Management of Castrate Resistant Prostate Cancer—Recent Advances and Optimal Sequence of Treatments

Until 2010, chemotherapy with docetaxel was the only approved agent for treatment of metastatic castrate resistant prostate cancer (mCRPC). Since then, the therapeutic landscape of mCRPC has changed rapidly. Multiple novel agents have received regulatory approval after demonstrating improved overall survival in separate randomized Phase 3 studies. These include immunotherapeutic agent sipuleucel-T, androgen axis inhibitors abiraterone and enzalutamide, and a novel microtubule inhibitor cabazitaxel. More recently, radium-223, a bone-targeting alpha emitting radiopharmaceutical, was reported to improve skeletal related events, as well as overall survival in a Phase 3 randomized study. Additionally, there are several promising agents in the advanced stages of clinical development. Here, we describe the agents recently shown to improve overall survival, and those that have reached the advanced stages of development in Phase 3 clinical trials. We will also propose a strategy for optimal sequencing of these agents in the treatment of mCRPC.     

Finding the optimal treatment sequence in metastatic castration-resistant prostate cancer—a narrative review

Over the last two decades, there has been significant progress in the treatment of metastatic prostate cancer. Multiple treatments with diverse mechanisms of action have improved clinical outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC) including taxane chemotherapy, immunotherapy, potent androgen receptor pathway inhibitors (ARPI), and radiopharmaceuticals (radium-223). As these treatments have entered standard clinical practise, clinicians have been challenged on how to optimally select and sequence them as the landmark studies establishing their efficacy had control arms with placebo or minimally effective therapy and there is a paucity of prospective trials examining treatment sequencing. More recently, the situation has been further complicated as the earlier up-front use of docetaxel and ARPI with standard gonadal testosterone inhibition has been shown to impart substantial improvements in disease control and survival for patients with castration sensitive prostate cancer. As new therapies enter into clinical practise such as the inhibitors of Poly (ADP-Ribose) Polymerase and Prostate Specific Membrane Antigen (PSMA)-targeted therapy, how to optimally select and sequence available treatments will be a continued dilemma in the absence of validated predictive biomarkers. This review will summarize the literature supporting the use of each active agent in mCRPC. We will propose a framework which will guide the selection of appropriate agents based on prior therapies, disease characteristics and biomarkers.     

Radio-223 en la secuencia terapéutica del cáncer de próstata resistente a la castración metastásico

Context

Radium-223 is an □ -particle transmitter with specific action on bone metastases. The Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) study showed that radium-223 extended overall survival and delayed the onset of bone events in patients with symptomatic castration-resistant prostate cancer with bone metastases (mCRPC) and without visceral metastases, with a good safety profile.

Radio-223 en el tratamiento del cáncer de próstata resistente a la castración metastásico: una ventana de oportunidad

Context

The elimination of bone metastases, restoration and/or preservation of bone morphology and prevention and/or delay of skeletal events are a fundamental objective in the management of metastatic castration-resistant prostate cancer (mCRPC). Radium-223 is the first targeted alpha therapy with effects on bone that has been shown to increase survival in these patients, besides providing other bone-related benefits.

Treatment sequencing in metastatic castrate-resistant prostate cancer

Six different treatments have demonstrated improved survival in phase III trials targeted to patients with metastatic castration-resistant prostate cancer （mCRPC）. Front-line therapeutic options for mCRPC include docetaxel, sipuleuceI-T, abiraterone and radium-223. Post-docetaxel options include cabazitaxel, abiraterone, enzalutamide and radium-223. Despite much progress in recent years, much is yet unknown and debates occur over optimal treatment choices and sequences. None of the new agents have been compared to one another, thus physicians in practice today must make choices based on non-randomized comparisons, toxicity considerations and various assumptions. Abiraterone is now moving into the front line mCRPC space given recent regulatory approvals and enzalutamide will follow soon. Both of the hormonal agents have less toxicity when compared to chemotherapeutic options and both of these hormonal agents are expected to be used in a considerable number of mCRPC patients in the years ahead. Little data are available for the post-abiraterone or post-enzalutamide setting. In this review the currently available sequencing data are summarized and interpreted. It is now clear that cross resistance is a potential issue between various treatments, especially those agents that target the androgen axis. This review highlights the need for additional studies to optimize the current treatments for these patients.     

