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Background and Objective: Innovations have improved outcomes in advanced prostate cancer (PC). Nonetheless, we continue to lack high-level evidence on a variety of topics that greatly impact daily practice. The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) surveyed experts on key questions in clinical management in order to supplement evidence-based guidelines. Here we present voting results for questions from APCCC 2024., Methods: Before the conference, a panel of 120 international PC experts used a modified Delphi process to develop 183 multiple-choice consensus questions on eight different topics. Before the conference, these questions were administered via a web-based survey to the voting panel members ("panellists")., Key Findings and Limitations: Consensus was a priori defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. The voting results show varying degrees of consensus, as discussed in this article and detailed in the Supplementary material. These findings do not include a formal literature review or meta-analysis., Conclusions and Clinical Implications: The voting results can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers in prioritising areas for future research. Diagnostic and treatment decisions should always be individualised on the basis of patient and cancer characteristics, and should incorporate current and emerging clinical evidence, guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2024 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Recently, research on treatment intensification has gathered momentum, and three novel therapy combinations were approved for metastatic castration-resistant prostate cancer (mCRPC). This systematic review summarizes the current and emerging evidence around intensified strategies for mCRPC and provides guidance for an ideal therapeutic sequencing., Methods: Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) guidelines were followed to perform this review. PubMed, EMBASE, Web of Science, Cochrane Library, ClinicalTrials.gov, and major international societies' online proceedings were searched comprehensively until May 15, 2024, for terms related to treatment intensification and sequencing for mCRPC., Key Findings and Limitations: Overall, 28 clinical trials and 24 ongoing studies of intensification treatments were included in this review. Algorithms of optimal sequencing of approved treatments for mCRPC were outlined according to the use of androgen receptor pathway inhibitors (ARPIs) with or without docetaxel for earlier disease states. In first line, poly(ADP-ribose) polymerase inhibitor + ARPI combinations improve radiographical progression-free survival (rPFS), particularly for those with BRCA1/2 alterations. The AKT inhibitor combination of ipatasertib + abiraterone extends rPFS in those with PTEN loss or PIK3CA/AKT1/PTEN alterations. In those with two or more risk factors for early progression on enzalutamide, radionuclide 177-Lu-PSMA-617 + enzalutamide prolongs progression-free survival. Ongoing research of intensified approaches for mCRPC, and available and potential predictive and prognostic biomarkers are discussed., Conclusions and Clinical Implications: Recent approvals and ongoing investigations of single agents and intensification approaches will keep transforming the mCRPC treatment landscape. Improvement of patient profiling applying recognized genomic, molecular, and clinical predictive and prognostic indicators is fundamental to optimize sequential use of available therapies., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Innovations in imaging and molecular characterisation and the evolution of new therapies have improved outcomes in advanced prostate cancer. Nonetheless, we continue to lack high-level evidence on a variety of clinical topics that greatly impact daily practice. To supplement evidence-based guidelines, the 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) surveyed experts about key dilemmas in clinical management., Objective: To present consensus voting results for select questions from APCCC 2022., Design, Setting, and Participants: Before the conference, a panel of 117 international prostate cancer experts used a modified Delphi process to develop 198 multiple-choice consensus questions on (1) intermediate- and high-risk and locally advanced prostate cancer, (2) biochemical recurrence after local treatment, (3) side effects from hormonal therapies, (4) metastatic hormone-sensitive prostate cancer, (5) nonmetastatic castration-resistant prostate cancer, (6) metastatic