h-index is 30. According to SCOPUS, her papers were cited more than 3400 times (more than 2900 without auto citations).

Part I

Recent Advances in Prostate Cancer Etiology and Pathogenesis

Chapter 1

Prostate Cancer: Epidemiology, Etiology, Pathogenesis, and Risk Factors Tomislav Pejčić

Abstract  Prostate cancer is today the most common cancer in men in developed countries. The very high incidence of prostate cancer in the developed world differs significantly from the low incidence in Asia, especially in rural areas of China. The different incidences can be explained by ethnic and hereditary factors, dietary habits, exposure to sunlight, and different carcinogens. The main role of the prostate is the production of secretions that enable the nutrition and movement of spermatozoa. However, the prostate is a gland that produces important hormones, such as dihydrotestosterone and estrogens, which act as paracrine and intracrine factors. The concentration of sex hormones in the prostate tissue is significantly different in a healthy and diseased organ and significantly affects pathological processes in the prostate. Keywords  Prostate cancer · Benign prostatic hyperplasia · Testosterone · Dihydrotestosterone · Estrogen · Intraprostatic sex hormones

1 Epidemiology Prostate cancer (PCa) is mostly diagnosed in men over the age of 65 and very rarely in men under the age of 50. Today, PCa is the most frequently diagnosed cancer in men in Europe, America, Australia, and sub-Saharan Africa. Prostate cancer is the cancer with the highest incidence in 114 countries and the leading cause of cancer-­ related death in 56 countries. In the period from 2007 to 2017, an increase in the incidence of PCa of 42% was recorded at the global level [1–3]. Epidemiological studies conducted in the USA show different incidences of PCa in different ethnic groups. From 2013–2018, the incidence of PCa for all ethnic groups was 105 new cases per 100,000 population per year, but the incidence in T. Pejčić (*) Clinic of Urology, Clinical Center of Serbia, Medical Faculty, University of Belgrade, Belgrade, Serbia © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 G. Kocic et al. (eds.), Prostate Cancer, https://doi.org/10.1007/978-3-031-51712-9_1

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Fig. 1.1  Incidence of various cancers in the EU in 2022. Source: ECIS—European Cancer Information System [8]

African Americans was 172, in Caucasians 98, in Latin Americans 86, and in Asians 54 [4]. In Brazil, an average incidence of 62 new cases per 100,000 men was found. The incidence was higher in more developed areas. Also, African Americans had a higher incidence [5]. According to WHO data from 2012, the incidence of PCa was 4.5 in Central Asia and 10.5 in East Asia. The lowest incidence was measured in rural China (2.6) and in North Korea and Mongolia (2–3), while in Japan it was 31 [6, 7]. According to data from 27 EU countries, in 2022, about 1,450,000 new cases of cancer were detected in men, of which PCa accounts for 23.2% (Fig. 1.1). According to data from 2020, in Europe, the incidence was highest in Northern Europe (195) and lowest in Eastern Europe (115). The highest incidence is found in Scandinavian countries (Sweden and Norway, 220 each), followed by Western European countries (France, 215; UK, 185; and Germany, 160), then Poland (125), and then Italy (125). In the Balkan countries, Montenegro (60) and Serbia (90) have the lowest incidence. The incidence in Croatia is 130, and in Slovenia, there are 180 newly detected cases per 100,000 inhabitants annually [9]. According to the data of the Institute for Health Protection of Serbia “Dr. Milan Jovanović Batut,” the average unstandardized incidence of PCa in 2019 in Belgrade was 70, and the highest was in the North Banat District, where it was 96.8 [10].

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2 Etiology Prostate cancer is most often adenocarcinoma of the glandular acini of the prostate, and it consists of malignant epithelial cells. Given that the largest percentage of glandular acini are in the peripheral zone (PZ) of the prostate, adenocarcinoma of the prostate occurs by far most often in the PZ. Prostate cancer grows very slowly at first and doubles in size in about 3 years (Stamey). Considering that it grows in PZ, PCa very rarely leads to urethral obstruction and dysuric disturbances at the beginning, which usually happens in BPH. During growth, PCa occupies a larger part of the prostate, and if not detected in time, it spreads beyond the borders of the prostate and metastasizes to the pelvic lymph glands and bones. The etiology of PCa is complex and multifactorial and has not been fully studied to date. In the following text, we will present the basics of prostate physiology, which is necessary to know to understand the processes that influence the formation of PCa.

3 Prostate Physiology In all mammals, the prostate participates in the production of seminal fluid, which serves as a medium for the transport and nutrition of spermatozoa. The function of the prostate is under the control of steroid hormones and the autonomic nervous system, and its structure is basically similar in all mammals [11, 12]. The prostate consists of connective stroma and epithelial cells. The stroma consists of the basic substance, axons of nerve cells, and stromal cells—fibroblasts, endothelial cells of blood and lymphatic vessels, and smooth muscle cells. The prostate epithelium consists of secretory, neuroendocrine, basal, and intermediate cells. In the basal layer, there are also stem cells, from which all prostate epithelial cells arise. The basic physiological functions of the prostate are secretory and hormonal. The prostate synthesizes and secretes numerous non-peptide substances, such as polyamines, cholesterol, lipids, citrates, and zinc. Citrates and zinc are found in the prostate in a much higher concentration than in other organs and tissues [13, 14]. The most important proteins of prostate secretion are prostate-specific antigen (PSA), glandular kallikrein (hK2), and prostatic acid phosphatase (PAP). The most important enzyme of the seminal fluid, PSA, performs its physiological function only in the vagina, where it cleaves the proteins of the seminal coagulum and thus enables active sperm motility [15]. PSA molecules constantly leak from the acini of the prostate into the urethra, from where they are flushed out during urination [16–20].

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3.1 Stroma-Epithelium Interaction Numerous reciprocal reactions constantly take place between the stroma and epithelium of the prostate. The sum of these reactions is called stroma-epithelium interaction; this process begins during embryonic development, continues during prostate development, and continues throughout adulthood and old age [21, 22]. Apart from the normal prostate, the stroma-epithelium interaction is also involved in pathological processes in the prostate. The most important players in the stroma-epithelium interaction are growth factors and sex hormones. Growth factors (GFs) are small peptide molecules that influence the processes of cell division and differentiation by activating cell receptors for GF.  The balance between cell proliferation and death is dictated by complex interactions between GF and steroid hormones. Fibroblastic GF (FGF), vascular endothelial GF (VEGF), and insulin-like GF (IGF) are thought to promote cell proliferation in BPH, while dihydrotestosterone (DHT) enhances their effects. Important factors in the interaction of the stroma and epithelium are FGF-7, transforming GF-β (TGF-β1) and epidermal growth factor (EGF) [23]. TGF-β1 performs a great number of important functions: It stimulates mitosis in fibroblasts and inhibits the proliferation of epithelial cells. Increased expression of TGF-β1 on stromal cells is associated with an increase in the stromal compartment [24]. EGF pathway includes epithelial and stromal EGF receptors, FGF receptors, TGF-beta peptides, and the Notch signaling pathway. The EGF receptor (EGFR-1 or HER-1) is essential for epithelial development, angiogenesis, fibrogenesis, and tumor growth. Signals via ER alpha in the mesenchyme initiate prostate growth. Testosterone affects prostate morphogenesis, but elongation and branching of the prostate duct occur in the communication between urogenital mesenchyme and epithelium and are regulated by ER alpha, FGF10, and other factors. It has been proven that the action of prostatic mesenchymal GF, FGF10, is not regulated by androgens [25] (Fig. 1.2).

4 Sex Hormone Signaling Pathways Testosterone molecules enter the prostatic cell by diffusion, after which about 90% of testosterone is converted into DHT by the action of the enzyme 5αR. This enzyme reduces the C=C double bond between C4 and C5 in the A ring of testosterone. This change ensures a stronger binding of DHT to the AR and a slower release from it, resulting in a stronger androgenic effect than testosterone [26–28] (Fig. 1.3). There are two 5αR isozymes in the human prostate. The main and most abundant type is 5αR-2, which is found in stromal and basal cells, but not in epithelial cells. Type 5aR-1 is less abundant and is present in both stromal and epithelial cells. Newly formed DHT molecules and remaining testosterone molecules afterward bind to AR and enter the nucleus, where they bind to DNA and start the process of protein synthesis [29, 30]. The largest number of DHT molecules and various

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Fig. 1.2  Stroma-epithelium interaction. E2 = estradiol, T = testosterone, DHT = dihydrotestosterone, BM = basement membrane, GF = growth factor, SF = survival factor, ERα = estrogen receptor alpha, ERβ = estrogen receptor beta, AR = androgen receptor, 5αR1 = 5 alpha-reductase type 1, 5αR2 = 5 alpha-reductase type 2, PSA = prostate-specific antigen, hK2 = human glandular kallikrein 2, BC = basal cell, SC = secretory cell. (Drawing: Pejčić T, 2023)

Fig. 1.3  Conversion of testosterone to dihydrotestosterone

growth and survival factors are produced in the fibroblasts of the stroma. DHT, GF, and SF then stimulate cell growth, proliferation, and protein synthesis in epithelial cells [23, 31]. Estrogens easily diffuse through the cell membrane; once inside the cell, estrogens bind to and activate estrogen receptors, modulating the expression of various

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genes. There are two types of estrogen nuclear receptors: ERα and ERβ. In men, the ERα receptor is present in the prostate and testicles, but also in bones and fat tissue. The ERβ receptor is primarily found in non-gonadal tissues, colon, urinary bladder, and bone marrow. In the prostate, ERα is present primarily in the stroma, while ERβ expression is strongest in secretory cells and lower in basal and stromal cells [32–35]. Activation of ERα stimulates cell proliferation, while activation of ERβ opposes proliferation [36, 37]. When estrogen binds to the ER, the biochemical response depends on coregulatory proteins and numerous other factors. Ligand-bound estrogen receptors can bind directly to estrogen-responsive elements (EREs) on DNA, or they can enter reactions with other transcription factors. Apart from ERα and ERβ in the cell nucleus, the action of estrogen is carried out through receptors on the surface, that is, the cell membrane [38]. There are several different estrogen signaling pathways. The classical, or direct, pathway involves ligand activation and direct binding to ERE on DNA before modulating gene regulation. During this process, the nuclear receptors ERα and ERβ act as ligand-activated transcription factors. When estrogen binds to ERα and ERβ in the cytoplasm, a conformational change occurs that leads to receptor dimerization. This complex is then translocated into the nucleus, where it binds to chromatin at ERE sequences near promoters, or target genes. In addition to the classical pathway, there are pathways in which other transcription factors are involved, non-genomic pathways, via “second messengers,” and a ligand-independent pathways, via growth factors and the membrane receptor GPER1 [39–41]. More recently, DHT has also been shown to play an important role in estrogen signaling. As is known, the aromatase enzyme converts testosterone to E2. However, there is another estrogen, which is not formed from testosterone, but from DHT, via the enzyme 17b-hydroxysteroid dehydrogenase type 6 (17bHSD6), which has been demonstrated in ERβ-positive prostate epithelial cells. This steroid is a potent ERβ agonist and is called 5α-androstane-3β, 17β-diol (3β-Adiol). In the prostate, 3b-Adiol activates ERβ and thus exerts antiproliferative activity, while DHT via the AR stimulates the proliferative effect. Thus, prostate growth is regulated by the balance between AR and ERβ activation. The formation of 3b-Adiol via 17bHSD6 from DHT is an important regulatory pathway that is lost in prostate cancer. Therefore, since ERβ activation opposes androgen signaling, 3b-Adiol is a potential drug for the treatment of PCa [42, 43].

5 Sex Hormone Levels in Prostatic Tissue Traditionally, pathological conditions in the prostate are mainly associated with reduced androgen concentrations in the serum. It is known that men in their seventh decade of life have an average of 35% lower T level than young people [44]. However, no correlation between serum androgen and estrogen levels and prostate disease has ever been demonstrated. That is, the concentration of sex hormones in

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the prostate tissue affects most normal and pathological processes in the prostate. In the blood, serum testosterone concentration is about ten times higher than DHT, at the molar level [45, 46]. However, DHT is the major tissue androgen in the males; DHT activates the growth of male genitalia and secondary sex characteristics and affects the growth and function of the adult prostate. The most important source of DHT in the human body is the prostate. After a radical prostatectomy, a significant drop in DHT levels is registered in the serum. DHT production is highest in the stroma, where ten times more DHT is produced than in the prostate epithelium [47–50]. Although they are primarily known as the primary female sex hormones, estrogens also have a great number of important physiological functions in men. The strongest estrogen produced in the body is 17 beta-estradiol (E2). Two metabolites of E2, estrone and estriol, are much weaker estrogen receptor agonists. Today, the word estrogen is often used mainly for 17β-estradiol. In men, testosterone is metabolized to estradiol by the action of aromatase in peripheral tissues, such as adipose tissue and bones, and in the reproductive tract, in Sertoli and Leydig cells and mature spermatocytes [51]. The presence of aromatase in the prostate partially explains why there is an increase in E2 and prostate volume during testosterone administration in older men. On the contrary, when aromatase inhibitors are administered, these phenomena are not observed. Aromatase is expressed in normal stromal cells; however, the aromatase expression in PCa is higher in epithelium. An increased activity of aromatase in PCa is followed by an increased transformation of testosterone to E2. A high concentration of E2 has been demonstrated in PCa tissue [52–55].

6 Sex Hormones in Hyperplastic and Malignant Prostatic Tissue Like some other endocrine glands, the prostate accumulates various substances, such as zinc, citrates, and sex hormones. As the prostate grows and BPH develops, there is a progressive accumulation of testosterone and, especially, DHT. However, there is an accumulation of estrogen in PCa tissue [56]. Hyperplastic prostate tissue contains more testosterone and DHT than normal transition zone (TZ) tissue. A strong correlation was found between tissue testosterone and DHT levels and prostate volume [57]. In surgical specimens, the level of ERα is higher in BPH than in normal prostate tissue, while the level of ERβ is higher in the epithelium of BPH and similar in the stroma [58]. In unpublished results, Pejčić and Tosti found that the concentration of E2 was higher in hyperplastic tissue (36 pg/g) than in normal prostate tissue (15 pg/g). Androgens are essential for the initiation, growth, and survival of PCa. It is very well known that castration leads to the apoptosis of malignant cells and a reduction of PCa metastases in bones. Unfortunately, testosterone level is higher in malignant

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tissue than in normal prostatic tissue. However, the level of DHT in PCa is low and the lowest in aggressive PCa [59–61]. Locally produced estrogens stimulate the proliferation of malignant cells, via the activation of ERα. Local production of estrogen in the prostate is responsible for all estrogenic effects in PCa [62]. Receptors ERα and ERβ have specific roles in PCa; ERα promotes proliferation, inflammation, and migration, while ERβ has antiproliferative and tumor-suppressive effects. Estrogens regulate the development of hormone-­sensitive tumors; any compound that increases the expression of aromatase increases the levels of E2, the activation of Erα, and the level of GPER. Activation of ERα promotes cell proliferation, while increased levels of GPER promote mitosis and endothelial damage. Numerous studies have shown high ERα expression in PCa and higher in epithelial cells than in stromal cells. High expression of ERα in PCa is essential for the formation of osteoblastic lesions and lung metastases. In hormone refractory PCa, there is high expression of ERα, as well as loss of ERβ, decreased suppression of PCa development [35, 63, 64]. Activation of ERβ inhibits the stroma-epithelial interaction and leads to an antiproliferative and pro-apoptotic effect. However, a loss of ERβ has been proven in PCa, which facilitates disease progression [65–68]. Therefore, blockade of ERα and stimulation of ERβ are required to prevent carcinogenesis. ER-beta expression in PCa gradually decreases with an increasing Gleason score. Also, there is a shift of the epidermal GF receptor (EFGR) from the cell surface to the nucleus. Translocation of EGFR to the nucleus increases the resistance of PCa to radiotherapy and drugs. In a study in which patients received androgen deprivation therapy + enzalutamide, nuclear translocation of EFGR was demonstrated in PCa cells, suggesting that perhaps AR blockade affects EFGR translocation. After a short treatment with an inhibitor of the AR signaling pathway (abiraterone), there was increased expression of ERβ and inhibition of EGFR translocation, as well as inhibition of cell growth. However, after prolonged ADT, ERβ expression gradually disappears. Therefore, the balance of action between AR and ERβ is crucial for the treatment of PCa [69, 70]. Recently, several different ERβ receptor isoforms, which are similar in structure but have different functions, have been isolated in PCa tissue. Activation of the ERβ-1 isoform reduces tumor progression and AR expression and induces apoptosis in PCa. However, there is a high expression of ERβ-2 in metastases. Nuclear localization of ERβ-2 correlates with increased tumor proliferation and invasiveness, as well as decreased survival. In addition, ERβ-2 has been shown to induce drug resistance, and ERβ-5 has been shown to increase the sensitivity of PCa to chemotherapy [71, 72].