Real-world use of systemic therapies in men with metastatic castration resistant prostate cancer (mCRPC) in Canada

BackgroundManagement of advanced prostate cancer has evolved rapidly with the availability of multiple systemic treatments such as androgen-receptor axis-targeted therapies (ARATs), taxane-based chemotherapy, radium-223, and other approaches. However, limited data exists on real-world treatment selection and clinical outcomes. This study examines the utilization and survival impact of these therapies in men with metastatic castration-resistant prostate cancer (mCRPC) in the real-world setting of Ontario, Canada.MethodsThis study was a retrospective, longitudinal, population-based study of administrative claims data between January 2016 and April 2020. Men ≥ 66 years with mCRPC receiving advanced treatment were included. Patients were indexed on the day they initiated mCRPC treatment and followed up until death or end of study period to assess treatment and survival. Multinomial regression was used to model the association between baseline covariates, treatment and survival.ResultsMedian age was 75 years among the 944 mCRPC patients who received life-prolonging therapies during this time period. Over 90% of patients used an ARAT as a first-line therapy, and 71.5% received only first-line therapy before death or censoring. Of patients that received two or more lines, over 80% received subsequent therapy with a different mechanism of action. Median overall survival was 18.9 months.ConclusionsARATs have become the predominant first-line systemic treatment option for mCRPC patients in recent years. Notably, the majority of patients received only a single line of life-prolonging therapy after developing mCRPC. In keeping with the recognized efficacy-effectiveness gap, real-world outcomes in this cohort appear poorer than in clinical trials.     

UnCHAARTED territory: The role of docetaxel rechallenge following chemohormonal therapy for metastatic castration-sensitive prostate cancer

ObjectiveTo assess the effectiveness of docetaxel rechallenge (DR) for metastatic castration-resistant prostate cancer (mCRPC) following chemohormonal therapy for metastatic castrate-sensitive prostate cancer (mCSPC). Additionally, we sought to define clinical factors predicting treatment response.Patients and MethodsRetrospective analysis of men treated with docetaxel for mCSPC and then rechallenged in the mCRPC setting from four cancer centers in Ontario, Canada. Prostate specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) following DR were evaluated.ResultsFifty five patients were identified between 2015 and 2020. Prior to DR, 94.5% of patients received androgen-receptor axis targeted therapy, 20% received radium-223, and 1.8% received cabazitaxel. Among 54 evaluable patients, 27.8% had a PSA decline ≥50%. Median PFS was 4.1 months (95% CI, 2.1?4.8) and median OS from androgen deprivation therapy initiation was 38.3 months (95% CI, 32.9?41.0). A Gleason Score of ≥8 was an independent predictor of prolonged PFS (HR 0.32, 95% CI, 0.12?0.81; P=0.02).ConclusionsDR following chemohormonal therapy for mCSPC produced a meaningful PSA response in approximately one-quarter of patients, with relatively short PFS. The impact of Gleason Score on docetaxel response warrants further investigation.     

Effects of six-cycle completion and earlier use of radium-223 therapy on prognosis for metastatic castration-resistant prostate cancer: A real-world multicenter retrospective study