castration-resistant prostate cancer, and (7) oligometastatic and oligoprogressive prostate cancer. Before the conference, these questions were administered via a web-based survey to the 105 physician panel members ("panellists") who directly engage in prostate cancer treatment decision-making. Herein, we present results for the 82 questions on topics 1-3., Outcome Measurements and Statistical Analysis: Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement., Results and Limitations: The voting results reveal varying degrees of consensus, as is discussed in this article and shown in the detailed results in the Supplementary material. The findings reflect the opinions of an international panel of experts and did not incorporate a formal literature review and meta-analysis., Conclusions: These voting results by a panel of international experts in advanced prostate cancer can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers prioritise areas for future research. Diagnostic and treatment decisions should always be individualised based on patient and cancer characteristics (disease extent and location, treatment history, comorbidities, and patient preferences) and should incorporate current and emerging clinical evidence, therapeutic guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2022 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials., Patient Summary: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with health care providers and patients worldwide. At each APCCC, a panel of physician experts vote in response to multiple-choice questions about their clinical opinions and approaches to managing advanced prostate cancer. This report presents voting results for the subset of questions pertaining to intermediate- and high-risk and locally advanced prostate cancer, biochemical relapse after definitive treatment, advanced (next-generation) imaging, and management of side effects caused by hormonal therapies. The results provide a practical guide to help clinicians and patients discuss treatment options as part of shared multidisciplinary decision-making. The findings may be especially useful when there is little or no high-level evidence to guide treatment decisions., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Biomarkers predicting second-generation novel hormonal therapy (NHT) benefit relative to taxanes are critical for optimized treatment decisions for metastatic castration-resistant prostate cancer (mCRPC) patients. These associations have not been reported simultaneously for common mCRPC genomic biomarkers., Objective: To evaluate predictive associations of common genomic aberrations in mCRPC using an established comprehensive genomic profiling (CGP) system., Design, Setting, and Participants: A retrospective cohort study used data from a deidentified US-based clinicogenomic database comprising patients treated in routine clinical practice between 2011 and 2020, evaluated with Foundation Medicine CGP in tissue biopsies obtained around the time of treatment decision. The main cohort included 180 NHT and 179 taxane lines of therapy (LOTs) from 308 unique patients. The sequential cohort comprised a subset of the main cohort NHT LOTs immediately followed by taxane from 55 unique patients., Outcome Measurements and Statistical Analysis: Prostate-specific antigen (PSA) response, time to next treatment (TTNT), and overall survival (OS) were assessed. Main cohort analyses were adjusted for known treatment assignment biases via inverse probability of treatment weighting (IPTW) in treatment interaction models., Results and Limitations: In the main cohort, patients with AR amplification (ARamp) or PTEN aberrations (PTENalt) had worse relative PSA response on NHT versus taxanes compared with patients without. Patients with ARamp, PTENalt, or RB1 aberrations (RB1alt) also had worse relative TTNT and OS on NHT but not on taxanes. In multivariable models for TTNT and OS adjusted via IPTW, ARamp, PTENalt, and RB1alt were shown as poor prognostic factors overall and demonstrated significant treatment interactions, indicating reduced hazards of therapy switch and death on taxanes versus NHT. Consistent associations favoring increased benefit from subsequent taxane despite prior NHT treatment line were observed only for ARamp in the sequential cohort, in which very few patients had RB1alt for assessment., Conclusions: ARamp status is a candidate biomarker to predict poor effectiveness of NHT relative to taxanes in mCRPC in scenarios where both options are considered., Patient Summary: Specific alterations in the DNA of tumors may assist in choosing between