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7 Cellular Metabolic Pathways and the Development of Prostate Cancer Disorders at the level of cellular signaling pathways play a significant role in the development of malignant tumors. In PCa, the PI3K/Akt/mTOR pathway is often mentioned in basic research. The main proteins in this pathway are phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt). The enzyme mechanistic target of rapamycin (mTOR) was named after rapamycin, which inhibits mTOR and thus has an immunosuppressive and antiproliferative effect. Rapamycin was used as an antifungal antibiotic, but later its immunosuppressive effect was discovered [73]. The PI3K/Akt/mTOR pathway regulates cell quiescence and proliferation and is essential for promoting the growth and proliferation of adult stem cells. In many cancers, this pathway is overactive, thus reducing apoptosis and allowing proliferation. In most cancers, mTOR activity is disrupted due to increased activity of PI3K or Akt [74, 75]. Increased mTOR activity increases cell proliferation and tumor growth. PI3K/Akt activity is enhanced by EGF, IGF-1, and insulin. However, the natural inhibitor of PI3K/Akt, the tumor suppressor gene PTEN, reduces the activity of this signaling pathway. The PTEN gene provides instructions for the synthesis of an enzyme that acts as a tumor suppressor and regulates the normal rate of cell division; PTEN phosphatase negatively affects mTOR signaling by interfering with PI3K.  One of the most common reasons for mTOR activation is mutations in PTEN.  There are two complexes created by mTOR.  They are mTOR complex 1 (MTORC1) and mTOR complex 2 (MTORC2). The MTORC1 complex is the most important regulator of cell growth, responding to and integrating various signals from food and the environment, including growth factors, energy levels, cellular stress, and amino acids. It combines these signals to stimulate cell growth. This complex is inhibited by rapamycin. The MTORC2 complex promotes cell survival through Akt activation and regulates cytoskeletal dynamics. Aberrant mTOR signaling is responsible for the development of many diseases [76–78]. The PI3K/Akt pathway has reciprocal interactions with the AR, such that the inhibition of one leads to the activation of the other, which maintains tumor viability. AR-mediated transcriptional activity plays a role in early genomic rearrangements in PCa; transcriptional activity via AR is a key signaling pathway for the onset of primary and advanced disease [79, 80]. Receptor AR plays a significant role in the progression of castration-resistant PCa; these changes include mutations and amplifications of the AR, which lead to its marked sensitivity to low levels of intratumoral androgens.

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8 Risk Factors 8.1 Hereditary Factors and Ethnicity About 15% of PCa is thought to be hereditary. The risk of getting PCa increases with the number of affected family members and the degree of consanguinity. Thus, the risk is two times higher if the father had PCa, three times higher if the brother had PCa, and five times higher if both father and brother had PCa [81]. The prevalence of PCa varies greatly between different racial groups. This is best seen in the USA, where African American men have an average PCa incidence of 160; White men, 95; and Native and Asian/Pacific Islanders, about 50. One hypothesis is that variants of chromosome 8q24, which is associated with an increased risk for PCa, are responsible for the high incidence of PCa in African Americans [82–84].

8.2 Infections Infections are associated with about 16% of all cancers. Chronic inflammation accompanied by tissue repair and cell hyperproliferation participates in the development of many cancers. Prostate cancer is thought to have a similar process, arising because of inflammation caused by infection, diet, or other agents. However, frequent ejaculations are associated with a lower risk of developing PCa [85, 86].

8.3 Diet Paleopathologists believe that the drastic increase in the incidence of PCa, as well as breast cancer, occurred because of a major change in human nutrition, which occurred some 12–15,000 years ago. Namely, at that time, man was no longer an obligate herbivore like his ancestors. Man started to build settlements, raise livestock, and feed on the meat of domestic animals. At the same time, man reduced the participation of fruits, vegetables, and cereals in the diet, from about 3000 types to only about 20 types of plants [87]. Oxidative stress, which is a consequence of the action of reactive oxygen and nitrogen species that bind to DNA and lead to mutations, and oxidative stress from endogenous and exogenous sources participate in the accumulation of DNA damage that appears in old age and leads to malignant alteration [88]. Carcinogens from food, especially from cooked and fried meat, estrogens, and infectious agents, are potential triggers for inflammation. Reactive oxygen species created by frying meat rich in iron and oxidation of lipids play a major role in causing damage to DNA and other molecules.

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Differences in the incidence of PCa are associated with meat consumption and the so-called Western diet and, however, with the consumption of plant sources, especially food rich in isoflavones and other phytoestrogens, which is a traditional way of eating in Asia, Japan, and the East Pacific. There are great differences in meat consumption in the world. Thus, meat consumption is highest in the USA, Australia, and Spain (100–120  kg of meat per inhabitant annually), high in the EU (70–90 kg), lower in China (60 kg) and Japan (50 kg), and lowest in the Central Africa (15–20 kg) and India (4 kg). In the Balkan countries, meat consumption is relatively low and ranges from 35 to 50 kg of meat annually [89]. However, it is interesting to compare the consumption of soybeans in the world. Soy isoflavones, genistein, daidzein, and glycitein are phytoestrogens, known for their selective effect on estrogen receptors, so they are also called selective estrogen receptor modulators (SERMs). Genistein, which is a highly selective activator of ERβ, is particularly potent, so it acts as an inhibitor of stromal proliferation in the prostate, breast, and other organs [90, 91]. Namely, in Japan, soybean consumption is about 8  kg per capita annually; in China, about 4  kg; and in the USA, only 0.04  kg annually. That is, the average Japanese person eats in 1 day is the amount of soybeans that the average American eats in a year. The recommendation of the “Health Japan 21” campaign is to eat 100 g or more of legumes per day. However, the average intake in Japan is around 60 g per day [92] (Fig. 1.4). The fact that Chinese immigrants in the USA have a significantly higher incidence of PCa than Chinese in China emphasizes the importance of diet. Namely, in China and Southeast Asia, people eat much more vegetables and less animal proteins and fatty foods than in the West [93]. Studies show that the risk of developing PCa increases in first-generation immigrants from Japan and China to the USA, possibly due to the transition to a Western diet. A similar trend of increasing incidence of PCa and colon cancer is observed in large Chinese cities, where in the

Fig. 1.4  Soybean consumption in major countries. Source: 2007 Soybean production and consumption. UN Food and Agriculture Organization (FAQ)

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period from 1960 to 2000, the intake of animal fats increased by almost 600% [94, 95]. Men with vitamin D deficiency have a higher incidence of PCa. This category includes the elderly, people from the North, and African Americans; in the latter, a large amount of melanin in the skin reduces the production of active vitamin D. The vitamin D receptor (VDR), to which serum vitamin D binds, is present in normal and malignant prostate epithelium. Vitamin D inhibits the growth of normal prostate cells [96, 97]. Several studies have demonstrated a link between obesity and an increased risk of developing PCa. In obese men, there is an increased concentration of estradiol, insulin, free IGF-1, and leptin in the serum and a decreased concentration of free T and adiponectin. Leptin from adipose tissue plays a role in the development of advanced PCa. Obese people have elevated serum leptin concentrations, but also leptin resistance in tissues [98, 99]. Finally, increasing human life span is a significant factor that enables the cumulative effect of carcinogens. In the Neolithic, the average life expectancy of a man was about 20 years, while today it is 70 years and, in the most developed countries, over 80 years [100].

9 Conclusion Prostate cancer is today the most common cancer in men in developed countries. The very high incidence of prostate cancer in the developed world differs significantly from the low incidence in Asia, especially in rural areas of China. The different incidences can be explained by ethnic and hereditary factors, dietary habits, exposure to sunlight, and different carcinogens. However, population screening for prostate cancer and better health care for the population contribute to the difference in the detection of this disease. Apart from the factors that lead to oxidative stress and genetic damage, sex hormones and their concentration in the prostate tissue play an important role in various pathological conditions.

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Chapter 2

Genetic Susceptibility to Prostate Cancer Tatjana Simic, Marija Matic, and Djurdja Jerotic

Abstract  Prostate cancer (PCa) is the second most diagnosed cancer type globally and is one of the leading causes of death in men. Genetic susceptibility plays a significant role in PCa development with a reported heritability of 57%. Mutations in the different DNA damage repair (DDR) genes (BRCA1, BRCA2, CHEK2, ATM, and PALB2) and in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) are hallmark of hereditary prostate cancer (HPCa) and are included in National Comprehensive Cancer Network (NCCN) guidelines for PCa germline genetic testing. In addition to rare high-risk mutations in susceptibility genes, polygenetic inheritance of low-risk germline variants in the form of single-nucleotide polymorphisms (SNPs) may be utilized to distinguish an individual’s susceptibility to PCa onset and progression. Over the past decade, the number of detected variants has increased to 269, due to the genome-wide association studies (GWAS). The large number of identified variants led to the development of polygenic risk scores (PRS) that aggregates common PCa-associated genetic variants into a single measure. The incorporation of diverse genetic analyses and PRS is highly anticipated to those individuals with positive PCa family history and may lead to improvements in clinical outcomes for this population through early prevention screening efforts. Keywords  Prostate cancer susceptibility · Single-nucleotide polymorphism · GWAS · Polygenic risk score T. Simic (*) Faculty of Medicine, University of Belgrade, Belgrade, Serbia Institute of Medical and Clinical Biochemistry, Belgrade, Serbia Center of Excellence for Redox Medicine, Belgrade, Serbia Serbian Academy of Sciences and Arts, Belgrade, Serbia e-mail: [email protected] M. Matic · D. Jerotic Faculty of Medicine, University of Belgrade, Belgrade, Serbia Institute of Medical and Clinical Biochemistry, Belgrade, Serbia Center of Excellence for Redox Medicine, Belgrade, Serbia © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 G. Kocic et al. (eds.), Prostate Cancer, https://doi.org/10.1007/978-3-031-51712-9_2

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1 Germline Mutations in Prostate Cancer Prostate cancer (PCa) is the second most diagnosed cancer type globally and is one of the leading causes of death in men [1]. The etiology of this disease is multifaceted and includes well-recognized PCa risk factors: family risk, ethnicity, age, obesity, and environmental influences [1], which is the reason why all men do not have the same susceptibility for PCa development. Malignant diseases, including PCa, arise due to DNA alterations, usually point mutations, single-nucleotide polymorphisms (SNPs), and copy number variations. These changes in DNA sequence may initiate cancerogenesis by silencing various tumor suppressors and activating oncogenes [2], often leading to uncontrolled cell division and lack of apoptosis. Mutations may be inherited or be obtained by an individual. There is a lot of evidence that genetic susceptibility plays a significant role in PCa development and some studies reported that heritability is as high as 57% [3]. Familiar prostate cancer (FPCa) is associated with hereditary factors and accounts for 5–20% of all PCa cases [4]. FPCa has the highest heritability of all most important malignancies in men [5]. A particular subtype of FPCa is hereditary prostate (HPCa) cancer which is recognized in approximately 5–10% of men with PCa [4]. HPCa is characterized by the following: more than three affected first-degree relatives, PCa in three successive generations of the same line (paternal or maternal), or two first-degree relatives with early-onset disease (≤ 55 years) [6]. FPCa accounts for the rest of the diagnosed FPCa (who do not complete the abovementioned criteria). Positive FPCa history is associated with twofold to eightfold greater PCa risk, with an increase of the risk if more relatives are affected [7]. HPCa is usually related to detectable genetic germline mutations, while FPCa includes patients with a strong family PCa history, but not necessarily with detectable inherited mutations [8]. Furthermore, genetic studies have pointed out that mutations in the different DNA damage repair (DDR) genes, such as BRCA1, BRCA2, CHEK2, ATM, and PALB2, and in the DNA mismatch repair genes (MMR), such as MLH1, MSH2, MSH6, and PMS2, are the hallmark of HPCa [4, 8, 9]. Moreover, the National Comprehensive Cancer Network (NCCN) included these genes in their guidelines for prostate cancer-recommended germline genetic testing (version 1.2022) [10]. The DNA repair machinery involves several pathways, but the two most important are (a) homologous recombination (HR) repair and (b) mismatch repair (MMR) [11]. Homologous recombination repair is the key tool for high-fidelity reparation of double-strand DNA breaks during replication and strongly depends on BRCA1/2, CHECK2, ATM, and PALB2 proteins [12, 13]. However, the mismatch repair system scans the DNA and eliminates base pair mismatches from the newly synthesized DNA strand during replication [14]. Genes encoding MSH and MLH proteins are involved in this process [15]. Mismatch repair decreases DNA errors 100–1000-fold and therefore reduces mutation rate during cellular proliferation [16]. Without this effective anticancer barrier, the damaged DNA may lead to mutations and [17] genome instability which facilitate tumor development [18]. Indeed, there are a lot data implicating alterations in genes involved in androgen signaling, cell-cycle progression, chromatin remodeling, the

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p53, the PI3K, the WNT, DDR, and MMR pathways in PCa cells [19–22]. Moreover, the Prostate Cancer Foundation-Stand Up To Cancer (SU2C-PCF) group identified a high percentage of inherited functional mutations in PCa, including 23% mutations in DNA damage repair genes, such as BRCA2 (13%), ATM (7.3%), and BRCA1 (0.3%), along with mutations in mismatch repair genes, such as MSH2 (2%) [23]. In a cross-sectional study by Nicolosi et  al. comprising 3607 PCa patients, germline testing showed that pathologic variants were present in 17.2% of patients, mostly in BRCA1/2 (30.7%), CHEK2 (14.1%), ATM (9.6%), and HOXB13 (4.5%) gene, while 1.7% of them had mutations in MMR genes (MLH1, MSH2, MSH6, and PMS2) [24].

1.1 BRCA1 and BRCA2 BRCA (BRCA1 and BRCA2) is the most frequently tested genetic biomarker in oncology. BRCA1 gene is placed on chromosome 17q21 and BRCA2 on chromosome 13q12–13 [25]. Both BRCA1 and BRCA2 are tumor suppressor genes, with a crucial role in genomic stability by controlling DNA damage responses, which are essential for normal cellular proliferation [25]. In particular, BRCA1 and BRCA2 have been involved in homologous recombination, an effective DNA damage repair pathway for DNA double-strand breaks [26, 27]. More than 3500 mutations have been detected for BRCA1 and BRCA2 genes. Most of the mutations belong to deletions, insertions, or missense mutations, usually causing premature protein synthesis [25]. It has been reported that approximately 0.1–0.2% of the general population are carriers of those mutations [28]. The relationship between germline mutations in the BRCA1 and BRCA2 genes and various types of cancer have been issue of numerous studies since nineties of the last century, when the genes’ were first discovered [29, 30]. Firstly, it has been recognized that BRCA mutations are associated predominantly with breast and ovarian cancers [31]. However, since then, it has been suggested that individuals with BRCA mutations are at higher risk to develop various cancers, such as prostate, pancreas, stomach, biliary duct, gallbladder, and colon cancers [28, 32]. Regarding PCa, it seems that BRCA2 mutations have a greater impact, since data from the Consortium of Investigators of Modifiers of BRCA1/2 showed that men with BRCA2 mutations have an increased PCa risk development when compared to BRCA1 carriers [33]. Indeed, genetic studies reported that carriers of BRCA2 mutation have the highest risk of PCa development, about 8.6-fold in men younger than 65 years, while BRCA1 mutation carriers demonstrated PCa risk in a reduced range, but still significantly increased (3.8 times) [34]. However, meta-analysis by Oh et al. from 2019 reported a 1.90-fold higher PCa risk in overall BRCA (BRCA1 and/or BRCA2) mutation carriers, while BRCA2 mutation carriers exhibit 2.64-fold higher PCa risk and BRCA1 carriers exhibit 1.35-fold higher PCa risk [35]. Most genetic studies showed that the incidence of BRCA1 and BRCA2 mutations in PCa patients was 0.9% and 2.2%, respectively. Moreover, some DNA sequencing studies have found frequencies of

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germline BRCA2 mutation in even 56% PCa patients [36–39]. Although most studies have shown that alterations in BRCA1 and BRCA2 genes increase PCa risk [40, 41], there is an open question of how to deal with these men, and how this lack of DNA repair is related to PCa outcome [42]. Most studies have shown that BRCA2 mutation has been associated with poorer PCa-specific and OS outcomes and more aggressive disease [43, 44]. However, the data in this field still are not consistent. Some authors suggest that this biomarker is reliable in prostate cancer diagnosis [45, 46], and others do not [23]. Among men with BRCA mutations, the family PCa history increases the risk for PCa. Indeed, Nyberg et al. reported that for BRCA1 carriers, PCa risk was about 2.3 times higher for those with a positive family PCa history, while men without such history had about 3.2 times greater PCa risk. The risk was even higher for men with a positive family PCa history carrying BRCA2 mutations since they had 7.3 times greater PCa risk, while those without such history had 4.5-fold higher risk [47]. Regarding BRCA genes, 64% of the BRCA2 mutations found in HPCa are frameshift, 31% missense, and 5% splice. In BRCA1 gene, 63% of the mutations found are missense, 31% frameshift, and 6% splice [48]. In a study by Castro et al. performed on a cohort of 2019 HPCa patients, the frequency of BRCA1 and BRCA2 mutation was 0.9% and 3%, respectively [49]. However, another study has shown that BRCA2 deletions accounted for a very small number of HPCa (1–2%), even in cases with early onset and proven family history [4]. The latest meta-analysis by Domrazek et  al. from 2023  year which included more than 20,000 PCa cases reported that, with a collective calculation, BRCA1 mutation was found in 2.74%, while BRCA2 mutation was found in 1.96% of PCa cases [50], which is definitely higher than the frequencies of BRCA mutations in the general population. Obviously, this meta-analysis did not confirm previous results about BRCA1 and BRCA2 PCa susceptibility.