ObjectivesTo evaluate the effect of 6-cycle completion and earlier use of radium-233 dichloride (Ra223) on the prognosis of patients with metastatic castration-resistant prostate cancer (mCRPC).MethodsWe retrospectively evaluated 75 patients with bone metastases-predominant mCRPC who were treated with Ra223 between August 2016 and August 2021. The primary purpose of the study was to assess the effect of Ra223 completion (6 cycles) on patient prognosis, and the secondary purpose was to investigate factors associated with Ra223 incompletion (fewer than 6 cycles) and overall survival.ResultsThe median age of the patients was 72 years. The median number of Ra223 administrations was 6 (interquartile range, 5–6), and the median Ra223 completion rate was 75%. The median time from mCRPC diagnosis to Ra223 administration was 17 months, and the median number of prior treatments was 2. Multivariable analysis indicated that unfavorable performance status (>0), prostate-specific antigen (PSA) level >10 ng/ml, extension of bone metastasis score 3 to 4, and Ra223 incompletion were significantly associated with poor overall survival. In addition, EOD 3 to 4 and 3 or more prior CRPC treatments were significantly associated with Ra223 incompletion.ConclusionSix-cycle completion and earlier administration of Ra233 are potentially associated with favorable survival. Unfavorable factors (EOD 3–4 and ≥3 prior treatments) were significantly associated with Ra223 incompletion.     

Treatment options in castration-resistant prostate cancer: Current therapies and emerging docetaxel-based regimens

BackgroundDocetaxel-based chemotherapy remains the standard of care for metastatic castration-resistant prostate cancer (mCRPC) and it is the only globally approved first-line therapy. Although docetaxel offers improved survival for this patient population, it is also associated with toxicity and resistance in many patients, representing a need for more efficacious therapies. Preclinical advances have led to improved understanding of the molecular biology of prostate cancer, and targeted therapies that exploit the signaling pathways and molecular targets that underscore the disease are being clinically investigated in combination with docetaxel.DesignThis article briefly highlights recent data from phase III trials in mCRPC that have led to agent approval. This article also reviews phase II and III trials in which docetaxel-based regimens have been investigated in mCRPC.ResultsRecently approved agents, including sipuleucel-T, cabazitaxel, abiraterone acetate, and enzalutamide, have diversified the mCRPC treatment landscape. Phase III trials evaluating docetaxel in combination with targeted therapies, including potent oral tyrosine kinase inhibitor, dasatinib, in the READY trial and clusterin inhibitor, custirsen, in the SYNERGY trial, are currently ongoing.ConclusionsIn combination with docetaxel, targeted agents dasatinib and custirsen will likely expand the existing treatment paradigm for mCRPC if results from phase III trials are positive.     

Castration-Resistant Prostate Cancer: From New Pathophysiology to New Treatment

ContextUntil recently, the only approved agent for metastatic castration-resistant prostate cancer (mCRPC) was docetaxel chemotherapy. But over the last 5 years, significant advances in the field have led to the approval of five new agents, each with different mechanisms of action and demonstrating improved overall survival in separate randomized phase 3 trials. Many of these novel agents are now also being evaluated in earlier stages of the disease, which may ultimately lead to even better outcomes.ObjectiveTo summarize the current literature on the management of mCRPC with a particular focus on novel chemotherapy approaches, hormonal approaches, immunotherapy, and radiopharmaceuticals showing survival benefits in phase 3 clinical trials. Emerging therapies in late stages of development are also discussed briefly.Evidence acquisitionA comprehensive search of PubMed, identified studies pertaining to novel therapies evaluated in mCRPC since the initial approval of docetaxel in 2004. Abstracts from major international meetings were hand searched to identify studies of novel agents in late stage development in mCRPC. The Clinical Trials.gov database was used to find ongoing clinical trials in the area of mCRPC. A detailed search of each new agent was also performed to ensure that additional trials of these agents in other stages of the disease were included where relevant.Evidence synthesisThe main agents discussed are the androgen synthesis inhibitor abiraterone acetate, the androgen receptor inhibitor enzalutamide, the novel taxane chemotherapy cabazitaxel, the immunotherapy sipuleucel-T, and the radiopharmaceutical radium 223. Other emerging agents and a brief discussion of negative phase 3 results are also included.ConclusionsIt is a very exciting time in the field of mCRPC, where therapeutic advances have improved outcomes in this disease, although once metastatic overall median survival remains a dismal 2–3 years. The key now will be to understand how best to use these new agents, understand the mechanisms of resistance to them, continue to develop novel treatment strategies, and ultimately test these agents earlier in the disease when cure may be possible.     

