Germline and somatic testing for homologous repair deficiency in patients with prostate cancer (part 1 of 2).

BACKGROUND/OBJECTIVES: Unfortunately, not all metastatic castration resistant prostate cancer (mCRPC) patients receive available life-prolonging systemic therapies, emphasizing the need to optimize mCRPC treatment selections. Better guidelines are necessary to determine genetic testing in prostate cancer. SUBJECTS/METHODS: In this two-part expert opinion-based guide, we provide an expert consensus opinion on the utilization of germline and somatic testing to detect HRR alterations in patients with mCRPC. This guide was developed by a multidisciplinary expert panel that convened in 2023-2024, including representatives from medical oncology, urology, radiation oncology, pathology, medical genomics, and basic science. RESULTS/CONCLUSION: We argue for the widespread adoption of germline testing in all patients with prostate cancer and for somatic mutations testing in patients at the time of recurrent/metastatic disease. In this first part, we review how genomic testing is performed. We also review how to overcome certain barriers to integrate genetic and biomarker testing into clinical practice.

Expert Perspectives on Controversies in Castration-Sensitive Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 1.

Purpose: Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC. Materials and Methods: The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy. Results: The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC. Conclusions: CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.

Expert Perspectives on Controversies in Metastatic Castration-Resistant Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 2.

Background: Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature. Materials and Methods: The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators. Results: This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1/2 mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)-positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non-BRCA1/2 mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies. Conclusions: The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.

Three- and Seven-month Prostate-specific Antigen Levels as Prognostic Markers for Overall Survival in Metastatic Hormone-sensitive Prostate Cancer: Results from SWOG S1216, a Phase 3 Randomized Trial of Androgen Deprivation Plus Orteronel or Bicalutamide.

BACKGROUND: A robust decrease in prostate-specific antigen (PSA) in response to androgen deprivation therapy (ADT) has been evaluated as a prognostic factor in patients with metastatic hormone-sensitive prostate cancer (mHSPC) since 2006, but the treatment of mHSPC has since evolved to include intensified therapy. OBJECTIVE: We assessed the association of PSA levels at 3 (PSA-3mo) and 7 (PSA-7mo) mo with overall survival (OS) in patients with mHSPC treated with ADT combined with either bicalutamide or orteronel in the S1216 phase 3 clinical trial. DESIGN, SETTING, AND PARTICIPANTS: PSA responses to treatment of patients in the S1216 trial were categorized as: complete response (CR) if PSA was ≤0.2 ng/ml, partial response if PSA was >0.2 and ≤4 ng/ml, and no response (NR) if PSA was >4 ng/ml. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A Cox analysis (adjusted for treatment arm and three stratification factors: performance status, severity of disease, and early vs late induction) was used for OS association. While PSA-7mo association was a prespecified objective, PSA-3mo association was also evaluated. RESULTS AND LIMITATIONS: A total of 1251 and 1231 patients from the S1216 study were evaluable for PSA-3mo and PSA-7mo, respectively. A PSA-7mo CR was associated with improved OS compared with NR (HR: 0.20; p < 0.0001). A PSA-3mo CR showed a similar association to NR (HR: 0.34; p < 0.0001). The association of a PSA response with survival did not differ by treatment arm at either time point. CONCLUSIONS: The PSA-3mo and PSA-7mo responses were strongly associated with OS; taken with other emerging prognostic biomarkers, these markers may allow for early identification of patients at the highest risk of death, aid with counseling in clinical practice, and permit design of future clinical trials targeting these patients. PATIENT SUMMARY: A low prostate-specific antigen level at 3 or 7 mo after starting treatment for metastatic hormone-sensitive prostate cancer predicts longer survival regardless of the first treatment given with androgen deprivation therapy.

A multidisciplinary approach to address unmet needs in the management of patients with non-metastatic castration-resistant prostate cancer.