1.2 Checkpoint Kinase 2 (CHEK2) The checkpoint kinase 2 (CHEK2) gene is localized on chromosome 22 and encodes the serine–threonine kinase protein CHEK2. This protein is activated when DNA is damaged and is involved in the regulation of cell cycle and apoptosis [51, 52]. CHEK2 has pleiotropic functions, and its well-known targets are proteins important for cell-cycle control (CDC25A and CDC25C phosphatases), regulation of apoptosis (p53), and DNA damage repair (BRCA1 and KAP1) [53, 54]. Thus, it is supposed to be a tumor suppressor, since it delays cell-cycle progression to allow DNA to be repaired or eliminate unrepaired cells by apoptosis induction [55]. In 2002, it had been reported that the variant CHEK2 c.1100delC/p.T367Mfs is associated with a moderate risk of breast cancer [56, 57]. Meanwhile, many genetic studies indicated that germline pathogenic and likely pathogenic (P/LP) of CHEK2 variants are associated with a significantly increased risk of developing several other cancer types, including PCa, particularly HPCa [58–60]. These findings definitely established CHEK2 a low to moderate penetrance cancer susceptibility gene. CHEK2

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variants are rare in men of Asian, Hispanic, or African origin. However, the 1100delC variant is more common in Northern Europe, while the missense I157T variant occurs more frequently in Finnish and Polish populations with the rate of 16% in FPCa, 7.8% in all PCa cases, and 4.8% in the control group [7]. The genetic study by Seppala et al. analyzed 537 PCa patients from Finland for the 1100delC and missense I157T CHEK2 variants and reported that both variants were significantly associated with HPCa [61]. Hale et al. preformed a pooled analysis of five studies and reported that carriers of 1100delC variant had about two times higher risk for developing PCa, while this risk was even higher in familial PCa (3.5 times higher) [62]. In the same line, the study by Zhen et al. reported that the c.1100delC and I157T missense mutation increased the PCa risk by 3.3% and 1.8%, respectively [9]. These findings were supported by a large-scale meta-analysis which showed that CHEK2 1100delC del (rs555607708) and I157T mutations are associated with the risk of PCa. However, this study did not find CHEK2 1100delC del (rs555607708) del association with HPCa [63]. The study by Cybulski et al. examined PCa risk associated with the variant 1100delC in addition to two other variants (IVS2 + 1 G > A (c.444 + 1 G.A), del5395) and p.I157T missense variant in Polish population. The p.I157T missense variant increased PCa risk about two times, alone or when combined with two other variants. In case of 1100delC variant, PCa risk was increased approximately five times [59]. The results from the latest study by Alorjani et al. are in line with prior findings about CHEK2 variants’ role in the PCa susceptibility, since CHEK2 mutation had a frequency of 1.4% [64]. CHEK2 mutations are identified in less than 1% of the general population (0.61% in the Exome Aggregation Consortium) and in 2% of metastatic PCa (mPCa) patients. Within CHEK2 gene, 44% of the mutations found in HPCa are frameshift, 31% missense, and 25% splice. As mentioned, CHEK2 gene is frequently mutated in mPCa, and it has been shown that variant carriers had a three times higher risk for mPCa development [65]. Interestingly, the study on Croatian population showed that men with CHEK2 P/LP variant had an increased risk for early-onset PCa (almost 9 years earlier), while carriers of the c.1100delC, p.Thr367Metfs15* had a risk for more aggressive PCa [66].

1.3 Ataxia-Telangiectasia Mutated (ATM) Gene ATM (ataxia-telangiectasia mutated, ATM) gene is localized on chromosome 11 and encodes a serine/threonine kinase, a protein of 350  kDa that contains 3056 amino acids [67, 68]. ATM is a signaling kinase activated by DNA double-strand breaks and is a main part of DNA damage repair system since it enables DNA repair and therefore regulates cell cycle, senescence, and apoptosis [69–72]. In particular, it phosphorylates several key proteins, such as p53, CHEK2, BRCA1, NBS1, and H2AX which are tumor suppressors. Inactivation of ATM leads to the generation of DNA double-strand breaks, thus initiating DNA injury, mitotic dysregulation, senescence, and/or apoptosis [73]. Moreover, ATM inhibition is a major step in stimulating androgen-induced genomic instability and initiation of carcinogenesis

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in prostate cells [30, 74]. A PRACTICAL Consortium Study provided strong evidence for ATM as a moderate penetrance PCa risk gene in European-origin men. They reported that men carrying harmful germline ATM variant were at approximately fourfold risk for PCa development and had a higher risk for early-onset disease [75]. The noteworthy finding is that ATM mutations predispose to familial PCa. In particular, ATM mutations were detected in 2.8% of familial cases compared to 0% in controls in Polish population [76]. Many studies additionally proved that ATM gene variants contribute to PCa susceptibility and progression [77, 78]. Among the mutated DNA damage repair genes, the ATM gene is mutated particularly in mPCa with an estimated frequency of 7.3%, which is only exceeded by BRCA2 mutations (13.3%) [79]. The incidence of ATM variation is nearly 0.5% in the general population (Exome Aggregation Consortium), to 1% in men with localized PCa, while 1.6% of men with mPCa have ATM mutation [80]. As regards the HPCa, 50% of ATM mutations are missense; 37%, frameshift; and 13% splice. It is still not fully understood how the inactivation of ATM promotes cancer genesis and/ or more aggressive disease [81].

1.4 Partner and Localizer of BRCA2 (PALB2) PALB2 gene is localized on chromosome 16 and encodes partner and localizer of BRCA2 protein (PALB2). This protein acts as a bridge between BRCA1 and BRCA2 to form a BRCA complex that initiates homologous repair [82]. In early 2000, it has been identified that PALB2 germline pathogenic variants are involved in predisposition to breast cancer [83–85]. However, further genetic studies have shown that germline PALB2 variants have been associated not only with breast cancer but also with pancreatic [86, 87] and gastric cancer as well [88–90]. There are many literature data about PALB2 association with breast and pancreatic cancers, whereas few studies have reported PALB2 variants in HPCa patients. In 2016, Pritchard et al. analyzed 692 patients with mPCa for germline DDR mutations and found that these mutations were present in 4.6% patients with localized disease and up 11.8% in mPCa. Among DDR mutations, PALB2 germline pathogenic variations were detected in 0.4% PCa patients [65]. Similarly, Nicolosi et al. reported pathogenic PALB2 germline mutations in 0.5% of patients diagnosed with PCa [24]. The precise role of PALB2 in the pathogenesis and development of PCa is still unclear [10]. In particular, previous studies did not find a strong link between germline PALB2 mutations and HPCa in families with a high ratio of PCa before the age of 55  years or more affected family members [91–93]. However, findings of more recent studies have supported an increasing role of PALB2 in HPCa [94] and suggested the association of germline PALB2 pathogenic variations with more aggressive disease [95, 96]. In PALB2 gene, 83% of the mutations found in HPCa are frameshift and 17% missense.

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1.5 The Mismatch Repair Genes The mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2, located on chromosomes 3, 2, 2, and 7, respectively) play a key role in genomic stability since proteins they encoded function as sensors, recognizing mismatched DNA [14]. Germline mutations in these genes are collectively known to cause Lynch syndrome (LS), but also it has been found that they are associated with significantly increased risk for colon cancer (15–46%), endometrial cancer (43–57%), and ovarian cancer (10–17%) [97–101]. The reported frequency of mismatch repair system deficit in PCa cases has been 3%–5% [102]. This estimated prevalence of mismatch repair gene mutations is low when compared to alterations in genes of DNA damage repair pathways [103]. Among the mismatch repair genes, according to the Prospective Lynch Syndrome Database and some other studies, mutations within the MSH2 gene have been most strongly associated with PCa, with an increased risk of about 25% to age 75 [48, 104, 105]. The study of Lynch syndrome mutation carriers and their first-degree male relatives conducted by Barrow et al. found a tenfold increased PCa risk associated with MSH2 mutation [97]. Another study with the cohort of 3607 PCa patients reported that 2% PCa cases carried a mutation in one of four mismatch repair genes examined (MLH1, MSH2, MSH6, and PMS2). Again, MSH2 gene is regarded as the highest percentage of these mutations followed by PMS2 and MSH6 [106]. Moreover, many studies suggested that patients with germline mutations in the these mismatch repair genes have increased risk for HPCa [49, 107]. In particular, the study by Brandao et  al. showed approximately fivefold increased HPCa risk in men with Lynch syndrome [48]. Furthermore, according to Pilarski, the HPCa risk in individuals with mismatch repair gene mutation is estimated to be within rate of 2.0–3.7% [108]. Concerning mismatch repair genes, 47% of the mutations found in HPCa are frameshift; 44%, missense; and 9%, splice. Additionally, most studies have underlined a noticeably greater PCa risk for MSH2 mutation carriers, but failed to show differences in the earlier onset and aggressiveness between mismatch repair mutation-related PCa and sporadic PCa cases [102, 109] (Table 2.1).

2 Polygenic Risk Scoring in Prostate Cancer Susceptibility In addition to rare high-risk mutations in susceptibility genes, recent findings underline the substantial role of polygenetic inheritance of low-risk germline variants in the form of single-nucleotide polymorphisms (SNPs). As such, SNPs emerge as valuable genetic markers to distinguish an individual’s susceptibility to PCa onset and progression [110]. SNPs are common genetic variations that occur at a single position in the DNA sequence, where one nucleotide (A, T, C, or G) is replaced by another. Typically, to be classified as a polymorphism, a single-nucleotide variation must be present in the

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Table 2.1  DNA damage repair and DNA mismatch repair genes involved in PCa genetic susceptibility

Gene BRCA1

Risk for Association aggressive with PC riska PCa ++ +

BRCA2

+++

+++

CHECK2 ++

++

ATM

+

++

PALB2

+

+

MSH2

++

+

Germline testing for other associated/ hereditary cancers HBOC syndrome; breast (male and female), ovarian, pancreatic cancers, melanoma HBOC syndrome; breast (male and female), ovarian, pancreatic cancers, melanoma Breast, ovarian, colon, thyroid, and kidney cancer Breast, colorectal, gastric, and pancreatic cancers Breast, pancreatic cancers Lynch syndrome; colorectal, ovarian, uterine, gastric, small bowel, pancreas, upper tract urothelial, kidney, sebaceous carcinoma

Germline mutation frequency in general populationb (%) 0.22

Germline mutation frequency in FPCc (%) 0.90–1.25

0.29

1.20–5.30

0.61

1.80–2.80

0.25

1.60–2.70

0.12

0.40–0.50

0.04

0.7–1.74

Evidence from case–control, familial, cohort, or clinical studies: strong (+++); moderate (++); low (+); and conflicting data (+/−) b Evidence from Exome Aggregation Cohort General Population n = 53,100 c Vietri et al. Int J Mol Sci. 2021 Apr; 22(7):3753 FH: family history, HBOC: hereditary breast and ovarian cancer, PC: prostate cancer a

DNA of at least 1% of the population [111]. Importantly, these variations may be functional, affecting gene expression and protein function. Concisely, SNPs positioned inside the coding regions of an exon can modify messenger RNA (mRNA) stability or protein translation efficiency, thereby modifying the structure or activity of translated proteins [112]. Altered properties of the resulting protein influence its molecular and biological functions within the prostate microenvironment. However, the majority of SNPs (>90%) are located beyond the exonic domain of the functional gene and exert an impact on the expression of one or multiple genes through diverse molecular mechanisms [113]. SNPs associated with an increased PCa susceptibility were found in genes involved in various processes, including cell cycle, DNA repair, steroid metabolism, inflammation, oxidative stress, cell adhesion, and angiogenesis [110, 114–117].

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Over the past decade, the number of recognized variants that have consequential implications for PCa has significantly risen due to the development of genome-wide association studies (GWAS) and the collaborative efforts of international consortia that have led to the exchange of extensive genotyping data [118]. This approach has enabled researchers to prevail the limitations, such as small sample sizes and low number of variants which were assessed in earlier linkage mapping studies. Subsequently, this has placed GWAS in a position of the gold standard to discover the link between germline variants and complex diseases, such as PCa [119]. Following the first GWAS conducted in 2006, more than 40 PCa GWAS have been reported (listed in NHGRI-EBI Catalogue of published GWASs: http://www.ebi. ac.uk/gwas) [118, 120]. In recent times, GWAS initiatives have pooled their data through meta-analyses which increased both study sample size and statistical power, consequently leading to heightened identification of variants related to PCa. As such, the latest multiancestry meta-analysis of prostate cancer GWAS, which included thousands of cases and controls, identified 86 novel genetic risk variants which were independently associated with PCa risk [121]. Notably, variants revealed by GWAS have functional implications on PCa. For instance, both coding variants influencing the activity of prostate-specific antigen (PSA) and noncoding variants regulating the expression level of PSA have been found in PCa [113, 122]. As such, the conduction of functional analyses of these variants and the establishment of their association with PSA levels in men could offer insights into the factors underlying diminished PSA levels in certain individuals with PCa, as well as elevated PSA levels in those with indolent disease. Such insights could pave the way for establishing personalized PSA diagnostic test, which includes these germline variants. In the next section, specifics of landmark GWAS studies and the impact of these findings on current practices will be presented in detail. Given the large number of identified variants that have been associated with PCa so far, it is reasonable to assume that the impact of individual SNP on PCa is relatively modest and that the effects of these SNPs on prostate tumorigenesis are rather cumulative. Indeed, this large number of SNPs suggests that the PCa development relies on multiple genes that should be taken into account when identifying individuals at high risk. Thus, the polygenic risk scores (PRSs), which aggregate common prostate cancer-associated genetic variants mapped from GWAS into a single measure, have been developed. In addition to PCa genetic risk variants, the recent studies suggest the incorporation of other variables into the PRS models, such as age, ethnicity, family history, and clinical parameters [123–126]. According to the reports, PRS has emerged as a valuable tool for identifying individuals at the highest risk of PCa which could potentially lead to the development of more effective screening strategies [127–131]. Men with a family history are more prone to early onset of the PCa. Moreover, men who inherited germline variants in DNA repair genes are especially at risk of aggressive course of the disease, as mentioned previously. The ability to assess SNPs at any age, requiring a one-off collection usually in the form of a blood draw or saliva sample, and their low cost make them attractive candidates for predicting the risk of prostate cancer development in suspected high-risk patients [132]. In the

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view of the preceding facts, it is reasonable to evaluate the feasibility and effectiveness of targeted screening in the aforementioned groups of individuals at high risk, who would particularly benefit from early detection of the disease and its management. At the same time, individuals with a low PRS may avoid the possible complications associated with invasive examinations, such as overbiopsy of indolent or benign tissue [7]. In this chapter, the latest data regarding genetic testing in PCa will be presented, outlining the indisputable impact of genetic susceptibility to prostate cancer development and prognosis, as well as the application of the current knowledge in clinical practice. Several GWASs on the discovery of new single genetic variants of importance in PCa susceptibility have been recently published and reviewed [133]. The largest PCa GWAS, which was published until now, reported 147 predominantly noncoding genomic loci estimated to collectively explain 28.4% of familial risk of prostate cancer [134]. According to this study, men in the top 1% of the risk profile have more than fivefold relative risk of developing prostate cancer compared with men in the 25–75th or “average” percentiles of risk. With the vast majority of variant risk alleles detected by PCa, GWASs are outside protein-coding regions, and the molecular mechanisms responsible for pathobiology of prostate cancer have only been described for a relatively small number of genetic loci [135–140]. GWAS loci predominantly colocalize with tissue-specific regulatory elements, thus supporting the hypothesis that risk variants exert their effects on the disease by influencing the transcriptional levels of their target genes. For example, a substantial proportion of prostate cancer heritability lies in regions marked by H3K27ac, a histone modification, marking active enhancers and promoters [141–143]. Still, a central issue driving post-GWAS studies is a mechanistic understanding of non-protein-coding risk loci, which account for over 90% of GWAS variants. The most frequently used approach to study functional relevance of detected SNPs is fine-mapping of GWAS loci by the presence of expression quantitative trait loci, in order to capture the combined, yet consistent supporting data of overlapped assigned genes. Expression quantitative trait loci (eQTL) analysis seeks to identify genetic variants that affect the expression of one or more genes: a gene-SNP pair for which the expression of the gene is associated with the allelic configuration of the SNP is referred to as an eQTL. This is supposed to be a practical analytical paradigm of prioritizing genes and regulatory elements at GWAS loci for follow-up functional studies [113]. Besides, very recently, Giambartolomei et al. applied a systematic approach, based on chromosome conformation capture technology, to link regulatory element(s) to possible candidate target genes in GWAS prostate cancer risk regions [144]. In addition to the necessity to further recognize the functional relevance of variant risk loci in PCa development, an important issue in the application of GWAS results in the assessment of PCa risk is the ethnicity of the participants. It is important to note that about 78% of participants in GWAS studies are of European ancestry [145]. Regarding PCa, the ethnic heterogeneity exists in terms of PCa susceptibility. Thus, the incidence is 1.8 times higher and the mortality 2.1 times higher in men of African ancestry than in men of European ancestry [146]. A previously mentioned recent meta-analysis published in Nature Genetics by Conti and

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coworkers took this notion into account and combined the data of 136 GWAS for 107,247 prostate cancer cases and 127,006 controls, including 85,554 cases and 91,972 controls of European ancestry, 10,368 cases and 10,986 controls of African ancestry, 8611 cases and 18,809 controls of East Asian ancestry, and 2714 cases and 5239 controls from Hispanic populations [121]. This study represents the largest multiancestry genetic analysis that has ever been conducted for PCa [147]. Over the 136 research populations, 5.8–16.8 million genetic variations including SNPs, insertions, and deletions with ≥1% frequency were analyzed for their association with PCa risk. These authors found 86 novel independent genetic loci that were associated with PCa risk. Taken together with the results of other researchers, the number of genetic risk variants associated with PCa susceptibility increased to 269 [121]. Interestingly, the proportion of variant risk alleles was similar among Europeans, Africans, and Hispanics, while the proportion of variant risk alleles was lower in East Asians. Based on multiancestry weights of these variants, a polygenic risk score was made to capture the cumulative contribution of genetic risk variants to PCa susceptibility. This score could not discriminate the risk of aggressive versus nonaggressive PCa, still 45–51% of all men with aggressive disease were in the two top decile categories of genetic risk score. The risk for the men in the top 10% of genetic risk score, when compared to those with average risk (40%–60% GSR category), was over five times higher in European population; 4.47, in East Asians; 4.15, in Hispano population; and 3.74, in African population. Regarding the distribution of this genetic risk score among controls, more than twofold difference between men of European and African ancestry was found. Therefore, these genetic variants are supposed to be responsible for a big portion of the differences in PCa susceptibility. Special benefit from timely and frequent testing may be for men who have increased risk. This kind of preventive strategy would enable the early discovery of patients with PCa and consequently their better clinical outcomes. Investigation of GWAS in PCa susceptibility has the potential to pave the way for the application of precision medicine concept in genetic risk predisposition in PCa. Although GWAS enabled significant improvement in the detection of genetic variants associated with common diseases, it is often the case that a gene variant found to be associated with the disease is not the causal polymorphism, but a proxy to it as a result of linkage disequilibrium. Therefore, the attempt to include different populations with their genetic variability would increase the probability of the detection of causal SNPs [148]. This multiancestry approach has led to the development of a genetic risk score that is effective in stratifying PCa across populations of different ancestry and greatly improves upon discriminative models based on age and family history. The application of genetic risk scores undoubtedly improves the detection of PCa and stratification of these patients. Thus, Xu et al., has shown by using 14 identified PCa SNPs in combination with presence or absence of a familiar history of the disease almost five times higher risk for prostate cancer development in individuals with a present familial history [149]. In another study, Kader et  al. investigated germline SNPs in control subjects from the REDUCE trial, which analyzed the chemopreventive benefits of dutasteride. All of these participants had an initial