novel oral hormonal therapies and standard chemotherapy in advanced prostate cancer patients., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Better blood tests to elucidate the behaviour of metastatic castration-resistant prostate cancer (mCRPC) are urgently needed to drive therapeutic decisions. Plasma cell-free DNA (cfDNA) comprises normal and circulating tumour DNA (ctDNA). Low-pass whole-genome sequencing (lpWGS) of ctDNA can provide information on mCRPC behaviour., Objective: To validate and clinically qualify plasma lpWGS for mCRPC., Design, Setting, and Participants: Plasma lpWGS data were obtained for mCRPC patients consenting to optional substudies of two prospective phase 3 trials (FIRSTANA and PROSELICA). In FIRSTANA, chemotherapy-naïve patients were randomised to treatment with docetaxel (75 mg/m 2 ) or cabazitaxel (20 or 25 mg/m 2 ). In PROSELICA, patients previously treated with docetaxel were randomised to 20 or 25 mg/m 2 cabazitaxel. lpWGS data were generated from 540 samples from 188 mCRPC patients acquired at four different time points (screening, cycle 1, cycle 4, and end of study). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: lpWGS data for ctDNA were evaluated for prognostic, response, and tumour genomic measures. Associations with response and survival data were determined for tumour fraction. Genomic biomarkers including large-scale transition (LST) scores were explored in the context of prior treatments., Results and Limitations: Plasma tumour fraction was prognostic for overall survival in univariable and stratified multivariable analyses (hazard ratio 1.75, 95% confidence interval 1.08-2.85; p = 0.024) and offered added value compared to existing biomarkers (C index 0.722 vs 0.709; p = 0.021). Longitudinal changes were associated with drug response. PROSELICA samples were enriched for LSTs (p = 0.029) indicating genomic instability, and this enrichment was associated with prior abiraterone and enzalutamide treatment but not taxane or radiation therapy. Higher LSTs were correlated with losses of RB1/RNASEH2B, independent of BRCA2 loss., Conclusions: Plasma lpWGS of ctDNA describes CRPC behaviour, providing prognostic and response data of clinical relevance. The added prognostic value of the ctDNA fraction over established biomarkers should be studied further., Patient Summary: We studied tumour DNA in blood samples from patients with prostate cancer. We found that levels of tumour DNA in blood were indicative of disease prognosis, and that changes after treatment could be detected. We also observed a "genetic scar" in the results that was associated with certain previous treatments. This test allows an assessment of tumour activity that can complement existing tests, offer insights into drug response, and detect clinically relevant genetic changes., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Context: Genomic stratification can impact prostate cancer (PC) care through diagnostic, prognostic, and predictive biomarkers that aid in clinical decision-making. The temporal and spatial genomic heterogeneity of PC together with the challenges of acquiring metastatic tissue biopsies hinder implementation of tissue-based molecular profiling in routine clinical practice. Blood-based liquid biopsies are an attractive, minimally invasive alternative., Objective: To review the clinical value of blood-based liquid biopsy assays in PC and identify potential applications to accelerate the development of precision medicine., Evidence Acquisition: A systematic review of PubMed/MEDLINE was performed to identify relevant literature on blood-based circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and extracellular vesicles (EVs) in PC., Evidence Synthesis: Liquid biopsy has emerged as a practical tool to profile tumor dynamics over time, elucidating features that evolve (genome, epigenome, transcriptome, and proteome) with tumor progression. Liquid biopsy tests encompass analysis of DNA, RNA, and proteins that can be detected in CTCs, ctDNA, or EVs. Blood-based liquid biopsies have demonstrated promise in the context of localized tumors (diagnostic signatures, risk stratification, and disease monitoring) and advanced disease (response/resistance biomarkers and prognostic markers)., Conclusions: Liquid biopsies have value as a source of prognostic, predictive, and response biomarkers in PC. Most clinical applications have been developed in the advanced metastatic setting, where CTC and ctDNA yields are significantly higher. However, standardization of assays and analytical/clinical validation is necessary prior to clinical