BACKGROUND: With the availability of second-generation androgen receptor inhibitors (SGARIs), the treatment landscape has changed dramatically for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). In clinical trials, the SGARIs (apalutamide, enzalutamide, darolutamide) increased metastasis-free survival (MFS), overall survival (OS), and patient quality of life compared to placebo. These drugs were subsequently integrated into nmCRPC clinical practice guidelines. With advances in radiographic imaging, disease assessment, and patient monitoring, nmCRPC strategies are evolving to address limitations related to tracking disease progression using prostate-specific antigen (PSA) kinetics. METHODS: A panel of 10 multidisciplinary experts in prostate cancer conducted reviews and discussions of unmet needs in the management and monitoring of patients with nmCRPC in order to develop consensus recommendations. RESULTS: Across the SGARI literature, patient MFS and OS are generally comparable for all treatments, but important distinctions exist regarding short- and long-term drug safety profiles and drug-drug interactions. With respect to disease monitoring, a substantial proportion of patients using SGARIs may experience disease progression without rising PSA levels, suggesting a need for enhanced radiographic imaging in addition to PSA monitoring. Recent data also indicate that novel prostate-specific membrane antigen positron emission tomography radiotracers provide enhanced accuracy for disease detection, as compared to conventional imaging. CONCLUSIONS: Clinical decision-making in nmCRPC has become more complex, with new opportunities to apply precision medicine to patient care. Multidisciplinary teams can ensure that patients with nmCRPC receive optimal and individualized disease management.

A real-world experience of pembrolizumab monotherapy in microsatellite instability-high and/or tumor mutation burden-high metastatic castration-resistant prostate cancer: outcome analysis.

BACKGROUND: The efficacy of pembrolizumab monotherapy in metastatic castration-resistant prostate cancer patients (mCRPC) when stratified by MSI-H and/or TMB-H is poorly defined. Additionally, outcomes based on sequencing source (i.e., tissue or liquid biopsy) have not been well described. We sought to assess outcomes of pembrolizumab monotherapy in patients with mCRPC and compare efficacy based on MSI-H and/or TMB-H when identified by tissue or liquid biopsy. METHODS: A retrospective analysis was performed of mCRPC patients treated at Mayo Clinic with pembrolizumab monotherapy between 2018 and 2023. Objective response rates (ORR), median progression-free survival (mPFS), and overall survival (mOS), were determined by RECIST v1.1 criteria. RESULTS: Twenty-two patients with mCRPC received pembrolizumab monotherapy for at least 3 cycles for a MSI-H or TMB-H indication. All patients had next generation sequencing (NGS) performed via tissue (n = 11) or liquid (n = 10) biopsy source. The ORR was 50% (27.3% complete response and 22.7% had partial response). The mPFS for TMB 10-14.9 mut/Mb (n = 4), TMB 15-24.9 mut/Mb (n = 6), and TMB ≥ 25 mut/Mb (n = 10) was 2.1, not reached (NR), and NR, respectively (p = 0.0003). The mOS for these same groups was 5.1 months, 20.5 months, and not reached, respectively. Among patients with TMB-H without co-occurring MSI-H or CDK12 (n = 6), none experienced a response and only one patient had stable disease compared to patients with MSI-H (n = 12) for whom the ORR was 75%. Immunotherapy responsive alterations such as ATRX and PTCH1 mutations were frequently noticed among patients who had complete response (CR). CONCLUSIONS: Our hypothesis-generating study suggests that MSI-H drives the efficacy of pembrolizumab in mCRPC with better survival outcomes as TMB increases. Clinicians should consider alternative treatment strategies for advanced prostate cancer when TMB-H is present without co-occurring MSI-H or CDK12.

Early PSA decline after starting second-generation hormone therapy in the post-docetaxel setting predicts cancer-specific survival in metastatic castrate-resistant prostate cancer.

BACKGROUND: The objective of this study was to evaluate the prognostic value of early PSA decline following initiation of second-generation hormone therapy (2nd HT), namely abiraterone acetate or enzalutamide, in patients with taxane-refractory metastatic castrate-resistant prostate cancer (mCRPC) and evaluate utility of this metric in informing intensified surveillance/imaging protocols. METHODS: We retrospectively identified 75 mCRPC patients treated with 2nd HT following docetaxel failure (defined as PSA rise and radiographic progression). Patients were categorized patients into two cohorts based on the first PSA within 3 months after initiation of therapy: PSA reduction ≥50% (Group A) and PSA reduction <50% (Group B). The primary endpoint was cancer-specific mortality (CSM). The secondary endpoint was radiographic disease progression (rDP) on 2nd HT. In univariate and multivariate analyses, we investigated factors associated with rPD and CSM. RESULTS: We included 75 patients (52 in Group A, 23 in Group B) in the analytic cohort. Baseline clinico-demographic characteristics, including median age, primary Gleason score risk group, median pre-treatment PSA, disease burden, site of metastases, and pre-treatment ECOG score were not statistically different between the two groups. Median follow up time was 30 months and the median time to radiographic disease progression was 28.1 and 12.5 months (p = 0.002) in cohorts A and B, respectively. On univariate and multivariate analyses, both PSA reduction ≥50% and volume of metastatic disease were significantly associated with a decreased risk of radiographic disease progression (HR 0.41, 95% CI 0.21-0.80, p = 0.0113) as well as a decreased risk of cancer-specific mortality (HR 0.29, 95% CI 0.09-0.87, p = 0.0325). CONCLUSION: PSA reduction ≥50% within 3 months of starting 2nd HT was associated with significantly improved radiographic disease progression-free survival and 3-year cancer-specific mortality. This suggests using PSA 50%-decline metric in surveillance patients with on 2nd HT and identifies patients who require further evaluation with imaging.