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negative prostate biopsy, with subsequent prostate biopsies at 2 and 4  years. Interestingly, this group showed that adding a genetic score based on 33 risk SNPs together with clinical variables was an independent predictor for PCa on a repeated prostate biopsy. Moreover, by using such an approach, it was possible to decrease the number of repeated biopsies required [150]. Recently, Na et  al. analyzed the relationship between a genetic risk score and the age of the patient at the moment of PCa diagnosis in comparison with the familial history of disease. The study was performed in a large cohort of 3225 white men (also from the REDUCE trial), by using stratifiers consisting of 110 known PCa risk SNPs for each participant. Higher genetic risk scores were associated with earlier age at the moment of PCa diagnosis, independently of familial history status [151]. Callender et al. investigated the cost-­ effectiveness and benefits/harms of using a polygenic risk score screening in a simulation. Three screening models were compared: no screening, age-based screening (PSA every 4  years from age 55 to 69), and risk-tailored screening (PSA every 4 years only in men whose risk is at or above a certain absolute risk threshold based on their polygenic risk score) with respect to cost, overdiagnosed cancers, and amount of PCa-related deaths. It has been shown that an age-based model prevented the most deaths, but induced more overdiagnosed cancers, while a precision-based screening strategy averted a third more cases of overdiagnosis but also fewer PCa-­ specific deaths than the age-based model [152]. The first population-based study on PCa screening that prospectively assessed a targeted screening approach was the STOCKHOLM3 study (STHLM3) [125]. The study used 232 risk SNPs and plasma markers of prostate cancer including PSA and clinical characteristics of patients and compared this with PSA alone (using a threshold of≥3 ng/ml) [125]. A significant improvement of sensitivity for the discovery of PCa risk was found by using this model (AUC 0.74 vs 0.56) in comparison to PSA alone. This approach also decreased the number of biopsies by 32% and avoided 44% of benign biopsies. Furthermore, this project aims to further improve the PCa diagnosis by comparing the role of the STHLM3 test versus standard diagnostics procedures such as PSA determination and standard systematic biopsy. The participants will be randomized at the point of diagnostic test after either a PSA ≥ 3 ng/ml or STHLM3 > 11, with the diagnostic test either being a traditional systematic or MRI-guided biopsy [153]. Another study of interest is BARCODE1, which is a prospective UK study that uses a germline 130 SNP profile to assess prostate cancer screening in the general population, recruiting patients via their general practitioners. In the case where the participants fall in the top 10% of polygenic score risk, an MRI-guided prostate biopsy is performed. This kind of approach will allow the determination of the utility of MRI in men who have an increased genetic risk of PCa based on polygenic risk scoring. In the ABARCODE1 pilot study, uptake of SNP profiling by providing a saliva sample via general practitioner was 26% with 25/303 identified for intervention based on a PRS falling in the top 10% of risk; 45% of these men had an abnormal MRI with (any) cancer detected in 38.8% [154]. The applicability of the previously mentioned genetic risk score developed by Conti et  al. [121] to non-European populations has not yet been confirmed.

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Therefore, ethnicity-specific studies in men of African descent could be a valuable population for future analysis. In order to expand the scope of ethnicity-specific genetic analyses in non-European populations, Leon et al. suggested that the predictive potential of the genetic risk score can be further improved or refined through the RESPOND study (Research on Prostate Cancer in African American Men: Defining the Roles of Genetics, Tumor Markers, and Social Stress), which should be one of the largest genetic studies conducted on PCa in men of African descent. Besides, the predictive utility of genetic risk scores and their implementation in the clinical setting will largely depend on the recently published new standards for reporting and understanding the scores, especially the inclusion of ancestry information of the study population [155]. Since the overdiagnosis was recognized as a limitation in the application of polygenic risk scoring, Pashayan et al. assessed its implications for reducing overdiagnosis. They used data from three large studies (ProtecT, SEARCH, and UKGPCS) and constructed a PRS on 17,000 men aged 50–69 using 66 known PCa risk SNPs, separating men with and without PCa into risk quartiles. They concluded that polygenic risk scoring should be applied for the stratification of men in higher risk quartiles who would mostly benefit from diagnosis and reducing the overdiagnosis [156]. It is noteworthy to mention that the polygenic risk score effect was higher when familiar history was present or in individuals with PCa who were younger than 55 years. It has been suggested that a risk model using a SNP profile with familial history status could become a part of a targeted screening strategy to identify those individuals at the highest risk. In the study by Zheng et al., who analyzed five common polymorphisms known to be related to PCa, it was concluded that these polymorphisms in combination with familial history of disease were responsible for 46% of the PCa cases. The PCa risk was over ninefold higher when compared with the population of men who did not have these factors, independent of PSA level [157]. In another study, Lecarpentier and coworkers analyzed the effect of SNP pattern on PCa risk in 1802 men with BRCA1/2 variants, taking into account 103 known prostate cancer susceptibility genes. They found an increasing PCa risk for increasing polygenic risk score quartiles, with an estimated PCa risk of 61% by age 80 in men with BRCA2 variants who were in the 95th percentile of risk according to their polygenic risk score. It is important to note that such an approach is of key importance in the risk stratification of men, since it enables timely screening and intervention [158]. Therefore, prostate risk score has a power in predicting individualized cancer risk, especially in BRCA1/2 carriers. Although the number of these patients is relatively small, this group is particularly important because of their high risk. Siltari et al. from PIONEER Consortium recently summarized the published evidence and conducted meta-analyses of polygenic risk score as a predictor of PCa risk in Caucasian men [126]. Based on data from 59 studies, with a total of 20,786 cases and 69,106 controls identified through a systematic search of ten databases, they found that the ability of polygenic risk score to identify men with PCa was modest (AUC 0.63), while combining polygenic risk score with clinical variables increased the pooled AUC to 0.74. Therefore, the authors concluded that the

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polygenic risk score accuracy is comparable to PSA or family history, indicating mediocre performance for polygenic score alone.

3 Guidelines The importance of germline testing in clinical practice is outlined by the latest European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) guidelines. EAU guidelines specify that individuals with a personal or family history of PCa or other cancer types that originate from mutations in DNA repair genes are suitable candidates for germline testing [159]. This includes men with metastatic PCa, those with one or multiple family members who diagnosed with PCa at age 9 h), technical difficulties with instruments, and a steep learning curve [9, 10]. The initial experience demonstrated no additional benefit over the standard of care at the time, i.e., open radical prostatectomy (ORP). The pure laparoscopic approach lost its popularity after the early 2000s not only due to

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the technical difficulty of procedure itself, but also due to the approval by the Food and Drug Administration in the United States of a new Endoscopic Instrument Control System (designed by Intuitive Surgical, Inc.), later known as the Da Vinci Surgical System. The first robotic-assisted radical prostatectomy was performed in 2001 [11, 12]. After initial series of five consecutive subjects, the authors concluded no clear patient benefit of such approach over pure laparoscopy, but there were clear advantages for the surgeon in regards to visualization due to three-dimensional camera system, motion scaling, tremor filtration, and improvement in ergonomics [13]. Over time, it became evident that with the establishment of a well-structured training robotics program a surgeon could achieve superior outcomes much sooner than with pure laparoscopy [14]. As a result, the Da Vinci system gained its wide use beyond urologic world and became popular among other surgical specialties including gynecology and general surgery.

2 Perioperative, Functional, and Oncologic Outcomes Over the past two decades, multiple studies have demonstrated improved perioperative morbidity and mortality in RALRP when compared to the traditional ORP. For example, Hu et al. reviewed early experience outcomes (between 2003 and 2005) in 2702 men undergoing RALRP, ORP, and perineal radical prostatectomy and found that men undergoing RALRP experienced fewer postoperative overall complications (including cardiac, respiratory, vascular, and wound-related problems) [15]. However, there was initially a higher rate of urethral strictures at the anastomosis site and an increase in need for salvage therapy within 6 months [15]. Importantly, after further subgroup analysis, the same investigators showed an improvement of the latter outcomes at higher volume centers (tertiary care facilities), indicating that experience and training could overcome such complications. Liu et  al. similarly observed during a later time frame, between 2005 and 2010, a significant decrease in incidence of blood transfusions and other major complications with RALRP compared to ORP, including a lower mortality rate of 0.05% vs. 0.4%, respectively [16]. Some series showed a difference of almost 600 ml in blood loss in favor of RALRP [17]. By the year 2011, 80% of all radical prostatectomies were performed robotically in the United States, and a new retrospective database review by Pilecki et  al. demonstrated higher readmission rates among men undergoing ORP when compared to RALRP [18]. Robotic approach has also proven to induce less postoperative pain and to likely be the main contributor to earlier patient discharge from the hospital. Of important note is that the beneficial effects of robotic surgery have been also supplemented by the enhanced recovery after surgery pathways, which gained popularity in parallel with evolution of robotic surgery over the years. In one particular series, Abaza et al. were able to discharge home almost 50% of men undergoing RALRP on same day of surgery [19]. This was proven to be safe and effective since  T and c.1129–5923C > G (HapB3). The CPIC guidelines offer dosage guidance for fluoropyrimidines that takes into account an individual’s DPYD genotype/phenotype (Table 17.1). Within the European population, the HapB3 gene polymorphism stands out as the most commonly observed variant (prevalence 4.1–4.8%). When all four of these variants

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are taken into consideration collectively, it is estimated that around 7% of Europeans carry at least one of these DPYD variants associated with decreased function [26]. Certain studies have indicated that fluoropyrimidines could serve as an alternative treatment for patients with advanced prostate cancer. By this, DPYD genotyping would enhance the safety of these patients. Nevertheless, the existing evidence is not sufficient for fluoropyrimidines to establish their place in the therapy of prostate cancer [27–29]. The ambitious goal of personalized (precision) oncology is to predict how a cancer patient will respond to a particular treatment strategy. By tailoring therapies based on the patient’s characteristics and the genetic and molecular profile of the tumor, precision oncology seeks to optimize treatment efficacy and diminish adverse effects, improving patient outcomes and quality of life. Therefore, oncology pharmacogenomics deals with germline and somatic variations acquired within the cancer tissue itself. Somatic mutations could be the drivers that define the cancer subtype (pharmacogenomic biomarker), or they may be non-relevant passenger mutations. In certain types of cancer, these driver mutations can play a pivotal role in guiding the selection of anticancer agents, indicating which tumors are more or less likely to respond to specific treatment options. Over the past few years, the focus of drug development has shifted toward identifying and targeting the molecular drivers of cancer. In addition, the FDA has generally approved companion diagnostic tests in conjunction with new agents, while the EMA has been relatively less stringent in this regard [4].

Table 17.1  CPIC guidelines regarding fluoropyrimidines dosing [26]

Probable phenotype DPYD normal metabolizer

Relative DPD activity score 2

DPYD intermediate metabolizer

1.5

DPYD poor metabolizer

0.5

1

0

Genotype (allele combinations) Active/active

Dosing recommendations Based on the genotype, continue with the standard treatment, there is no need to adjust the dosage Active/decreased Reduce starting dose based on activity activity or inactive score. Dose titration based on toxicity or TDM (if available) Decreased activity/decreased Score 1: Reduce dose by 50% Score 1.5: Reduce dose by 25–50% activity Decreased Score 0.5: Avoid the use of 5-FU and activity/inactive pro-drugs. If there is no alternative drug, 5-FU in a maximally reduced dose with Inactive/inactive early TDM should be applied Score 0: Avoid use of 5-FU and pro-drugs

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4 Driver Mutations and Targeted Therapies Traditionally, patients diagnosed with cancer have been treated according to the location and histological characteristics of the tumor. However, with the progression of molecular technology, next-generation sequencing (NGS), and the emergence of medications designed to target specific biomarkers unique to tumors (targeted therapies), a new era toward precision and personalized cancer treatments has begun. Targeted therapy represents a type of cancer treatment that strives to enhance treatment efficacy while minimizing adverse effects and acting against specific molecules or proteins crucial for the growth and spread of cancer cells. Numerous mutations lead to increased oncogenic activity, resulting in the production and accumulation of proteins with altered functionalities. Those proteins can be cell surface receptors and/or intercellular proteins, such as kinases that contribute to increased proliferation, tumor growth, metastasis, and the development of resistance to existing drugs [30, 31]. Considering targeted therapies in precision oncology, two main groups are evident: antibodies and small molecules. Antibodies are characterized by high selectivity, and targets are often restricted to the cell surface. Small molecule inhibitors vary in selectivity, whereas they are small-sized and can potentially bind a wider range of extracellular and intracellular targets [32]. Historically, the precision oncology and targeted therapies era started with the discovery of HER2 overexpression or amplification in breast cancer and later research and development of trastuzumab, a humanized anti-HER2 antibody, which got FDA approval in 1998. This was followed by the development of tyrosine kinase inhibitors (TKIs), which have been successfully used in non-small cell lung cancer (NSCLC) among other malignancies. One huge step forward in the treatment of malignancies was the development and wider application of the NGS techniques that provide rapid, economically sustainable, massively parallel DNA and RNA sequencing [33].

4.1 Monoclonal Antibodies Monoclonal antibodies can be engineered to precisely bind to specific molecules, including receptors on the surface of cancer cells or extracellular ligands. Once attached to a receptor or extracellular ligand, these antibodies possess the ability to inhibit signals critical for the growth and division of cancer, which leads to the death of tumor cells. When a ligand binds to a receptor on a cancer cell’s surface, it triggers a chain reaction that aims to activate intracellular signaling pathways. An overexpression or abnormal expression of these receptors can contribute to irregular growth, avoidance of programmed cell death, and the metastasis of the tumor. This progression can be hindered by utilizing monoclonal antibodies aimed at specific receptors, all the while minimizing adverse effects on normal cells. An example is the previously mentioned HER2/neu receptor, a member of the EGFR receptor

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family, and trastuzumab, which has exhibited notable efficacy in breast cancer treatment [30]. Besides surface receptors, antibodies can also attach to extracellular ligands that would otherwise bind to receptors on the surface of cancer cells. An illustrative example of this mechanism is bevacizumab, an antiangiogenic agent. Bevacizumab binds to the soluble vascular endothelial growth factor A (VEGF-A), preventing its interaction with the VEGF receptor (VEGFR) and inhibiting the formation of new vascular pathways. Bevacizumab has demonstrated its effectiveness and utility, either in combination with chemotherapy or as a standalone treatment in maintenance therapy, across various cancers such as colorectal, lung, and others [30, 34, 35]. Furthermore, attempts have been made to integrate bevacizumab into the treatment protocol for advanced prostate cancer, which will be discussed later in this chapter. In addition, monoclonal antibodies have found utility in the realm of immunotherapy for diverse types of cancer, including prostate cancer [36]. Cancer immunotherapy modulates the immune system to eradicate cancer cells and impede their uncontrolled growth. Certain proteins play a role in regulating the immune system’s response to external threats, including cancer cells. However, cancer cells can hijack these “checkpoint” proteins to evade detection and suppress the immune system’s ability to recognize and counteract them. [37]. Programmed cell death-1 (PD-1) is present on the surfaces of activated T cells, B cells, dendritic cells, monocytes, and natural killer cells. It is assumed that PD-1 inhibits T-cell responses by interference with T-cell receptor, whereby it interacts with PD ligand 1 (PD-L1) and ligand 2 (PD-L2), which are effective in suppressing T-cell responses [38]. Immune checkpoint inhibitors (ICIs) help activate T cells, empowering them to recognize cancer cells as foreign entities and inhibiting the deactivation of the immune system’s response. The monoclonal antibodies that exert their effects as immune checkpoint inhibitors are shown in Table 17.2 [39, 40]. A crucial advancement in the field of oncology was the tissue-agnostic FDA approval of the PD-1 inhibitor pembrolizumab, an ICI, for the treatment of any tumor with mismatch repair deficiency (MMRd) or high microsatellite instability (MSI-H), regardless of the tissue of origin. In addition, clinical trials focusing on patients with advanced prostate cancer have been underway [39, 41].