The role of sipuleucel-T in therapy for castration-resistant prostate cancer: a critical analysis of the literature

Context

Sipuleucel-T, an autologous antigen-presenting cell vaccine loaded with prostate acid phosphatase conjugated with granulocyte-macrophage colony-stimulating factor (GM-CSF), yielded a survival advantage in men with metastatic castration-resistant prostate cancer (mCRPC).

Objective

Critically analyze the role of sipuleucel-T in therapy for mCRPC.

Evidence acquisition

A systematic review of the literature was performed in June 2011 using Medline and an abstract search of major cancer conferences. The search strategy included the terms sipuleucel-T, APC-8015, castration-resistant, prostate cancer, and immunotherapy.

Evidence synthesis

The era of targeted immunotherapy was initiated with the regulatory approval in 2010 of sipuleucel-T for asymptomatic and minimally symptomatic mCRPC. The median survival was prolonged by 4.1 mo (25.8 vs 21.7 mo; hazard ratio: 0.78; 95% confidence interval, 0.61–0.98; p = 0.03), coupled with an improvement in 3-yr survival (31.7% vs 23.0%). Outcomes were characterized by the lack of tumor regression or delay in progression. Further development is proceeding in earlier stages of prostate cancer and in the context of a host of emerging agents.

Conclusions

The addition of sipuleucel-T, an immunotherapeutic agent, to the armamentarium represents a paradigm shift in therapy for mCRPC. The rational combination and proper sequencing of sipuleucel-T with other newly approved agents (abiraterone acetate, cabazitaxel) and emerging agents (MDV3100, TAK-700, ipilimumab) will be important to evaluate.     

血管生成抑制剂在去势抵抗性前列腺癌治疗中的新发现

近年来,去势抵抗性前列腺癌的治疗方法已由传统的抗雄激素及化疗提升到新的雄激素受体信号抑制剂、新一代紫杉醇及免疫疗法阶段。卡巴他赛、恩杂鲁胺、阿比特龙,放射性同位素镭223和sipuleucel-T随机临床试验显示能延长去势抵抗性前列腺癌患者生存期。然而,最终出现肿瘤抵抗也是难免的,去势抵抗性前列腺癌仍是一种主要临床负担,迫切需求新的治疗方法进一步改善CRPC患者生存期及生活质量。新生血管在前列腺癌的形成和进程中发挥至关重要的作用。部分临床试验显示,对失去手术和内分泌治疗时机的去势抵抗性前列腺癌,抗新生血管形成的靶向治疗是一种有效的补充疗法。本文将综述血管生成抑制剂在去势抵抗性前列腺癌治疗中的新发现。     

Current clinical challenges in prostate cancer

Prostate cancer is the most common malignancy and the second leading cause of cancer death in men in the United States. Close to $12 billion are spent annually on the treatment of prostate cancer in the US alone. Yet still there remain tremendous controversies and challenges that exist in all facets of the disease. This review and discussion will focus on issues and challenges for clinicians and patients diagnosed with the disease.Appropriate risk stratification for men with newly diagnosed prostate cancer is an appropriate first step for all patients. Once risk-stratified, for those with low-risk of death, it is increasingly recognized that overtreatment creates an unnecessary burden for many patients. This is particularly evident when put in the context of competing comorbidities in an elderly population. For those with advanced or high-risk localized disease, under-treatment remains too common. For those with a high-risk of recurrence or failure following primary treatment, adjuvant or salvage therapies are an option, but how and when to best deploy these treatments are controversial.Recently, tremendous progress has been made for those with advanced disease, in particular those with metastatic castrate-resistant prostate cancer (mCRPC). Within the last 4 years, five novel FDA approved agents, acting through distinct mechanisms have been FDA approved for mCRPC. With the introduction of these new agents a host of new challenges have arisen. Timing, sequencing and combinations of these novel agents are welcomed challenges when compared with the lack of available therapies just a few years ago.In this summary of current clinical challenges in prostate cancer we review critical recent studies that have created or shifted the current paradigms of treatment for prostate cancer. We will also highlight ongoing issues that continue to challenge our field.     