implementation., Patient Summary: Traces of tumors can be isolated from blood samples from patients with prostate cancer either as whole cells or as DNA fragments. These traces provide information on tumor features. These minimally invasive tests can guide diagnosis and treatment selection., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Context: Genomic testing is becoming increasingly important in patients with advanced prostate cancer (PC) and is being incorporated in clinical practice to guide treatment., Objective: To 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 Acquisition: We 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 Synthesis: mCRPC 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., Conclusions: Genomic 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 Summary: Similar 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., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Deleterious ATM alterations are found in metastatic prostate cancer (PC); PARP inhibition has antitumour activity against this subset, but only some ATM loss PCs respond., Objective: To characterise ATM-deficient lethal PC and to study synthetic lethal therapeutic strategies for this subset., Design, Setting, and Participants: We studied advanced PC biopsies using validated immunohistochemical (IHC) and next-generation sequencing (NGS) assays. In vitro cell line models modified using CRISPR-Cas9 to impair ATM function were generated and used in drug-sensitivity and functional assays, with validation in a patient-derived model., Outcome Measurements and Statistical Analysis: ATM expression by IHC was correlated with clinical outcome using Kaplan-Meier curves and log-rank test; sensitivity to different drug combinations was assessed in the preclinical models., Results and Limitations: Overall, we detected ATM IHC loss in 68/631 (11%) PC patients in at least one biopsy, with synchronous and metachronous intrapatient heterogeneity; 46/71 (65%) biopsies with ATM loss had ATM mutations or deletions by NGS. ATM IHC loss was not associated with worse outcome from advanced disease, but ATM loss was associated with increased genomic instability (NtAI:number of subchromosomal regions with allelic imbalance extending to the telomere, p = 0.005; large-scale transitions, p = 0.05). In vitro, ATM loss PC models were sensitive to ATR inhibition, but had variable sensitivity to PARP inhibition; superior antitumour activity was seen with combined PARP and ATR inhibition in these models., Conclusions: ATM loss in PC is not always detected by targeted NGS, associates with genomic instability, and is most sensitive to combined ATR and PARP inhibition., Patient Summary: Of aggressive prostate cancers, 10% lose the DNA repair gene ATM; this loss may identify a distinct prostate cancer subtype that is most sensitive to the combination of oral drugs targeting PARP and ATR., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumour cells (CTCs) is associated with worse outcome in metastatic castration-resistant prostate cancer (mCRPC). However, studies rarely report comparisons with CTC counts and biopsy AR-V7 protein expression., Objective: To determine the reproducibility of AdnaTest CTC AR-V7 testing, and associations with clinical characteristics, CellSearch CTC counts, tumour biopsy AR-V7 protein expression and overall survival (OS)., Design, Setting, and Participants: CTC AR-V7 status was determined for 227 peripheral blood samples, from 181 mCRPC patients with CTC counts (202 samples; 136 patients) and matched mCRPC biopsies (65 samples; 58 patients)., Outcome Measurements and Statistical Analysis: CTC AR-V7 status was associated with clinical characteristics, CTC counts, and tissue biopsy AR-V7 protein expression. The association of CTC AR-V7 status and other baseline variables with OS was determined., Results and Limitations: Of the samples, 35% were CTC+/AR-V7+. CTC+/AR-V7+ samples had higher CellSearch CTC counts (median CTC; interquartile range [IQR]: 60, 19-184 vs 9, 2-64; Mann-Whitney test p<0.001) and biopsy AR-V7 protein expression (median H-score, IQR: 100, 63-148 vs 15, 0-113; Mann-Whitney test p=0.004) than CTC+/AR-V7- samples. However, both CTC- (63%) and CTC+/AR-V7- (62%) patients had detectable AR-V7 protein in contemporaneous biopsies. After accounting for baseline characteristics, there was shorter OS in CTC+/AR-V7+ patients than in CTC- patients (hazard ratio [HR] 2.13; 95% confidence interval [CI] 1.23-3.71; p=0.02); surprisingly, there was no evidence that CTC+/AR-V7+ patients had worse OS than CTC+/AR-V7- patients (HR 1.26; 95% CI 0.73-2.17; p=0.4). A