4.2 Small Molecule Inhibitors Certain types of cancers exhibit a notable reliance on particular oncogenes, whereas others display unique molecular susceptibilities that allow for selective targeting of pathways, such as those related to DNA repair or apoptosis. The utilization of selective small molecule inhibitors offers the benefit of precisely aiming at the intended site while reducing off-target inhibition, which can lead to undesirable adverse effects [32]. Initially, most of the approved small molecule inhibitors were TKIs. These drugs target intracellular kinases, which play a crucial role in intracellular signaling by facilitating the transfer of phosphate groups to specific target proteins, involved in the growth and spread of cancer cells [30]. The notable success of TKIs

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Table 17.2  Monoclonal antibodies as immune checkpoint inhibitors Drugs/target Ipilimumab/ CTLA-4 (human IgG1) Pembrolizumab/ PD-1 (humanized IgG4)

Indications approved by the FDA and/or EMA Inoperable or metastatic melanoma; renal cell carcinoma (RCC); colorectal cancer; hepatocellular carcinoma; metastatic non-small cell lung cancer (NSCLC); malignant pleural mesothelioma Inoperable or metastatic melanoma; stage IV nonsquamous and squamous NSCLC; recurrent or metastatic head and neck squamous cell carcinoma; refractory classical Hodgkin lymphoma; primary mediastinal large B-cell lymphoma (PMBCL); locally advanced or metastatic urothelial carcinoma; high microsatellite instability (MSI-H) or mismatch repair deficiency (MMRd) cancers; high tumor mutational burden (TMB-H); recurrent or metastatic cervical cancer; hepatocellular carcinoma; advanced endometrial carcinoma that is not MSI-H or dMMR; cutaneous squamous cell carcinoma; recurrent locally advanced or metastatic gastric esophageal or gastroesophageal junction (GEJ) adenocarcinoma Nivolumab/PD-1 Inoperable of metastatic melanoma; stage III-B or IV squamous NSCLC; (fully human malignant pleural mesothelioma; advanced renal cell carcinoma; classical IgG4) Hodgkin lymphoma; recurrent or metastatic head and neck squamous cell carcinoma; locally advanced or metastatic urothelial carcinoma; MSI-H or MMRd cancers; hepatocellular carcinoma; advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma Cemiplimab/ Metastatic cutaneous squamous cell carcinoma; locally advanced basal cell PD-1 carcinoma (BCC); NSCLC (fully humanized IgG4) Atezolizumab/ Locally advanced or metastatic urothelial carcinoma; NSCLC; Small cell PD-L1 lung cancer (SCLC); hepatocellular carcinoma (HCC); inoperable or (humanized metastatic melanoma IgG1) Avelumab/ Metastatic Merkel cell carcinoma (MCC); locally advanced or metastatic PD-L1 urothelial carcinoma; renal cell carcinoma (completely human IgG1) Durvalumab/ Metastatic or locally advanced urothelial carcinoma; stage III NSCLC; PD-L1 extensive-stage small cell lung cancer (ES-SCLC) (human IgG1 kappa-IgG1κ)

demonstrated in metastatic lung cancer upon the discovery of relevant alterations in individuals. For instance, gefitinib showcased heightened effectiveness compared with chemotherapy in patients harboring the mutation within the intracellular domain of the epidermal growth factor receptor (EGFR) [42]. Over the years, the development of small molecule inhibitors targeting mutations or instances of amplification/overexpression of various receptors has progressed significantly across a multitude of cancers. These inhibitors encompass proteins such as ALK, ROS-1, BRAF, VEGF, MET, RET, and others. Examples of small molecule inhibitors in precision oncology are presented in Table 17.3 [6, 30, 43]. Multikinase inhibitors are designed to simultaneously target a wide range of kinases, while selective small molecules inhibit a more limited number of proteins, sometimes a single component

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Table 17.3  Examples of small molecule inhibitors in precision oncology (adapted from [43], Creative Commons Attribution 4.0, https://creativecommons.org/licenses/by/4.0/) Drugs Gefitinib, erlotinib, icotinib, afatinib, osimertinib Lapatinib, neratinib, tucatinib (only HER2) Crizotinib, ceritinib, alectinib (only ALK) Brigatinib Capmatinib, tepotinib Midostaurin, quizartinib Sorafenib

Targets EGFR

Indication NSCLC

EGFR/HER2

Breast cancer

ALK/ROS

NSCLC NSCLC NSCLC AML RCC, HCC, DTC, thyroid cancer RCC, GIST, pancreas neuroendocrine tumor CRC, GIST, HCC

Erdafitinib Avapritinib, ripretinib Selpercatinib, pralsetinib

ALK/ROS/IGF1R/EGFR/FLT3 c-Met FLT3 c-Kit/FLT3/RET/PTC/ VEGFR-­1/2/3/PDGFR-β PDGFR-α/β/VEGFR-1/2/3/ CSF1R/c-Kit/RET/FLT3 VEGFR-1/2/3/PDGFR-α/β/ FGFR-1/2/RAF/RET/cKit VEGFR-1/2/3 VEGFR-1/2/3/PDGFR-α/β/ MDR1/BCRP/FGFR-1/3 FGFR-1/2/3/4 c-kit/PDGFR-α RET

Larotrectinib, entrectinib

TRKA/B/C

Nilotinib, radotinib Acalabrutinib, zanubrutinib Fedratinib Vemurafenib, encorafenib, dabrafenib Trametinib, cobimetinib, binimetinib Palbociclib, ribociclib Idelalisib, duvelisib

Bcr-Abl BTK JAK2 BRAF

Urothelial carcinoma GIST NSCLC, MTC, thyroid cancer Solid tumors with NTRK fusion CML MCL Myelofibrosis Melanoma

MEK1/2

Melanoma

CDK4/6 PI3Kδ

Everolimus

mTOR

Tucidinostat

HDAC1/2/3/10

Breast cancer CLL Follicular lymphoma RCC Pancreatic cancer Breast cancer PTCL

Sunitinib Regorafenib Fruquintinib Nintedanib

CRC NSCLC

(continued)

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Table 17.3 (continued) Drugs Ivosidenib Sonidegib Olaparib, rucaparib

Targets IDH1 SMO PARP1/2/3

Indication AML BCC Ovarian cancer FTC Prostate cancer

NSCLC non-small cell lung cancer, MTC medullary thyroid cancer, RCC renal cell carcinoma, CML chronic myeloid leukemia, CLL chronic lymphocytic leukemia, PTCL peripheral T-cell lymphomas, AML acute myeloid leukemia, BCC basal cell carcinoma, FTC follicular thyroid carcinoma, MCL mantle cell lymphoma, GIST gastrointestinal stromal tumor, HCC hepatocellular carcinoma, CRC colorectal cancer

of a signaling pathway within a cancer cell. In the former scenario, these drugs are administered based on the histological diagnosis. While VEGFR remains a primary therapeutic focus for most multikinase inhibitors (cabozantinib, pazopanib, sorafenib, and others), they can also exert their effects against other targets such as KIT, PDGFR-α, RET, and a diverse array of additional targets [32]. Conversely, the utilization of selective inhibitors was preceded by a patient selection process, based on the presence or absence of specific predictive biomarkers within a tumor or blood sample. While germline DNA can be easily acquired through a blood sample or a buccal swab, the collection of somatic DNA primarily necessitates a tumor biopsy, making it a more invasive procedure and subject to the potential biases of sample selection [6, 32]. Besides TKIs, phosphatidylinositol 3-kinase (PI3K) inhibitors, such as idelalisib and duvelisib, showed proper efficacy in cases of relapsed or refractory chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL) [44, 45]. However, both drugs can lead to immune-mediated adverse events that limit their broader use in practice. Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) such as olaparib, niraparib, rucaparib, and talazoparib have established themselves as significant components of targeted therapies across various cancer types, including advanced prostate cancer [41, 46]. Notably, the recent FDA approvals of olaparib and rucaparib, which target both PARP1 and PARP2, for the treatment of advanced prostate cancer signify an advancement in precision medicine for this particular disease [47, 48]. The approvals of the majority of targeted therapies were substantiated by their ability to prolong the survival, progression-free survival (PFS), and/or overall survival (OS) of patients grappling with advanced cancer. In addition, numerous of these drugs have exhibited better safety profiles in comparison with cytotoxic chemotherapy. One of the challenges associated with targeted therapies is the rapid development of tumor resistance toward these medications. Comprehending the mechanisms behind the emergence of resistance to target-­ driven treatments can pave the way for the development of advanced next-­generation inhibitors that possess less susceptibility to resistance or selecting appropriate combination therapies to reduce resistance [6]. Bedard et al. highlighted several valuable insights gained from the experience with selective small molecules. Firstly, a direct correlation exists between the extent of target inhibition and the effectiveness

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of the drug. Approaches to achieve enhanced target inhibition include developing more potent inhibitors (excluding targets with a narrow therapeutic index) and highly selective inhibitors to minimize off-target toxicity. In addition to the enhancement of target inhibition, the recognition of vulnerabilities unique to tumors, the development of inhibitors with reduced susceptibility to resistance, and the ability to effectively reach sanctuary sites (e.g., CNS) are critically significant factors for ensuring the sustained success of the targeted therapy approach in the field of oncology. The utilization of potent and comprehensively penetrating next-generation small molecule inhibitors in the early phase of treatment can effectively postpone the onset of treatment resistance and yield superior treatment results. In cancers dependent on oncogenes, the sudden cessation of a small molecule inhibitor following disease progression can potentially trigger a disease flare [32].

4.3 Research Directions and Clinical Trials in Precision Oncology Two fundamental therapeutic approaches can be observed regarding the development and expansion of precision oncology: the use of combination therapy and molecularly specific/tumor-agnostic therapy. Most human diseases, including cancer, are influenced by multiple genes or, more precisely, molecular aberrations. Treatment involving a combination of chemotherapy and targeted therapy, chemotherapy and immunotherapy, targeted therapy and immunotherapy, or other modalities of combination therapies are under investigation aiming for better efficacy and reduced resistance frequency [33]. This has been shown as a potential combination in various types of cancer, including advanced prostate cancer [49–51]. Examining molecular-specific/tumor-agnostic therapies reveals their development through two distinct approaches. The first involves the presence of a tumor’s existence and a molecular anomaly for which targeted therapy is already approved for a different cancer category. The second strategy entails pinpointing uncommon anomalies that might potentially have corresponding targeted therapies spanning various tumor kinds, including rare and very rare carcinoma types. Both approaches are characterized by small sample sizes, making it impossible to conduct traditional clinical trial designs that involve a single tumor type defined by clear histopathology. All of this contributes to an increased frequency of off-label use of drugs directed at specific molecular targets [33]. For this reason, specialized protocols have been developed to investigate drugs within the realm of precision oncology—biomarker-driven oncology clinical trials [31]. With the advancement of precision oncology and targeted therapies, it became necessary to adapt clinical studies to the clinical practice context to some extent. As a result of this evolution, the concept of master protocols has emerged. These protocols encompass various types of precision medicine clinical trials that are guided by the presence of biomarkers. Included in these protocols are basket, umbrella, and platform trials [52]. Basket trials represent a subtype of master protocols that are both forward-­looking and tissue-agnostic. These trials examine the efficacy of a solitary drug among

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patients afflicted by distinct tumors, all of which share a common molecular aberration. Moreover, these trials are subdivided into parallel sub-studies. This design involves recruiting participants without regard to histology, aiming to determine a recommended dose for the subsequent phase that focuses on specific histopathology. A central criterion for eligibility in a basket trial often revolves around a distinct biomarker that can manifest across a spectrum of diverse cancer histopathology [53]. Basket trials are primarily single-arm trials that usually serve as hypothesis-generating or discovery trials and thus often still require confirmation of drug efficacy in a larger clinical trial. Also, the number of patients within each sub-­group can be quite limited, and it may lead to unreliable outcomes. Their primary endpoint is not efficacy but rather activity and safety. Randomized controlled trials (RCTs) should continue to be essential for drug approvals. However, in situations involving exceptionally rare conditions or targeted drugs demonstrating exceptional early signals of efficacy, conducting an RCT might not be practical or necessary for approval [33, 54]. Umbrella trials represent another category of biomarker-driven clinical trial design employed in drug development for precision oncology. In contrast to basket trials, umbrella trials focus on a single cancer type or histology but screen and assess multiple different biomarkers [55]. Considering multiple relevant biomarkers, these trials assess the efficacy of multiple drugs and interventions. Consequently, while basket trials are more suitable for cancers characterized by a driver mutation with low genomic complexity, umbrella trials find preference in cancers possessing various targetable biomarkers, such as common cancers, breast, and NSCLC [33]. However, these trials also have disadvantages, such as the requirement for multiple study arms, more subjects to participate, and active trial follow-up. Platform trials diverge from basket and umbrella trials in that they assess numerous hypotheses within a single protocol, and the specific design can exhibit substantial variations. These trials are adaptive, allowing for the expansion or discontinuation of study arms while the trial is ongoing. This adaptability stems from the utilization of Bayesian algorithms, which continuously update hypotheses as more evidence accumulates during data collection. Nonetheless, conducting these trials can present challenges due to the requirement for active and dynamic follow-up [31]. It is also important to mention the “N-of-1” trial design, where every patient is administered a personalized molecularly matched combination therapy. This type of trial demands specialized expertise to effectively decipher the molecular data unique to each patient [33].

5 Pharmacogenomics and Precision Therapy in Prostate Cancer Huge steps have been taken in understanding the genomics of prostate cancer, accompanied by ongoing trials aimed at translating this knowledge into clinical practice. However, the complete realization of precision therapy is disturbed by the multifocal nature and intralesional genomic heterogeneity intrinsic to prostate cancer. This makes the clinical application of pharmacogenomics complicated [56].

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Prostate cancer ranks as the second most prevalent cancer in men and the fourth most widespread cancer globally. In 2020, approximately 1,414,259 new cases were diagnosed, and approximately 375,304 deaths worldwide were noted [57]. Most localized prostate cancers represent an indolent disease with population studies indicating slow progression in the majority of patients over many years. In addition, patients with low-grade tumors rarely die from prostate cancer [58]. Conversely, patients afflicted with high-grade or metastatic prostate cancer face a considerably more aggressive disease trajectory, while metastatic prostate cancer still carries a grave prognosis, indicating it will remain a terminal diagnosis. Surgery and radiotherapy are treatment options for patients with localized prostate cancer, while patients with metastatic prostate cancer undergo androgen deprivation therapy (ADT) and many of them can progress to metastatic castration-resistant prostate cancer (mCRPC) and die after progression. Identifying alternative treatment approaches or combinations of therapies that can effectively target these mechanisms of resistance is imperative to potentially extend their long-term survival [59]. Hence, a more profound understanding of the genomic, transcriptomic, and epigenomic alternations in prostate cancer could pave the way for the creation of pharmacogenomic biomarkers. These markers, in turn, could facilitate the development of targeted treatments, potentially leading to improved patient outcomes. The androgen receptor (AR) plays a pivotal role in both the normal development of the prostate and essential growth and survival processes in prostate cancer. Initial prostate cancer development relies on androgen signaling, making androgen activity a central element in the development of prostate cancer. This activity triggers the formation and excessive expression of most ETS fusion genes, which are crucial factors in prostate cancer pathogenesis. The molecular profiling of primary prostate cancer samples identified seven genomic subtypes based on distinct oncogenic drivers: ERG fusions (46%) and ETV1/ETV4/FLI1 fusions or over-expressions (8%, 4%, and 1%, respectively) and SPOP, FOXA1, and IDH1 mutations (11%, 3%, and 1%, respectively). In total, 53% of investigated tumors had ETS-family gene fusions (ERG, ETV1, ETV4, and FLI1). The same study showed substantial heterogeneity in epigenetic profiles, where SPOP and FOXA1-mutant tumors exhibited homogeneous epigenetic profiles and belonged almost exclusively to a group that also contained a majority of the ETV1 and ETV4, but not ERG-positive tumors. Furthermore, tumors carrying mutations in IDH1 had significantly elevated levels of genome-­ wide DNA hypermethylation. In addition, those tumors also possessed the greatest number of epigenetically silenced genes. The ETS fusion-positive groups had variable AR transcriptional activity, while tumors with SPOP or FOXA1 mutations had the highest AR levels of AR-induced transcripts. In addition, it was noted that prostate cancer had a presumed actionable lesion in the PI3K or mitogen-activated protein kinase (MAPK) signaling pathways [60]. Also, mutations in genes involved in DNA repair pathways were identified (BRCA2, BRCA1, CDK12, ATM, FANCD2, or RAD51C.), indicating those patients as possible candidates for PARP inhibition therapy [60, 61]. Typically, primary prostate cancer tends to have a favorable prognosis due to its indolent nature. However, the most difficult challenge arises when dealing with individuals diagnosed with mCRPC, a condition associated with an

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overall poor prognosis. The genetic makeup observed in mCRPC diverges from that identified in  localized primary prostate cancer [56]. Several mCRPCs contain molecular changes that have significant clinical relevance. Previous studies demonstrated that AR, ETS gene fusions, TP53 tumor-suppressor gene, and PTEN inactivating mutations were frequent (40–60% of cases), with TP53 and AR alterations enriched in mCRPC compared with primary prostate cancer [62]. The same study identified alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF.  Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared with those in primary prostate cancers, which makes those cancers potentially prone to PARPi treatment. BRCA2, BRCA1, and ATM were the most common alternations of DNA repair pathways, precisely homologous recombination repair (HRR), and can occur at either a somatic or a germline level [63]. The germline mutations in BRCA1/2 and ATM are associated with prostate cancer risk, as well as aggressive prostate cancer phenotype. Chen et al. showed that the presence of two RB1 mutations in tumor DNA was independently associated with poor OS in mCRPC patients. In addition, the Wnt/β-catenin pathway plays an important role in enzalutamide resistance, while it was shown that β-catenin mutations were predictive of poor OS [64]. The study of the genomic profile of lethal primary prostate tumors demonstrated significant differences in AR, TP53, RB1, and PTEN alterations, but not in DNA repair genes (BRCA2, CDK12, ATM) when comparing the same patients with mCRPC and treatment-naive biopsies [65]. Therefore, genomic alterations in AR, TP53, RB1, and PTEN are enriched during disease progression. Profiling of matched tumors from individual patients revealed that somatic TP53 and BRCA2 alterations arose early in tumors from patients who eventually developed metastatic disease [63]. Tumors that experience a loss in the HRR pathway exhibit an increased sensitivity to PARP inhibition due to the mechanism of synthetic lethality [65, 66]. Moreover, prostate cancers that harbor deficiency in mismatch repair genes (MMRd), such as MSH2, MSH6, PMS2, and MLH1, are associated with MSI-H and enriched for higher T-cell infiltration and PD-L1 protein expression. Hence, it could be effectively treated by an anti-PD-1 antibody, such as pembrolizumab. Conducting screening for MSI-H/MMRd in advanced prostate cancer can be advantageous, as it aids in identifying patients who hold the potential for enduring responses to anti-PD-1/PD-L1 therapy [63, 67, 68]. Boysen et al. demonstrated that SPOP-mutated mCRPCs are strongly enriched for CHD1 loss and associated with a higher response rate to abiraterone [69]. Hatano and Nonomura in their review article pointed out that heterogeneity in the genomic landscape of prostate cancer has become apparent, while the genomic alterations of TP53, RB1, AR, and cell cycle pathway are associated with poor clinical outcomes and SPOP mutation is associated with better clinical outcomes [67]. An important challenge when using genomic profiling in cancer treatment is the presence of genomic heterogeneity. This heterogeneity is caused by clonal evolution and genomic instability. Therefore, novel clones emerge as cancer progresses, whereas distinct subclones can give rise to diverse metastases originating from a single primary cancer source [56]. The complexities of providing precision therapy through pharmacogenomics become