Efficacy Against Human Prostate Cancer by Prostate-specific Membrane Antigen-specific,Transforming Growth Factor-β Insensitive Genetically Targeted CD8+ T-cells Derived from Patients with Metastatic Castrate-resistant Disease

Current immunotherapy has limited efficacy on metastatic castrate-resistant prostate cancer (mCRPC). We therefore sought to improve the antitumor ability of mCRPC patient-derived CD8⁺ T-cells by the endowment of specificity to prostate-specific membrane antigen (PSMA) and insensitivity to immunosuppressant molecule transforming growth factor-β (TGF-ß) under the control of herpes simplex virus-1 thymidine kinase. CD8⁺ T-cells were collected by leukapheresis and cultured in a Food and Drug Administration-approved Cell Processing Work Station. We developed a chimeric antigen receptor retroviral construct using an anti-PSMA chimeric immunoglobulin-T-cell receptor(ζ) gene (PZ1) and dominant negative TGF-ß type II receptor (TßRIIDN), that could induce CD8⁺ T-cells to be PSMA reactive and insensitive to TGF-ß. Cr⁵¹ release assay was performed on PC-3 and PC-3-PSMA. The further antitumor functions of PSMA-specific, TGF-ß insensitive CD8⁺ T-cells was evaluated using an immunodeficient RAG-1^–/– mouse model. We found PSMA-specific, TGF-ß insensitive CD8⁺ T-cells from mCRPC were expanded with strong expression of PZ1 and thymidine kinase genes, and their growth was not suppressed by TGF-ß. The survival of these cells decreased sharply after treatment with ganciclovir. Treatment of PSMA-specific TGF-ß, insensitive CD8⁺ T-cells was associated with 61.58% specific lysis on PC-3-PSMA, and significantly suppressed PC3-PSMA tumor compared with the PC3 tumor. A large amount of tumor apoptosis and CD8⁺ T-cell infiltration were found only in the PC3-PSMA tumor. This study verified that PSMA-specific, TGF-ß insensitive CD8⁺ T-cells derived from mCRPC patients could be successfully expanded and used to overcome the immunosuppressive effects of the tumor microenvironment to control PSMA-expressing PC in vitro and in vivo. This may provide a promising approach for men with mCRPC who fail androgen deprivation therapy.

Novel molecular targets for the therapy of castration-resistant prostate cancer

Context

Improved understanding of mechanisms underlying metastatic castration-resistant prostate cancer (mCRPC) progression has led to the recognition of multiple molecular targets and advances in the therapeutic landscape. The addition of abiraterone acetate, sipuleucel-T, cabazitaxel, and denosumab to the therapeutic armamentarium and the impending addition of MDV-3100 and radium-223 underscore the importance of androgen pathway inhibition, immunotherapy, tubulin antagonism, and pathophysiology of bone metastasis.

Objective

Review the next generation of molecular targets in mCRPC.

Evidence acquisition

Medline databases were searched for >100 original articles published as of October 18, 2011, with the search terms metastatic castration-resistant prostate cancer, targeted therapy, biologic agents, and immunotherapy. Proceedings from the last 5 yr of conferences of the American Society of Clinical Oncology, American Urological Association, European Society of Medical Oncology, and the European Association of Urology were also searched. We included novel and promising drugs that have reached clinical trial evaluation.

Evidence synthesis

The major findings were addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed.