limitation of this study was the heterogeneity of treatment received., Conclusions: Studies reporting the prognostic relevance of CTC AR-V7 status must account for CTC counts. Discordant CTC AR-V7 results and AR-V7 protein expression in matched, same-patient biopsies are reported., Patient Summary: Liquid biopsies that determine circulating tumour cell androgen receptor splice variant-7 status have the potential to impact treatment decisions in metastatic castration-resistant prostate cancer patients. Robust clinical qualification of these assays is required before their routine use., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Context: Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) have rising prostate-specific antigen (PSA) and castrate testosterone levels, with no radiological findings of metastatic disease on computed tomography and bone scan. Given recent drug approvals for nmCRPC, with many other therapeutics and imaging modalities being developed, management of nmCRPC is a rapidly evolving field that merits detailed investigation., Objective: To review current nmCRPC management practices and identify opportunities for improving care of nmCRPC patients., Evidence Acquisition: A literature search up to July 2018 was conducted, including clinical trials and clinical practice guidelines (National Comprehensive Cancer Network, European Society for Medical Oncology, European Association of Urology, Prostate Cancer Clinical Trials Working Group, Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence). Keywords included prostate cancer, nonmetastatic, castration resistance, rising PSA, and biochemical relapse., Evidence Synthesis: Recommendations regarding indications for, and frequency of, imaging and PSA testing, as well as for initiating systemic therapy in nmCRPC are based on PSA rise kinetics and symptoms. Both enzalutamide and apalutamide have been shown to significantly increase metastasis-free survival in phase III placebo-controlled randomised trials in nmCRPC patients with PSA doubling time (DT) ≤10 mo. The expected impact of new imaging techniques in the assessment of nmCRPC is also reviewed., Conclusions: nmCRPC is a heterogeneous disease; while observation may be an option for some patients, enzalutamide and apalutamide may be appropriate to treat nmCRPC patients with PSA-DT ≤10 mo. The emergence of more accurate imaging modalities as well as circulating tumour biomarker assays will likely redefine the assessment of nmCRPC in the near future., Patient Summary: Herein, we review key literature and clinical practice guidelines to summarise the optimal management of patients with prostate cancer and rising prostate-specific antigen despite castrate testosterone levels, but with no evidence of distant metastasis on traditional imaging. New drugs are being developed for this disease setting; novel imaging and tumour biomarker blood tests are likely to define this disease state more accurately., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Platinum-based regimens have not been proved to increase survival from advanced prostate cancer (PCa). Incontrovertible evidence that a proportion of prostate cancers have homologous recombination DNA (HRD) repair defects, and that such genomic aberrations are synthetically lethal with both poly(ADP)-ribose polymerase inhibition and platinum, has increased interest in the utilisation of these drugs against a subset of these diseases. Here in we report three patients with advanced castration-resistant PCa with HRD defects having exceptional responses to carboplatin., (Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Germline DNA damage repair gene mutation (gDDRm) is found in >10% of metastatic prostate cancer (mPC). Their prognostic and predictive impact relating to standard therapies is unclear., Objective: To determine whether gDDRm status impacts benefit from established therapies in mPC., Design, Setting, and Participants: This is a retrospective, international, observational study. Medical records were reviewed for 390 mPC patients with known gDDRm status. All 372 patients from Royal Marsden (UK), Weill-Cornell (NY), and University of Washington (WA) were previously included in a prevalence study (Pritchard, NEJM 2016); the remaining 18 were gBRCA1/2m carriers, from the kConFab consortium, Australia., Outcome Measurements and Statistical Analysis: Response rate (RR), progression-free survival (PFS), and overall survival (OS) data were collected. To account for potential differences between cohorts, a mixed-effect model (Weibull distribution) with random intercept per cohort was