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considerably intricate. This situation may cause a disconnect between the genomic makeup of the primary prostate cancer lesion and the factors that affect the treatment of its metastatic counterparts. Løvf et al. demonstrated that even in the same patient, there are different tumor foci only rarely sharing any somatic gene mutations, including driver gene mutations. Hence, information from all tumor foci is necessary to draw valid conclusions and treatment implementation [70]. However, it has been observed that genomic heterogeneity tends to decrease in more advanced and aggressive later-stage prostate cancer. In their study, Ulz et al. demonstrated an abundance of focal amplifications in metastatic prostate cancer, whereby numerous of these amplifications are recognized as driver mutations for an advanced form of cancer [71]. Prostate cancer is an androgen-dependent malignancy, whereas most first-line therapies target androgen production and the AR signaling axis. The androgen receptor has a significant role in maintaining prostate function through positive regulation of prostate-specific antigen (PSA). However, in numerous cases of prostate cancer, PSA becomes dysregulated, characterized by elevated plasma levels, a finding which serves as a common clinical indicator of irregularities in prostate function [46]. As mentioned above ADT is the first-line systemic treatment for advanced prostate cancer and initially metastatic prostate cancer responds to it. However, these tumors inevitably adapt to ADT by maintaining sustained AR signaling via several back-door mechanisms, resulting in highly aggressive mCRPC. Therefore, ADT is combined with a next-generation AR-signaling inhibitor (ARSI) and/or chemotherapy (e.g., docetaxel) or radium-223 (223Ra) for patients unfit for the above treatments and/or bone-only metastases. These approaches have been followed by improved OS in this patient population. Although ARSI, such as abiraterone, apalutamide, and enzalutamide, intensively inhibit AR signaling, the median survival rates following diagnosis remain dismal [46, 72]. Androgen receptor splice variant 7 (AR-V7) is an AR mutation resulting in the truncation of the ligand-binding domain. This consequently leads to the over-activation of AR, regardless of androgen ligand binding, whereas AR-V7 mRNA detected in circulating tumor cells may be used as a predictive biomarker [73]. Antonarakis et al. demonstrated that in AR-V7-positive men, taxanes seem to be more efficient than enzalutamide or abiraterone, whereas, in AR-V7-negative men, taxanes and enzalutamide or abiraterone may have comparable efficacy [74]. Moreover, it seems that the higher expression of AR-V7 is dependent on the previous treatment with ARSI. These results suggested that AR-V7 splice mutation in prostate cancer can be a negative predictor of response to ARSI [73].

6 Targeted Therapies for Advanced Prostate Cancer In the case of patients diagnosed with mCRPC, there are treatment alternatives available that have been shown to extend survival. These include docetaxel, cabazitaxel, abiraterone, enzalutamide, sipuleucel-T, and 223Ra (Fig.  17.1) [72, 75].

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Fig. 17.1  Treatment algorithm for patients with prostate cancer. This figure illustrates a treatment algorithm for localized, non-metastatic castration-resistant prostate cancer, as well as metastatic hormone-naive and castration-resistant prostate cancer, incorporating recently approved therapies

However, these therapies do not provide a definitive cure and might come with challenges related to its tolerability. As previously stated, significant progress in precision oncology has been the introduction of tissue-agnostic FDA approvals [76]. In 2017, the FDA granted its first tissue-agnostic approval to pembrolizumab, a PD-1 inhibitor for patients with unresectable or metastatic, MSI-H or MMRd of any solid tumors that have progressed following previous treatment and who have no satisfactory alternative treatment options [77]. In 2020, the scope of pembrolizumab’s approval expanded to include adults and pediatric patients afflicted with unresectable or metastatic solid tumors characterized by high tumor mutational burden (TMB-H) (≥10 mutations/megabase (mut/Mb)), as confirmed by an FDA-approved test. The approval extension applies only when prior treatment has failed and no other treatment options are available. The FDA also approved the FoundationOne CDx assay (Foundation Medicine, Inc.) as a companion diagnostic test for pembrolizumab [78]. Besides pembrolizumab, the PARPi were approved for the treatment of men with mCRPC.  Olaparib gained FDA approval for HRR gene-mutated mCRPC [79]. In 2023, olaparib combination treatment with abiraterone and prednisone (or prednisolone) was approved for BRCA-mutated mCRPC [48]. Rucaparib was granted accelerated approval for BRCA-mutated mCRPC [80]. In June 2023, the FDA approves talazoparib with enzalutamide for HRR gene-mutated mCRPC [81]. Targeted therapies for the management of metastatic prostate cancer can be classified into four distinct categories: ICIs, inhibitors of DNA repair mechanisms,

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therapies centered around prostate-specific membrane antigen (PSMA)-targeted radiotherapy, and treatments aimed at impeding tumor neovascularization. Some of these treatments have been approved, while others are under investigation [41].

6.1 Immune Checkpoint Inhibitors The mismatch repair (MMR) process is crucial for genomic integrity and requires properly expressed MSH2, MSH6, MLH1, and PMS2 genes. The primary function of the MMR pathway is to recognize and repair base-base mismatches and insertions/deletions generated during DNA imperfect replication and faulty recombination between heteroallelic parental DNA, but also due to the occurrence of chemical or physical damage to nucleotides [46, 82]. Tumors with MMRd accumulate frameshift mutations resulting in MSI, characterized by repetitive DNA sequences (microsatellites) variable in their length, which leads to hyper-mutable phenotype [33]. Besides MSI-H (high-frequency MSI), MMRd can generate TMB-H, a high level of an estimated quantity of gene mutations present within the genome of a cancerous cell compared with normal cells [83]. About 83% of MSI-H tumors also present TMB-H (≥20 mut/Mb) [84]. Both MSI-H and TMB-H lead to an increase in neoantigen formation, strongly immunogenic mutant proteins, which make tumors more susceptible to existing immunotherapies, such as ICIs. Moreover, tumors exhibiting MSI-H often display an elevation in the expression of immune checkpoint proteins and are characterized by a substantial infiltration of lymphocytes into the tumor microenvironment [33, 46]. Immune checkpoints are critical in preventing autoimmunity, specific targeting, and destruction of healthy cells. Nevertheless, tumors can “seize” immune checkpoints, dampen T-cell reactivity, and evade immune eradication. ICIs can inhibit these “interactions” between tumors and T lymphocytes, enabling T-cell reactivation for the immune system to recognize and destroy cancer cells [33, 83]. Prostate cancers, characterized by MMRd, are rare, representing 12 months [96]. Median DOR had not been reached in the TMB-H group, while in the non-TMB-H group, it was 33.1 months. Median PFS and OS were 2.1 months and 11.7 months in the TMB-H group and 2.1 months and 12.8 months in the non-­ TMB-­H group, respectively. In this case, the FDA for the first time has approved a cancer treatment for an indication based on TMB, and the fourth approval is based on the presence of a biomarker rather than the primary site of origin [96]. The number of patients with prostate cancer in the prospective trials was limited, leading to pembrolizumab’s tissue-agnostic approval. However, considering treatment-refractory mCRPC, the KEYNOTE-199 study demonstrated new insights. The study consisted of three parallel cohorts: cohort 1 (PD-L1-positive status, 133 patients), cohort 2 (PD-L1-negative status, 65 patients), and cohort 3 (detectable bone metastases regardless of PD-L1 status, 59 patients). Mutations in MRR genes were determined by whole-exome sequencing of DNA isolated from formalin-fixed, paraffin-embedded tumor samples. Cohorts 1 and 2 showed ORR of 5% and 3%, respectively, while the median DOR was not reached in cohort 1 and 10.6 months in cohort 2. Moreover, disease control rate (DCR) was 10%, 9%, and 22% in all three cohorts, respectively, while DCR per Prostate Cancer Clinical Trials Working Group 3 (PCWG3)-modified RECIST were 13%, 18%, and 39%, respectively. Median radiographic PFS per PCWG3-modified RECIST was 2.1 months in cohort 1, 2.1 months in cohort 2, and 3.7 months in cohort 3, and median OS was 9.5  months, 7.9  months, and 14.1  months in all three cohorts, respectively. Across cohorts, 60% of patients experienced one or more TRAEs, including 15% with one or more grades 3–5 [97]. Hence, pembrolizumab monotherapy demonstrates effective antitumor activity and manageable safety in individuals with RECIST-measurable and bone-metastases mCRPC, but independent of the PD-1 status. These patients have previously undergone docetaxel chemotherapy and targeted endocrine therapy. The KEYNOTE-365 cohort B study included chemotherapy-­naive patients who experienced failure or were intolerant to at least

4 events are usually severe enough to warrant hospitalization, while Grade 5 events result in a fatal outcome (according to [94]).

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4  weeks of abiraterone or enzalutamide treatment for mCRPC and progressed within 6  months of screening. Therefore, patients received pembrolizumab, docetaxel, and prednisone. The study enrolled 104 treated patients (52 had measurable disease, and 24 with positive PD-L1 status), while 101 patients discontinued treatment, of which 81 were for disease progression. The observed ORR per RECIST v1.1 was 23%, and DCR was 54%, while ORR and DCR per PCWG3-­ modified RECIST v1.1 were 33% and 68% for patients with measurable disease. Median radiographic PFS and OS were 8.5 months and 20.2 months. Treatment-­ related adverse events occurred in 100 patients (96%), whereas grade 3–5 TRAEs occurred in 44% [51]. Hence, the combination of pembrolizumab with docetaxel and prednisone demonstrated antitumor activity in chemotherapy-naive mCRPC patients treated previously with abiraterone or enzalutamide. Moreover, PARPi can upregulate PD-L1 on the tumor cell surface, which could lead to immune activation of the tumor microenvironment and increased sensitivity to PD-1 inhibitors. Therefore, the addition of an anti-PD-1/PD-L1 immunotherapy to PARPi might enhance antitumor response. This was a rationale background for a clinical trial of combined treatment of pembrolizumab and olaparib. Yu et al. conducted a KEYNOTE-365 cohort A phase Ib/II study, which enrolled 102 treated patients (59 had measurable disease, and 29 with positive PD-L1 status) with molecularly unselected, docetaxel-pretreated mCRPC whose disease progressed within 6 months of screening [98]. Patients received pembrolizumab (200 mg intravenously every 3 weeks up to 35 cycles) for approximately 24 months and olaparib (400 mg capsules, first 40 patients enrolled, or 300 mg tablets orally twice daily). Patients received prior docetaxel, while 39% received prior cabazitaxel, as well as abiraterone and/or enzalutamide (92%). In a minimum of one testing method, Guardant360 assay and FoundationOne CDx analysis, 18 out of 102 patients were identified to have tumors carrying an HRR mutation. Among these, four patients exhibited a mutation in the BRCA gene, while no instances of MSI were observed. The confirmed ORR per RECIST v1.1 was 8.5% (for patients with measurable disease) and DCR was 26% (in all treated patients), while ORR and DCR per PCWG3-­ modified RECIST v1.1 were 12% and 36%, respectively. The median radiographic PFS in all 102 treated patients was 4.5 months, in the PD-L1-positive subgroup was 4.1 months, in the PD-L1-negative subgroup was 5.2 months, in patients with an HRR mutation was 6.5  months, and in patients with no HRR mutation was 4.5 months. In addition, the median OS was 14 months, while in the PD-L1-positive subgroup was 10  months, in the PD-L1-negative subgroup was 18  months, in patients with an HRR mutation was 8.9 months, and in patients with no HRR mutation was 17 months. Treatment-related adverse events occurred in 91% of patients, while grades 3–5 occurred in 48% of patients. The findings of the study suggested that the combination of pembrolizumab and olaparib demonstrated limited antitumor activity, independent of PD-L1 or HRR mutation status [98]. Another study of pembrolizumab and olaparib combination (Phase III KEYLYNK-010 Trial) was recently published. The trial enrolled 529 participants who were randomly assigned to pembrolizumab and olaparib and 264 participants to ARSI, abiraterone, or enzalutamide. Eligible participants had mCRPC that progressed after abiraterone or

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enzalutamide (but not both) and docetaxel treatment. The median radiographic PFS per PCWG3-modified RECIST v1.1 was 4.4  months in the pembrolizumab and olaparib group and 4.2 months in the ARSI group. Also, the median OS per PCWG3-­ modified RECIST v1.1 was 15.8 months and 14.6 months, respectively. ORR was higher with the combination of pembrolizumab and olaparib compared with ARSI (16.8% vs. 5.9%). Grade ≥ 3 TRAEs occurred in 34.6% and 9.0% of participants, respectively [99]. Although the pembrolizumab and olaparib combination demonstrated higher ORR, it did not significantly improve PFS or OS in comparison with ARSI within biomarker-unselected, heavily pretreated mCRPC patients. Considering pembrolizumab in combination with enzalutamide and ADT in mCRPC patients (phase III KEYNOTE-641 trial), it was discontinued after an interim analysis showed no improvement in radiographic PFS or OS [100]. Besides pembrolizumab, another anti-PD-1 drug, nivolumab, although in combination with ipilimumab, was explored in patients with mCRPC.  In the phase II CheckMate650 study, a combination of nivolumab and ipilimumab showed antitumor activity in chemotherapy-naive (cohort 1, asymptomatic/minimally symptomatic patients progressed after second-generation hormone therapy) and chemotherapy-experienced patients (cohort 2, progressed after cytotoxic chemotherapy), with early evidence of potential biomarkers of response [101]. Preliminary results showed ORR was 25% and 10%, with a median OS of 19.0 and 15.2 months and radiographic PFS of 5.5% and 3.8% in cohorts 1 and 2, respectively. However, in patients with TMB above and below the 50th percentile, the ORR was 50.0% vs. 5.3%, radiographic PFS was 7.4 vs. 2.4  months, and median OS was 19.0 vs. 10.1 months, respectively. In patients with HRR-positive and HRR-negative status, response rates were 50.0% and 22.6%, median radiographic PFS was 7.3 and 4.4 months, and median OS was not reached compared with 19 months. In patients with PD-L1 ≥ 1% and those with PD-L1 10%) adverse reactions in patients receiving 233Ra were nausea, diarrhea, vomiting, and peripheral edema [131]. Real-world evidence suggested that patients treated with 233Ra had OS between 8.2 and 29 months, a range that includes the median OS of 14.9 months reported in the ALSYMPCA trial [132]. In addition, it was indicated that 233Ra is safe and well tolerated in patients with mCRPC and importantly demonstrated a lack of rare TRAEs, e.g., second malignancies or cardiovascular events, which clinical trials would be underpowered to detect. Nonetheless, the effectiveness of 233Ra is constrained by its tendency to cause hematological toxicity, particularly among patients who have undergone extensive prior treatments [46]. Since 233Ra causes DNA damage through DSB, PARPi may increase the efficacy of radiation therapy [108]. Therefore, a phase I/II COMRADE study of a combination of olaparib and 233 Ra in patients with mCRPC and bone metastases is still in progress. Early clinical benefit was observed in phase I and will be further investigated in a phase II study [133]. 177 6.4.2  Lu-PSMA-617

The prostate-specific membrane antigen (PSMA) protein has been extensively studied in patients with prostate cancer. It has elevated expression in prostate cancer cells compared with normal epithelial cells, while its expression increases in the advanced stages of the disease, such as mCRPC. The PSMA is a transmembrane protein consisting of a small intracellular component, a transmembrane domain, and an extensive extracellular segment. Benign prostate cells, small intestine tissues, kidneys, and salivary glands express PSMA at lower levels than malignant prostate cancer cells [134]. Moreover, PSMA can be utilized for molecular imaging and targeted radiotherapy, which recently has become evident. PSMA PET imaging can be used to evaluate the expression of PSMA within tumors. This imaging technique provides detailed quantitative information about the uptake of PSMA, particularly when assisted by software tools. All the PSMA-targeted agents tested in clinical trials to date can be classified as small molecules or antibodies, which attach to the extracellular domain of PSMA.  The binding site for small molecules is distinct [135]. Beta emitters have a greater ability to traverse tissue distances and cause DNA damage through the release of electrons, compared with alpha particles. Lutetium-177 (177Lu)-PSMA-617 (or vipivotide tetraxetan) is a radioligand treatment that emits beta-particle radiation to PSMA-expressing cells and the

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surrounding microenvironment. This PSMA-specific radioligand has been approved for metastatic prostate cancer. In the study of Sartor et al. phase III VISION trial, 177 Lu-PSMA-617 and standard-of-care therapy showed prolonged radiographic PFS (8.7 vs. 3.4 months) and median OS (15.3 vs. 11.3 months) compared with control group (standard-of-care therapy) in patients with PSMA-positive mCRPC. The incidence of adverse events in grade 3 or higher was more frequent in the 177Lu-PSMA-617 group than in the control group. Fatigue, dry mouth, and nausea were the most common adverse events, and those were nearly all of grade 1 or 2. Based on the findings of this trial, 177Lu-PSMA-617 was FDA-approved in 2022 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with AR pathway inhibition and taxane-based chemotherapy [136]. However, many questions remain unanswered, such as the optimal dose and schedule of 177Lu-PSMA-617 infusions, the optimal criteria for patient selection, the efficacy in combination with other therapies, and the long-term safety. To address these questions, various phase II or III trials are being conducted. Among those, TheraP, a phase II trial is the only study that has been concluded. This study compared 177Lu-PSMA-617 monotherapy and cabazitaxel in patients with mCRPC and prior docetaxel treatment [41]. 177 Lu-PSMA-617 had a higher PSA response rate in comparison with cabazitaxel (66% vs. 37%). Therefore, 177Lu-PSMA-617 can be an effective treatment modality and a potential therapeutic alternative for this patient population. Besides 177Lu-PSMA-617, two other PSMA radioligand agents have been of great interest, 177Lu-PSMA I&T and 225Actinium-PSMA-617. According to Schuchardt et al. both 177Lu-PSMA I&T and 177Lu-PSMA-617 have adequate safety profiles in mCRPC patients. 177Lu-PSMA-617 demonstrated a higher absorbed dose to the whole body and lacrimal glands, but a lower in kidneys in comparison with 177 Lu-PSMA I&T.  The mean absorbed tumor doses were comparable for both 177 Lu-PSMA I&T and 177Lu-PSMA-617 (5.9 vs. 5.8  Gy/GBq) as well the doses absorbed by bone metastases (6.0 vs. 5.9 Gy/GBq) and lymph node metastases (7.1 vs. 6.9 Gy/GBq). Furthermore, personalized PSMA radioligand therapy appears to benefit from dosimetry tailored to each patient [137]. 225Actinium-PSMA-617 (Ac-PSMA) emits low-dose alpha radiation, which is highly cytotoxic and mainly generates DNA DSB [46]. It is expected that Ac-PSMA may be an option for patients who have progressed after 177Lu-PSMA-617 therapy. However, some safety issues should be addressed, such as hematological toxicity (anemia, leucopenia, and thrombocytopenia) and dry mouth [138].