Conclusions

mCRPC is a disease with multiple molecular drivers. Molecular pathways being targeted in ongoing phase 3 trials are androgen signaling (MDV3100, TAK700), immunoregulatory pathways (ipilimumab, Prostvac-VF-TRICOM), Src (dasatinib), Met (cabozantinib), clusterin (custirsen), and angiogenesis (aflibercept, tasquinimod). The strides made in identifying multiple other novel molecular targets offer potential opportunities for further improving outcomes.     

Current and emerging treatment modalities for metastatic castration-resistant prostate cancer

Docetaxel-based therapy is established as the standard first-line chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC), based on results from two landmark Phase III studies. However, prognosis remains poor, with a median survival of less than 2 years. There is no standard of care for patients who progress during or after docetaxel treatment, which represents a real unmet medical need. Several small retrospective studies suggest that patients with mCRPC who responded to first-line docetaxel-based therapy are sensitive to re-treatment, but a survival benefit in prospective randomized trials has not been demonstrated. Epithelial-stromal interactions in the tumour microenvironment appear to play a central role in prostate cancer progression and response to therapy. Recent insights into the molecular mechanisms that underpin prostate cancer progression have allowed the identification of potential therapeutic targets. New agents, including angiogenesis inhibitors, hormone therapies, chemotherapies, bone targeting agents, vaccines and immunotherapies are currently undergoing clinical development in advanced prostate cancer using docetaxel as a backbone. Several Phase III studies have now been completed. Sipuleucel-T prolonged survival compared with placebo in asymptomatic or minimally symptomatic patients with mCRPC. Cabazitaxel plus prednisone prolonged survival in patients with mCRPC who progressed during or after docetaxel-based therapy compared with the active agent mitoxantrone, plus prednisone. Multidisciplinary management and optimization of the role and timing of new agents in this evolving treatment continuum will be critical to maximizing patient outcomes. Identification of predictive markers and better gene expression profiling will be critical to tailoring therapies to individual patients and disease states, whereas validated surrogate markers of overall survival will help accelerate drug approval.     

Practical aspects of metastatic castration-resistant prostate cancer management: patient case studies

Interactive case studies formed a key feature of the third annual Interactive Genitourinary Cancer Conference held in April/May 2011 in Budapest, Hungary. These cases were used to discuss the practical aspects of the management of metastatic castration-resistant prostate cancer (mCRPC). Particular emphasis was placed on audience participation with potential management options posed as interactive questions to the delegates. This paper summarises these case studies and the related discussion. Docetaxel is the standard first-line chemotherapeutic agent for patients with mCRPC and, until recently, second-line therapeutic options were limited. Results from the recently completed TROPIC trial showed a statistically and clinically significant improvement in overall survival with the microtubule inhibitor cabazitaxel compared with mitoxantrone. Cabazitaxel has been shown to be well tolerated and has been approved in Europe and the USA as second-line chemotherapy for mCRPC. Prognostic factors have a potential benefit in individualised patient management in mCRPC. Pretreatment prognostic factors, including PSA doubling time, pain, visceral metastases, anaemia and progression of osseous metastases, have been shown to predict survival outcomes and can be used to guide treatment strategies, including appropriate timing of chemotherapy. Multiple treatment options and significant heterogeneity among patients with advanced prostate cancer necessitate multidisciplinary team management in addition to patient education, as part of a patient-centred approach. The development of second-line chemotherapeutic agents together with the use of prognostic factors and a patient-centred multidisciplinary team approach provide encouraging new management prospects for patients with mCRPC.     

Metastasiertes kastrationsresistentes Prostatakarzinom

Therapies currently available in Germany for metastatic castration-resistant prostate cancer (mCRPC) include docetaxel, cabazitaxel, abiraterone acetate, enzalutamide and radium-223, all of which offer a potential survival benefit that adds up in their sequential application to a significant overall survival benefit. However, the optimal sequencing of these agents is still unclear. In the absence of evidence, treatment selection is based on the particular situation and on comorbid conditions of each individual patient. Furthermore, predictive markers to facilitate the selection of patients for a specific therapy or sequence of therapies remain an unmet need. However, with the recently discovered androgen receptor splice variant V7, which mediates (cross)resistance to or between abiraterone and enzalutamide, the first such marker has been identified. It is critical to monitor the response to treatments at prespecified intervals in order to optimize treatment sequencing so that the patient does not miss a valuable therapeutic window to receive alternative treatment that may prolong his life along with good symptom control and preservation of quality of life.     