used., Results and Limitations: The gDDRm status was known for all 390 patients (60 carriers of gDDRm [gDDRm+], including 37 gBRCA2m, and 330 cases not found to carry gDDRm [gDDRm-]); 74% and 69% were treated with docetaxel and abiraterone/enzalutamide, respectively, and 36% received PARP inhibitors (PARPi) and/or platinum. Median OS from castration resistance was similar among groups (3.2 vs 3.0 yr, p=0.73). Median docetaxel PFS for gDDRm+ (6.8 mo) was not significantly different from that for gDDRm- (5.1 mo), and RRs were similar (gDDRm+=61%; gDDRm-=54%). There were no significant differences in median PFS and RR on first-line abiraterone/enzalutamide (gDDRm+=8.3 mo, gDDRm-=8.3 mo; gDDRm+=46%, gDDRm-=56%). Interaction test for PARPi/platinum and gDDRm+ resulted in an OS adjusted hazard ratio of 0.59 (95% confidence interval 0.28-1.25; p=0.17). Results are limited by the retrospective nature of the analysis., Conclusions: mPC patients with gDDRm appeared to benefit from standard therapies similarly to the overall population; prospective studies are ongoing to investigate the impact of PARPi/platinum., Patient Summary: Patients with inherited DNA repair mutations benefit from standard therapies similarly to other metastatic prostate cancer patients., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: For more precise, personalized care in prostate cancer (PC), a new classification based on molecular features relevant for prognostication and treatment stratification is needed. Genomic aberrations in the DNA damage repair pathway are common in PC, particularly in late-stage disease, and may be relevant for treatment stratification., Objective: To review current knowledge on the prevalence and clinical significance of aberrations in DNA repair genes in PC, particularly in metastatic disease., Evidence Acquisition: A literature search up to July 2016 was conducted, including clinical trials and preclinical basic research studies. Keywords included DNA repair, BRCA, ATM, CRPC, prostate cancer, PARP, platinum, predictive biomarkers, and hereditary cancer., Evidence Synthesis: We review how the DNA repair pathway is relevant to prostate carcinogenesis and progression. Data on how this may be relevant to hereditary cancer and genetic counseling are included, as well as data from clinical trials of PARP inhibitors and platinum therapeutics in PC., Conclusions: Relevant studies have identified genomic defects in DNA repair in PCs in 20-30% of advanced castration-resistant PC cases, a proportion of which are germline aberrations and heritable. Phase 1/2 clinical trial data, and other supporting clinical data, support the development of PARP inhibitors and DNA-damaging agents in this molecularly defined subgroup of PC following success in other cancer types. These studies may be an opportunity to improve patient care with personalized therapeutic strategies., Patient Summary: Key literature on how genomic defects in the DNA damage repair pathway are relevant for prostate cancer biology and clinical management is reviewed. Potential implications for future changes in patient care are discussed., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Treatment response biomarkers are urgently needed for castration-resistant prostate cancer (CRPC). Baseline and post-treatment circulating tumor cell (CTC) counts of ≥5 cells/7.5ml are associated with poor CRPC outcome., Objective: To determine the value of a ≥30% CTC decline as a treatment response indicator., Design, Setting, and Participants: We identified patients with a baseline CTC count ≥5 cells/7.5ml and evaluable post-treatment CTC counts in two prospective trials., Intervention: Patients were treated in the COU-AA-301 (abiraterone after chemotherapy) and IMMC-38 (chemotherapy) trials., Outcome Measures and Statistical Analysis: The association between a ≥30% CTC decline after treatment and survival was evaluated using univariable and multivariable Cox regression models at three landmark time points (4, 8, and 12 wk). Model performance was evaluated by calculating the area under the receiver operating characteristic curve (AUC) and c-indices., Results: Overall 486 patients (122 in IMMC-38 and 364 in COU-AA-301) had a CTC count ≥5 cells/7.5ml at baseline, with 440, 380, and 351 patients evaluable at 4, 8, and 12 wk, respectively. A 30% CTC decline was associated with increased survival at 4 wk (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.36-0.56; p<0.001), 8 wk (HR 0.41, 95% CI 0.33-0.53; p<0.001), and 12 wk (HR 0.39, 95% CI 0.3-0.5; p<0.001) in univariable and multivariable analyses. Stable CTC count (<30% fall or <30% increase) was not associated with a survival benefit when compared with increased CTC count. The association between a 30% CTC decline after treatment and survival was independent of baseline CTC count. CTC declines significantly improved the AUC at all time-points. Finally, in the COU-AA-301 trial, patients with CTC ≥5 cells/7.5ml and a 30% CTC decline had similar overall survival in both arms., Conclusions: A 30% CTC decline after treatment from an initial count ≥5 cells/7.5ml is independently associated with CRPC overall survival following abiraterone and chemotherapy, improving the performance of a multivariable model as early as 4 wk after treatment. This potential surrogate must now be prospectively evaluated., Patient Summary: Circulating tumor cells (CTCs) are cancer cells that can be detected in the blood of prostate cancer patients. We analyzed changes in CTCs after treatment with abiraterone and chemotherapy in two large clinical trials, and found that patients who have a decline in CTC count have a better survival outcome., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) occurs frequently in prostate cancers. Preclinical evidence suggests that activation of PI3K/AKT signaling through loss of PTEN can result in resistance to hormonal treatment in prostate cancer., Objective: To explore the antitumor activity of abiraterone acetate (abiraterone) in castration-resistant prostate cancer (CRPC) patients with and without loss of PTEN protein expression., Design, Setting, and Participants: We retrospectively identified patients who had received abiraterone and had hormone-sensitive prostate cancer (HSPC) and/or CRPC tissue available for PTEN immunohistochemical analysis., Outcome Measurements and Statistical Analysis: The primary end point was overall survival from initiation of abiraterone treatment. Relationship with outcome was analyzed using multivariate Cox regression and log-rank analyses., Results and Limitations: A total of 144 patients were identified who had received abiraterone post-docetaxel and had available tumor tissue. Overall, loss of PTEN expression was observed in 40% of patients. Matched HSPC and CRPC tumor biopsies were available for 41 patients. PTEN status in CRPC correlated with HSPC in 86% of cases. Loss of PTEN expression was associated with shorter median overall survival (14 vs 21 mo; hazard ratio [HR]: 1.75; 95% confidence interval [CI], 1.19-2.55; p=0.004) and shorter median duration of abiraterone treatment (24 vs 28 wk; HR: 1.6; 95% CI, 1.12-2.28; p=0.009). PTEN protein loss, high lactate dehydrogenase, and the presence of visceral metastases were identified as independent prognostic factors in multivariate analysis., Conclusions: Our results indicate that loss of PTEN expression was associated with worse survival and shorter time on abiraterone treatment. Further studies in larger and prospective cohorts are warranted., Patient Summary: PTEN is a protein often lost in prostate cancer cells. In this study we evaluated if prostate cancers that lack this protein respond differently to treatment with abiraterone acetate. We demonstrated that the survival of patients with loss of PTEN is shorter than patients with normal PTEN expression., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

A prognostic model was derived from the population of the COU-AA-301 phase 3 trial for metastatic castrate-resistant prostate cancer patients treated with abiraterone after docetaxel, and it stratifies patients into three risk groups based on clinical parameters. We validated this model in an independent cohort of patients treated with abiraterone after docetaxel outside a clinical trial (group A; n=94) and explored its utility in patients treated with abiraterone in the prechemotherapy setting (group B; n=64). For group A, median overall survival (mOS) was significantly different across the three prognostic groups (good: n=39, mOS: 21.8 mo; intermediate: n=44, mOS: 10.6 mo; poor: n=7, mOS: 6.8 mo; p<0.001; area under the curve [AUC]: 0.71). Analysis of group B confirmed the ability of the model to prognosticate for survival in the prechemotherapy setting: (good: n=44, mOS: 45.6 mo; intermediate or poor: n=20, mOS: 34.5 mo; p=0.042; AUC: 0.61). These results serve to validate the prognostic model in an independent population treated with abiraterone after docetaxel and support clinical implementation of the score. Calibration of the model was poorer in patients receiving abiraterone prechemotherapy. Prospective evaluation of this model in clinical trials is needed., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)