6.5 Vascular Targeted Therapy Vascular targeted therapy focuses on targeting specific molecules, such as vascular endothelial VEGF and endothelin, which are produced by the endothelial cells of tumors. This treatment strategy aims to inhibit the processes of angiogenesis and tumor growth. VEGF is a regulatory cytokine with prominent expression in the majority of cancer cells, having a significant role in various aspects of

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tumorigenesis, including the function of cancer stem cells and tumor initiation. It is also generated by fibroblasts, as well as by endothelial and immune cells within the tumor microenvironment [139]. The significance of VEGF-A, an isoform of VEGF, in promoting angiogenesis and the progression of prostate cancer has been firmly established. Namely, elevated levels of VEGF-A have been linked to distant metastasis and a less favorable prognosis. Consequently, this led to the clinical exploration of several VEGF inhibitors, which have undergone testing as potential treatments for advanced prostate cancer [41]. A randomized, double-blind, placebo-­ controlled phase III clinical study, which enrolled 1050 patients with mCRPC, demonstrated comparable OS between patients who received docetaxel, prednisone, and bevacizumab and those who received only docetaxel and prednisone (22.6 vs. 21.5 months), while the median PFS was superior in the bevacizumab group (9.9 vs. 7.5  months) as was the proportion of patients with ORR (49.4% vs. 35.5%). Conversely, grade 3 or higher TRAEs were more common in the bevacizumab arm, as was the number of treatment-related deaths (4.0% vs. 1.2%). Therefore, the addition of bevacizumab to standard therapies would not produce any additional value for prostate cancer patients [140]. Similar scenarios have been observed with other molecules that target the VEGF-A pathway, such as aflibercept and sunitinib [41]. In a study involving patients with progressive mCRPC, participants were randomly divided into two groups. One group received a combination of VEGFR inhibitor cediranib and olaparib, while the other group received olaparib alone. It was suggested that cediranib combined with olaparib improved radiographic PFS compared with olaparib alone in the intention-to-treat population (8.5 vs. 4.0 months). Among patients with HRR-deficient mCRPC, a median radiographic PFS was 10.6 months and 3.8 months in the combination and monotherapy arms, respectively. BRCA2-­ mutated subgroups treated with olaparib with or without cediranib were associated with a longer median radiographic PFS (13.8 vs. 11.3 months). Notably, the combination arm had a higher incidence of grade 3–4 adverse events as compared with the monotherapy arm (61% vs. 18%) [141]. Preclinical models showed that cediranib suppresses HRR genes and increases PARPi sensitivity, which led to the design of this trial. According to Sorrentino and Di Carlo, clinical trials may not produce the desired response due to the redundancy of angiogenic pathways. Targeting only one pathway could result in the increased activation of compensatory pathways. However, these treatment modalities were associated with increased toxicity, regardless of their efficacy [41].

7 Future Perspectives of Precision Therapy in Prostate Cancer The management approach for mCRPC has undergone a significant paradigm shift in recent years. Novel therapeutic approaches have emerged, with a distinct spectrum of mechanisms, including ARSI, PARPi, immunotherapies, theranostics,

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notably 177Lu-PSMA-617, and more. Despite advancements, treating mCRPC requires innovative strategies for long-term response [73]. Beyond the AR pathway, targeting prostate cancer with alternative approaches has proven clinically valuable, stimulating the development of new therapeutics and the synergistic utilization of existing ones. A paramount focus should be on identifying predictive biomarkers, thus enabling personalized therapeutic regimens for individuals with mCRPC.  Therefore, targeted therapy development is likely to proceed in several directions, including the formulation of innovative targeted therapies based on the tumor vulnerabilities, such as driver mutations, and epigenetic changes, but also an understanding of how to accurately select patients who are most inclined to benefit from existing and novel treatments. For instance, pembrolizumab and PARPi do produce adequate responses in certain patients, but substantial research efforts are needed to increase the proportion of patients who could benefit from these treatments. Besides, combining existing and novel targeted therapies with conventional approaches, such as chemotherapy and ADT in an effective administration sequence, is one way to achieve that [41, 46, 100]. Also, there is a constant pursuit for identifying and validating alternative biomarkers, such as alternative checkpoints as potential therapeutic targets in prostate cancer. In this endeavor, the B7-H3 molecule, also known as PD-L3, seems to be a promising target in prostate cancer treatment. In comparison with PD-L1 and PD-L2, B7-H3 has frequent overexpression in CRPC compared with normal tissue and other B7 family members, which implicates it as a highly relevant therapeutic target in these diseases [100, 142]. Hence, enoblituzumab, a B7-H3 monoclonal antibody, was administered to patients with high-risk localized prostate cancer, whereas preliminary data suggest potential clinical activity and acceptable safety. The current study serves as a pivotal validation of B7-H3 as a viable and rational target for the development of therapeutic interventions in prostate cancer [143]. The PI3K/AKT and AR pathways are dysregulated in approximately 40–60% of patients with mCRPC, and AKT signaling is hyperactivated in tumors with functional PTEN-loss. PTEN (phosphatase and tensin homolog) is a tumor suppressor gene involved in the PI3K/AKT signaling pathway. Roughly 50% of castration-resistant prostate cancers contain inactivating mutations in PTEN, which serve as a poor prognostic biomarker. A selective ATP-competitive small molecule, such as ipatasertib may inhibit the three isoforms of AKT. Attempts to combine ipatasertib or capivasertib with ARSI in mCRPC patients with PTEN-loss tumors had some promising results at the beginning, but further investigation is needed [36, 144]. In addition, development of combination therapies to enhance effectiveness in patients without specific selection criteria is an imperative area of focus. Though ICIs have revolutionized the treatment of various malignancies, their potential in mCRPC remains partially untapped. While ICI monotherapy in clinical trials has yielded limited promise in mCRPC patients, ongoing studies exploring the combinations of immunotherapy and various treatment modalities, such as chemotherapy, or radiotherapy, are important within the context of managing prostate cancer. Consequently, a deeper exploration of the tumor microenvironment is warranted, pinpointing supplementary targets that enhance tumor sensitivity to ICIs. Exploring this avenue could increase the potential of radioligand therapies to sensitize

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immunologically “cold or low active” prostate tumors to ICIs [100, 145]. Considering targeted therapies and their effectiveness, their long-term use is questionable due to frequently occurring resistance. Therefore, the development of combined therapies could overcome drug resistance and improve clinical outcomes. DNA methylation and demethylation are promising targets under investigation. Namely, two DNA methyltransferase inhibitors, decitabine and azacytidine, are currently used in preclinical studies and clinical trials for the treatment of mCRPC and demonstrate anti-tumoral effects mostly due to gene expression reprogramming. The most favorable outcomes were achieved when these agents were integrated with standard therapy strategies, such as conventional ADT, docetaxel, radiation therapy, or other medications that target the epigenetic machinery [41]. The AKT inhibitor ipatasertib effectively restored sensitivity to antiandrogens in androgen-independent cells. Furthermore, when ipatasertib was combined with enzalutamide, it resulted in significant inhibition of tumor cell growth, demonstrating remarkable efficacy in both in vitro and in vivo settings [146]. In addition, IL-6 may have a significant role in radiation resistance in prostate cancer through the upregulation of DNA repair-­ associated molecules ATM, ATR, BRCA1, and BRCA2, which was demonstrated in a preclinical study. Therefore, potential targeting of IL-6 signaling and/or ATM, ATR, and BRCA1/2 can increase the radiation sensitivity of prostate cancer cells. However, clinical trials are needed to investigate this therapeutic option [147]. Indeed, theranostics and radioligands hold significant potential as dual-purpose agents for both diagnosis and therapy. Furthermore, there is a requirement for future research to focus on predictive biomarkers for PSMA-targeted radioligand therapy, the most effective timing and order of administering these agents, and the optimal utilization of highly sensitive diagnostic scans [46]. Further investigation will focus on the safety of 177Lu-PSMA-617 within double and triple therapies because trials testing their efficacy have been already in motion, for instance, PRINCE (combination of 177Lu-PSMA-617 and pembrolizumab) and EVOLUTION (combination of 177 Lu-PSMA-617 and ipilimumab and nivolumab) clinical trials. Also, there is an ongoing study (LuPARP), an early phase, investigating the combination of olaparib with 177Lu-PSMA-617  in patients with mCRPC who have received prior chemotherapy and ARSI [148]. Moreover, nanotechnology is positioned as a promising frontier in future therapeutic solutions, including prostate cancer patients. Nanoparticles may provide additional advantages such as improved drug delivery and treatment efficacy, as well as diminished side effects. The nanoparticles can be intricately designed to encapsulate molecular targeted drugs, which can be selectively accumulated within prostate tumors through conjugation with antibodies that specifically recognize tumor-associated markers, like PSMA [41, 149]. It is important to note that many targeted therapies, particularly in the field of prostate cancer, were approved by regulatory agencies around 6–7  years ago. Therefore, future research efforts should not solely focus on developing new therapeutics to improve antitumor effectiveness. It is equally important to thoroughly examine their long-term safety profiles. Small molecule targeted inhibitors will play a crucial role in oncology for the next decade. The advances in technology like non-­ invasive liquid biopsies will accelerate the development of targeted therapies. In

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addition, the ability to retrieve actionable information from molecular profiling and translate it into pharmacogenomics-guided dosing recommendations will make bioinformatics of utmost importance. In conclusion, pharmacogenomics explores genetic or genomic variations that may affect treatment outcomes whether altering pharmacokinetic processes or influencing the pharmacodynamics of a drug. This can involve modifying its intended target or impacting biological pathways that alter the sensitivity to the drug’s desired effects. In addition, in the field of oncology, pharmacogenomic biomarkers (either germline or somatic) can function as diagnostic, prognostic, and/or predictive tools. They can provide an early detection of cancer, estimate the course and severity of the disease, and predict how an individual may respond to treatment, including the effectiveness of drugs and possible side effects. Pharmacogenomics has a distinctive application in cases involving somatic genomic alterations specific to cancerous tissue, whereas these mutations can influence the selection of anticancer therapies and essentially provide practical guidance for treatment decisions in certain types of cancer. Although progress has been made in diagnosing and treating prostate cancer, mCRPC remains a persistent challenge due to its terminal prognosis. Despite immunotherapy’s relatively modest effectiveness in prostate cancer, the tissue-agnostic approval of pembrolizumab is a significant advancement for patients with MSI-H, MMRd, or TMB-H tumors. In addition, PARP inhibition has shown efficacy in patients with HRRd, but its effectiveness is comparatively reduced without patient-­ specific selection criteria. Despite potential discrepancies and limitations in data availability, PSMA-targeted treatments have emerged as a reliable, effective, and relatively safe therapeutic approach for managing mCRPC that has progressed beyond standard treatments or involves extensive bone marrow. Much is expected from combination therapies that include the mentioned agents and new targeted therapies based on the pharmacogenomics and molecular drivers behind metastatic prostate cancer. Pharmacogenomics and precision therapy, in general, will enable the appropriate selection of combined therapies aimed to achieve optimal therapeutic outcomes, characterized by improved survival rates within a broader patient population.

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117. Clarke N, Wiechno P, Alekseev B, Sala N, Jones R, Kocak I et al (2018) Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 19:975–986 118. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, Mototsugu O, Shore N, Loredo E et  al (2022) Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid 2022 1(9). https://doi.org/10.1056/EVIDoa2200043 119. Chi KN, Rathkopf D, Smith MR, Efstathiou E, Attard G, Olmos D et al (2023) Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol 41:3339–3351 120. Efstathiou E, Smith MR, Sandhu S, Attard G, Saad M, David Olmos D et al (2023) Niraparib (NIRA) with abiraterone acetate and prednisone (AAP) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations: second interim analysis (IA2) of MAGNITUDE.  J Clin Oncol 41(6_suppl):170–170 121. Agarwal N, Azad AA, Carles J, Fay AP, Matsubara N, Heinrich D et al (2023) Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet 402:291–303 122. Hussain M, Carducci MA, Slovin S, Cetnar J, Qian J, McKeegan EM et al (2014) Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer. Investig New Drugs 32:904–912 123. Hussain M, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S et al (2020) Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med 383:2345–2357 124. Taza F, Holler AE, Fu W, Wang H, Adra N, Albany C et al (2021) Differential activity of PARP inhibitors in BRCA1- versus BRCA2-altered metastatic castration-resistant prostate cancer. JCO Precis Oncol 5:PO.21.00070 125. Quigley D, Alumkal JJ, Wyatt AW, Kothari V, Foye A, Lloyd P et al (2017) Analysis of circulating cell-free DNA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors. Cancer Discov 7:999–1005 126. Gogola E, Duarte AA, de Ruiter JR, Wiegant WW, Schmid JA, de Bruijn R et  al (2018) Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality. Cancer Cell 33:1078–1093.e12 127. Henneman L, van Miltenburg MH, Michalak EM, Braumuller TM, Jaspers JE, Drenth AP et al (2015) Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-­ deficient metaplastic breast cancer. Proc Natl Acad Sci U S A 112:8409–8414 128. Noordermeer SM, van Attikum H (2019) PARP inhibitor resistance: a tug-of-war in BRCA-­ mutated cells. Trends Cell Biol 29:820–834 129. Cheever MA, Higano CS (2011) PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin Cancer Res 17:3520–3526 130. Sgouros G, Bodei L, McDevitt MR, Nedrow JR (2020) Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov 19:589–608 131. Kluetz PG, Pierce W, Maher VE, Zhang H, Tang S, Song P et  al (2014) Radium Ra 223 dichloride injection: U.S.  Food and Drug Administration drug approval summary. Clin Cancer Res 20:9–14 132. O’Sullivan JM, McKay RR, Rahbar K, Fizazi K, George DJ, Tombal B et al (2022) Real-­ world effectiveness, long-term safety and treatment pathway integration of radium-223 therapy in patients with metastatic castration-resistant prostate cancer. Front Med (Lausanne) 9:fmed-09-1070392 133. Pan E, Xie W, Ajmera A, Araneta A, Jamieson C, Folefac E et al (2023) A phase I study of combination Olaparib and Radium-223 in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases (COMRADE). Mol Cancer Ther 22:511–518 134. Lundmark F, Olanders G, Rinne SS, Abouzayed A, Orlova A, Rosenström U (2022) Design, synthesis, and evaluation of linker-optimised PSMA-targeting radioligands. Pharmaceutics 14:1098