Enzalutamide: targeting the androgen signalling pathway in metastatic castration‐resistant prostate cancer

Significant progress has been made in the understanding of the underlying cancer biology of castration‐resistant prostate cancer (CRPC) with the androgen receptor (AR) signalling pathway remaining implicated throughout the prostate cancer disease continuum. Reactivation of the AR signalling pathway is considered to be a key driver of CRPC progression and, as such, the AR is a logical target for therapy in CRPC. The objective of this review was to understand the importance of AR signalling in the treatment of patients with metastatic CRPC (mCRPC) and to discuss the clinical benefits associated with inhibition of the AR signalling pathway. A search was conducted to identify articles relating to the role of AR signalling in CRPC and therapies that inhibit the AR signalling pathway. Current understanding of prostate cancer has identified the AR signalling pathway as a logical target for the treatment of CRPC. Available therapies that inhibit the AR signalling pathway include AR blockers, androgen biosynthesis inhibitors, and AR signalling inhibitors. Enzalutamide, the first approved AR signalling inhibitor, has a novel mode of action targeting AR signalling at three key stages. The direct mode of action of enzalutamide has been shown to translate into clinical responses in patients with mCRPC. In conclusion, the targeting of the AR signalling pathway in patients with mCRPC results in numerous clinical benefits. As the number of treatment options increase, more trials evaluating the sequencing and combination of treatments are required. This review highlights the continued importance of targeting a key driver in the progression of CRPC, AR signalling, and the clinical benefits associated with inhibition of the AR signalling pathway in the treatment of patients with CRPC.     

Genomic Testing in Patients with Metastatic Castration-resistant Prostate Cancer: A Pragmatic Guide for Clinicians

ContextGenomic testing is becoming increasingly important in patients with advanced prostate cancer (PC) and is being incorporated in clinical practice to guide treatment.ObjectiveTo review the current understanding of genomic alterations and the status of genomic testing in patients with metastatic castration-resistant PC (mCRPC), and the potential use of genomic tests in clinical practice.Evidence acquisitionWe reviewed recent publications (past 15 yr) from PubMed, proceedings of scientific conferences, and published guidelines. Reports on mCRPC in the following areas were selected: development, testing, and validation of techniques for identifying genomic alterations; molecular characterization; and trials of genetically targeted therapies.Evidence synthesismCRPC tumors harbor molecular alterations that are possible targets for treatment, and a number of therapies are in development to exploit these alterations (eg, PD-1 inhibitors, PARP inhibitors, tyrosine kinase inhibitors). Next-generation sequencing of DNA from tumor tissue can identify somatic alterations that would not be identified by germline testing. Work is ongoing to evaluate the use of less invasive somatic testing methods (eg, sequencing of cell-free circulating tumor DNA). Current international guidelines recommend germline and/or somatic testing for men with advanced and/or high-risk PC regardless of family history to identify those with homologous recombination repair gene mutations or mismatch repair defects/microsatellite instability who may be eligible for treatment with a PARP inhibitor or pembrolizumab, respectively.ConclusionsGenomic testing for mCRPC may provide information on prognostic, predictive, and resistance biomarkers. Although the incorporation of testing into clinical practice remains challenging, routine genomic testing of men with advanced PC is recommended to guide management and treatment decisions.Patient summarySimilar to many cancers, prostate cancer is caused by defects in the cancer’s DNA, which are called genetic or genomic defects. New treatments targeting these defects are approved for metastatic castration-resistant prostate cancer. Specific new tests are under development to detect these potentially treatable genetic defects.