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135. Sartor O, Baghian A (2022) Prostate specific membrane antigen binding radiopharmaceuticals: current data and new concepts. Front Med (Lausanne) 9:1060922 136. Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K et al (2021) Lutetium-177-­ PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med 385:1091–1103 137. Schuchardt C, Zhang J, Kulkarni HR, Chen X, Müller D, Baum RP (2022) Prostate-specific membrane antigen radioligand therapy using 177Lu-PSMA I&T and 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer: comparison of safety, biodistribution, and dosimetry. J Nucl Med 63:1199–1207 138. Feuerecker B, Tauber R, Knorr K, Heck M, Beheshti A, Seidl C et al (2021) Activity and adverse events of Actinium-225-PSMA-617 in advanced metastatic castration-resistant prostate cancer after failure of Lutetium-177-PSMA. Eur Urol 79:343–350 139. Goel HL, Mercurio AM (2013) VEGF targets the tumour cell. Nat Rev Cancer 13:871–882 140. Kelly WK, Halabi S, Carducci M, George D, Mahoney JF, Stadler WM et  al (2012) Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol 30:1534–1540 141. Kim JW, McKay RR, Radke MR, Zhao S, Taplin ME, Davis NB et al (2023) Randomized trial of Olaparib with or without Cediranib for metastatic castration-resistant prostate cancer: the results from National Cancer Institute 9984. J Clin Oncol 41:871–880 142. Guo C, Figueiredo I, Gurel B, Neeb A, Seed G, Crespo M et al (2023) B7-H3 as a therapeutic target in advanced prostate cancer. Eur Urol 83:224–238 143. Shenderov E, De Marzo AM, Lotan TL, Wang H, Chan S, Lim SJ et al (2023) Neoadjuvant enoblituzumab in localized prostate cancer: a single-arm, phase 2 trial. Nat Med 29:888–897 144. Hatano K, Nonomura N (2023) Systemic therapies for metastatic castration-resistant prostate cancer: an updated review. World J Mens Health. https://doi.org/10.5534/wjmh.220200 145. Bellavia MC, Patel RB, Anderson CJ (2022) Combined targeted radiopharmaceutical therapy and immune checkpoint blockade: from preclinical advances to the clinic. J Nucl Med 63:1636–1641 146. Adelaiye-Ogala R, Gryder BE, Nguyen YTM, Alilin AN, Grayson AR, Bajwa W et al (2020) Targeting the PI3K/AKT pathway overcomes enzalutamide resistance by inhibiting induction of the glucocorticoid receptor. Mol Cancer Ther 19:1436–1447 147. Chen X, Chen F, Ren Y, Weng G, Xu L, Xue X et al (2019) IL-6 signaling contributes to radioresistance of prostate cancer through key DNA repair-associated molecules ATM, ATR, and BRCA 1/2. J Cancer Res Clin Oncol 145:1471–1484 148. Jang A, Kendi AT, Sartor O (2023) Status of PSMA-targeted radioligand therapy in prostate cancer: current data and future trials. Ther Adv Med Oncol 15:17588359231157632 149. Zhao J, Zhang C, Wang W, Li C, Mu X, Hu K (2022) Current progress of nanomedicine for prostate cancer diagnosis and treatment. Biomed Pharmacother 155:113714

Chapter 18

Stereotactic Radiotherapy in the Treatment of Prostate Cancer Biljana Seha

Abstract  Stereotactic body radiotherapy (SBRT) is a technologically sophisticated form of radiotherapy and well-established treatment option for patients with a lowand intermediate-risk prostate cancer. Stereotactic body radiation therapy or radiotherapy (SBRT) and stereotactic ablative radiation therapy or radiotherapy (SABR) both describe an advanced form of radiation therapy that is used to treat many different types of cancer. The two terms are interchangeable which are usually conducted in one, three, or five fractions. SBRT can be used as therapy for radical treatment, or as a boost after IMRT (intensity-modulated radiation therapy) and IGRT—image-guided radiation therapy or conventional radiotherapy. It also can be used as boost therapy for patient with high-risk prostate. Keywords  Prostate cancer · Radiosurgery · SBRT · Linear accelerator

1 Introduction 1.1 History A pioneer of the stereotaxis development was Swedish neurosurgeon Lars Leksell. He is recognized as the father of radiosurgery as he formulates the term “radiosurgery” in 1951. He used radiotherapy in one fraction experiments on the brains of goats, cats, and rabbits using multiple cross-fired proton beams as he sought an optimum dose to produce discrete brain lesions of dimension. He found that a suitable maximum dose for the production of a discrete lesion within 1–2 weeks was 20 Gy in a single fraction. The first Gamma Knife procedure was performed in 1967. Lars Leksell (1907–1986) was a Swedish physician and Professor of Neurosurgery at the Karolinska Institute in Stockholm, Sweden. SRS was developed in the late 1980s B. Seha (*) University Clinical Center of Serbia, Clinic of Neurosurgery, Belgrade, Serbia © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 G. Kocic et al. (eds.), Prostate Cancer, https://doi.org/10.1007/978-3-031-51712-9_18

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due to historical development of computers; softer, radiological imaging; and development of liner accelerators, computed tomography, and magnetic resonance imaging. The use of SRS grew rapidly during the late 1980s and early 1990s. The Gamma Knife radiosurgery is used for both benign and malignant brain conditions. There are already more than 330 Gamma Knife centers around the world. SBRT developed about a decade later than SRS but was based on same principals. Both SRS and SBRT have their roots in the Karolinska Hospital, where radiation oncologist Henric Blomgren and physicist Ingmar Lax were employed. As they were very familiar with the brain SRS procedures being carried out in their institution, they reasoned that similar local control outcomes could be achieve at body sites with one or a few focally delivered fractions. Targeting and immobilization issues for non-brain sites were much more complicated (due to organ dynamics in body such as breathing, heartbeat, bowel movements, etc.). The technique was described in 1994 [3] and in 1995. The clinical outcomes were described in 31 patients with 42 malignant tumors of the liver, lung, or retroperitoneum, achieving local control in 80% of targets while prescribing at the 50% isodose surface [1–4]. Nowadays SBRT for prostate cancer is considered a standard of care option for any patient with low and intermediate risk and also patients with high-risk prostate cancer who are considering radiation therapy. In December 2000, the UCLA treated its first patient using contemporary prostate SBRT. Since then, a large amount of data and evidence have amassed demonstrating the safety and efficacy of SBRT for prostate cancer [5].

1.2 Terminology 1.2.1 SRS and SRT SRS stereotactic radiosurgery delivers a large dose of radiation on a single day, and SRT stereotactic radiotherapy has a fractionated treatment schedule in brain targets. 1.2.2 SBRT and SABRT Both stereotactic ablative radiation treatment (SABR) and stereotactic body radiation therapy (SBRT) refer to an advanced form of radiation therapy that is used to treat a variety of cancers. Both names can be used interchangeably.

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2 Immunology One of the key distinctions between SBRT and conventional radiation is that, whereas the former requires several weeks to complete, the latter can be done in just one or two sessions over the course of five or fewer sessions. Because it shapes and targets the radiation beams so precisely, SBRT reduces the collateral damage that radiotherapy usually does to surrounding healthy tissues. Usually SBRT is conducted in one, three, or five fractions. SBRT affects body immune system. There are indications that applying high dose of radiation causes disintegration of a significant number of malignant cells in SBRT (unlike conventional RT) that leads to massive release of tumor antigens, stimulating antitumor immunity. The term “abscopal effect” was coined about 70 years ago to describe the effect of radiation on disease located outside of the treatment field. Two decades ago, one of the first studies which identified that an abscopal effect may be caused by the immune-related sequels of ionizing was published, possibly leading to the response of previously untreated tumor sites elsewhere in the body [6]. Radiotherapy has its influence on changes in the tumor immune microenvironment. What is the tumor immune microenvironment (TIME)? Tumor immune microenvironment (TIME) accounts for tumor cells, inflammatory cells, immune cells, various signaling molecules, and extracellular matrix. It is of great importance to find out causes of failure of the treatment for the drug resistant tumors. By the remodeling of TIME can make a change from immunosuppressive phenotype cancer cell to immunostimulatory phenotype [7]. The effect of radiotherapy on cancer cells is direct DNA damage (breaking double-­chain structure of DNA) and endoplasmic reticulum (ER) stress which results to targeted cancer cell death. RT’s effects on the non-targeted and systemic have been identified [8]. Evidence of radiotherapy remodeling TIME exists in many new scientific researches. Initial immunosuppressive state of tumor after conduction of radiotherapy can be changed. There is substantial scientific evidence of beneficial effects of RT on the tumor response to immune therapy [9]. The immunomodulatory effects of radiation therapy are the stimulation of tumor-­ antigen release, the facilitation of antigen presentation, and the maturation and homing of T cells. Radiation can induce immunosuppressive changes in the tumor microenvironment (TME) through the induction of transforming growth factor beta (TGFβ), indolamine 2,3-dioxygenase (IDO), and PD-L1, which results in an increase in suppressive cells in the tumor .microenvironment, such as regulatory T cells (Tregs) and tumor-associated macrophages (TAMs). Delivery of highly potent ablative radiation doses, which stimulate expression of MHC class 1 molecules for enhanced tumor recognition, results in release of tumor damage-associated molecular patterns (DAMPs). DAMPs lead to maturation of dendritic cells, stimulation of cytotoxic T-cell activity via dendritic-cell antigen presentation, so it results with increased anti-tumor immunomodulation [10].

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Combination of SBRT and immunotherapy is the future in treating oncology patients. For radio-immunotherapy, there are strong evidence from preclinical work that radiotherapy and immunotherapy are synergistic, clinical reports detailing the interaction of radiotherapy and immunotherapy are limited and are currently under development [11].

3 Machine for SBRT Radiotherapy SBRT is performed on a linear accelerator, also referred to as LINAC, that aims radiation at cancer tumors with pinpoint accuracy, sparing nearby healthy tissue. It is used to deliver external beam radiation therapy. LINAC machines use X-rays, also known as photons, to treat tumors. Proton beam, also called charged particle can be used for SBRT. This newer type of stereotactic radiotherapy uses protons to treat tumors over several sessions. Proton beam radiotherapy might be used to treat tumors in parts of the body that have already had radiation therapy. Or they can treat tumors that are near vital organs. Different manufactures of machines for radiotherapy have different options for movement assessment and immobilization in prostate cancer. There is fusion of machines—MR Linac—fusion of MR and LINAC. Additionally, a new generation of radiation machines with visible controls has been introduced [12–14].

4 Indications for SBRT in Prostate Cancer SBRT can be used for treatment of prostate cancer and treatment of metastases caused by prostate cancer. Decision to treat patient with SBRT should be based on ECOG of patient, stage of diseases, aggressiveness of cancer—pathophysiology findings and Gleason score, PSA, and diagnostic findings—CT scan, MRI scan, scintigraphy, PSMA PET/CT, overall health of patient, and to respect patient’s preferences. Patients with low risk and favorable intermediate risk prostate cancer are candidates for SBRT. SBRT can be used as radical therapy, or as a boost after intensity-modulated radiation therapy (IMRT)) and IGRT—image-guided radiation therapy or conventional radiotherapy. It also can be used as boost therapy for patient with prostate cancer. Before considering patient for SBRT, the examination has to be performed per standard of care depending on risk group. The three main signs of a thorough anamnesis are pain in the bones, erectile dysfunction, and urine problems. For intermediate- and high-risk patients who are anticipating androgen deprivation, laboratory tests such as PSA, testosterone, and LFTs should be performed. Pathophysiology findings are based on TRUS-guided biopsy with prostate volume measurement. Bone scan or PSMA PET/CT sholud be perfomed for any of the following conditions: PSA >20 ng/ml; T2 stage tumors and PSA > 10 ng/ml; GS > 7 or T3 or T4

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stage tumors. Pelvic CT or MRI for T3 and T4 stages of the disease is mandatory, as assessment of lymph node involvement. Diagnostic imaging should be performed—pelvic CT scan and/or MRI scan.

4.1 Doses The radiotherapy regime with conventional fractions with daily dose 1.8–2 Gy, with total dose higher than 74  Gy, are beneficial in  local control of prostate cancer. However, SBRT for prostate cancer with its hypofractionation regime with small number of fractions (from 1 to 5 fractions) can increase the therapeutic response. The linear-quadratic (LQ) model is one of the tools in radiation biology and physics, which shows a simple relationship between cell survival and delivered dose. The main parameter in LQ model is α/β—the ratio of two parameters, which is a measure of the fractionation sensitivity of the cells. The α/β ratio is low for prostate adenocarcinoma. Prostate SBRT radical treatment regimens are usually delivered 7.25 Gy × 5 (most common) or 9.5 Gy × 4. Prostate SBRT boost treatment regimens are delivered after external radiotherapy 9.5 Gy × 2, 7 Gy × 3. Prostate post-RT salvage treatment regimens are delivered 6 Gy × 5. Single shoot—single fractioned radiotherapy as monotherapy with 19 or 20 Gy in single fraction, while waiting for results of presently ongoing randomized phase III trials comparing SBRT with other fractionation or treatment, if results turn to be positive, it may help to SBRT be considered as monotherapy in treatment of localized disease in prostate cancer [15–17]. Doses for bone metastases: • Limited disease in patients without prior radiation: • • • •

16–24 Gy in one fraction. Multi-segment disease without prior radiation: 20–27 Gy in 2–3 fractions. Multi-segment disease in previously irradiated field:

• 20–25 Gy in five fractions [18]. Liver metastases based on location and underlying liver function. • Peripheral: 23–30 Gy in 1 fraction, 27.5–60 Gy in 3–6 fractions. • Central: 40 Gy in five fractions. Abdominal and pelvic lymph node: 25–32.5 Gy in five fractions 45 Gy in three fractions. Adrenal metastases: 23 Gy in one fraction, 36 Gy in 3–5 fractions [19]. Peripheral lung metastases: 25–34 Gy × 1 fraction, 18 Gy × 3 fractions, 12 Gy × 4 fractions, 10 Gy × 5 fractions. Central lung metastases: 10 Gy × 5 fractions [20].

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4.2 Preforming In most radiotherapy centers in the world, the planning of SBRT radiotherapy starts TRUS-guided placement of at least three gold seed markers (2 at base, 1 at apex) at least 1 week prior to simulation. These “gold” seeds are about the size of a grain of rice and are placed in or around the tumor to show exactly where it is in the body to help with alignment during daily SBRT. Patient will be placed under general anesthesia for these procedures. These gold seeds remain in the prostate [21]. Varian, one of LINAC manufactures, has different types of tracking procedure during prostate radiotherapy. They have Calypso system which uses beacons. The same way that a global positioning system, or GPS, pinpoints the location of your car, the Calypso system can continuously locate the target during each radiation treatment—in effect, GPS for the body. Instead of gold markers this system uses beacon—transponders [22]. Simulation for SBRT: CT scan is performed in supine position with pelvic and leg immobilization, CT slices wide 1 or 2  mm, with full bladder of patient with application iv contrast. Fusion of prostate MRI performed on same day (if possible) with simulation CT scan. Fusion can also be done with PSMA PETCT. Image guidance on CyberKnife performed with real-time fiducial tracking using orthogonal kVx-ray fluoroscopy for intrafraction motion (preferred). Image guidance on Linac is performed with daily cone beam CT or helical tomo CT imaging. OAR—organs at risk—that need to be delineated in prostate cancer are the rectum, bladder, penile bulb, femoral heads, and urethra. Like any other therapy, SBRT is associated with the risk of side effects. In particular, SBRT can produce both early (acute) and delayed (late) damage to organs at risk (OARs); interest has grown in ways to reduce radiation-induced toxicity. Constrains for OAR in radiotherapy on safe dose limits are available in the literature for radiation oncologist and medical physicist. One of first publications in 2010 was Emami’s paper, the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) guidelines [23].

4.3 Technic of Radiotherapy Radiotherapy techniques include the following: 2D, 3D conformal, intensity-­ modulated radiotherapy (IMRT), and volumetric modulated arc therapy (VMAT). According to some authors, VMAT is considered as a type of IMRT (by some authors). VMAT does not have fixed radiotherapy fields like IMRT—during VMAT treatment machine—linear accelerator rotates around the target in the body. Machine sends X-ray beams shaped with MLC with defined energy (dose rates) toward the target using dynamic modulated arcs sparing healthy tissue—OAR as critical structure thanks to simultaneous motion of gantry [23].

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5 Toxicity The stereotactic radiotherapy of the prostate is well tolerating treatment with mostly grade 1–2 side effects most often presented as genitourinary (urinary frequency and urgency) and gastrointestinal symptoms (diarrhea and rectal discomfort). Grade 1 side effects do not require treatment and grade 2 side effects can be eliminated with medication such as corticosteroids. Toxicity greater than grade 2 is dependent on the radiation dose. The higher the dose, the more severe the side effects occur. Genitourinary side effects of grade 2 or higher are more likely to occur in patients that have large volumes of the prostate, that had previous urinary conditions, and that had trans-ureteral resection of the prostate. Wang et al. determined that grade 2 and higher toxicity is present 5% in 35 Gy in five fractions, while the same toxicity is present in 48% of patients if the dose is increased to 40 Gy in five fractions. Although the incidence of acute toxicity can be higher than in conventional radiotherapy, severe side effects, grade 3 or higher, are rare. The late side effects that can occur are stricture of the urethra, rectal ulcers, more frequents bowel movements, and erectile dysfunction. The frequency of erectile dysfunction is similar to other radiotherapy treatments [24].

6 Follow-Up After SBRT of the prostate, either as a radical treatment, or as a boost after conventional radiotherapy, follow-up of the patients is mandatory either by urologist or radiation oncologist. For the first 5 years the follow-up is every 3–6 months with PSA, MRI of the pelvis and bone scans. After 5 years follow-up is done once a year with the same imaging and blood tests. Complete principles of active surveillance and observation are documented NCCN Guidelines Version 4.2023 Prostate Cancer.

7 Efficacy of SBRT Stereotactic body radiotherapy (SBRT) is a technologically sophisticated form of radiotherapy and an established method for patients with a low and intermediate risk prostate cancer. There have been several phase I–II trials, prospective reports, and single institution retrospective studies; the largest study comes from a pooled analysis of 1100 patients that were treated with 35–40 Gy in 5 fractions. They concluded that 5-year freedom from biological failure (FFBF) was 95.2% in low-risk patients, 84.1% in intermediate-risk patients, and 81.2% in high-risk patients. As the results of the study demonstrate that the prostate SBRT is highly effective treatment for low-risk

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prostate cancer (FFBF 90–100%), and the efficiency in patients with high risk is suboptimal. Unfortunately, there are no phase III trials that compare outcomes of patients with prostate cancer treated with SBRT with those receiving conventional therapy treatment. Since the radiobiology of prostate cancer is characterized with a low α/β ratio (1.4–1.5), the total prescribed dose of 30–40 Gy is equivalent to biological 2  Gy dose of 85–93  Gy, which is more than the conventional dose with IMRT technique. Prostate SBRT appears to be overall well tolerated, with determinants of toxicity that include dosimetric factors and patient factors. Suggested dose constraints include bladder V(Rx dose) Gy