Performance of a Cell-Free DNA-Based Multi-cancer Detection Test in Individuals Presenting With Symptoms Suspicious for Cancers.

PURPOSE: A multi-cancer detection test using a targeted methylation assay and machine learning classifiers was validated and optimized for screening in prospective, case-controlled Circulating Cell-free Genome Atlas (ClinicalTrials.gov identifier: NCT02889978) substudy 3. Here, we report test performance in a subgroup of participants with symptoms suspicious for cancer to assess the test's ability to potentially facilitate efficient diagnostic evaluation in symptomatic individuals. METHODS: We evaluated test performance (sensitivity, specificity, and accuracy of cancer signal origin [CSO] prediction accuracy) in participants with clinically presenting cancers (CPCs) and noncancer with underlying medical conditions and among two subgroups (65 years and older and GI cancers). Overall survival (OS) of participants who had a cancer signal detected/not detected was compared with SEER-based expected survival. RESULTS: A total of 2,036 cancer and 1,472 noncancer participants were included. Specificity was high in all noncancer participants (99.5% [95% CI, 98.4 to 99.8]). In participants with CPCs, the overall sensitivity was 64.3% (95% CI, 62.2 to 66.4) and the overall accuracy of CSO prediction in true positives was 90.3%. For GI cancers, the overall sensitivity was 84.1% (95% CI, 80.6 to 87.1). In participants 65 years and older, test performance was similar to that of all participants. Individuals with cancers not detected had a significantly better OS than that expected from SEER (P < .01). CONCLUSION: This test detected a cancer signal with high specificity and CSO prediction accuracy and moderate sensitivity in symptomatic individuals, with especially high performance in participants with GI cancers. The survival analysis implied that the cancers not detected were less clinically aggressive than cancers detected by the test, providing prognostic insights to physicians. This multi-cancer detection test could facilitate efficient workup and stratify cancer risk in symptomatic individuals.

Approaches to Prevent and Manage Cardiovascular Disease in Patients Receiving Therapy for Prostate Cancer.

PURPOSE OF REVIEW: Prostate cancer (PCa) is amongst the most common cancers in men worldwide. Cardiovascular (CV) risk factors and CV disease (CVD) are common comorbidities in this patient population, posing a challenge for PCa-directed therapies which can cause or worsen CVRFs and CVDs. Herein, we summarize the approaches to prevent and manage CVD in patients with PCa receiving therapy. RECENT FINDINGS: While patients with locally advanced and metastatic PCa benefit from hormonal therapy, these treatments can potentially cause CV toxicity. Androgen receptor targeting therapies, such as androgen deprivation therapy (ADT), can induce metabolic changes and directly impact cardiovascular function, thereby reducing cardiorespiratory fitness and increasing CV mortality. Moreover, more than half of the PCa patients have poorly controlled CV risk factors at baseline. Hence, there is an urgent need to address gaps in preventing and managing CVD in PCa patients. Screening and optimizing CV risk factors and CVD in patients undergoing ADT are essential to reduce CV mortality, the leading non-cancer cause of death in PCa survivors. The risk of CV morbidity and mortality can be further mitigated by considering the patient's cardiovascular risk profile when deciding the choice and duration of ADT. A multidisciplinary team-based approach is crucial to achieve the best outcomes for PCa patients undergoing therapy.

Rucaparib for the Treatment of Metastatic Castration-resistant Prostate Cancer Associated with a DNA Damage Repair Gene Alteration: Final Results from the Phase 2 TRITON2 Study.

BACKGROUND: Initial TRITON2 (NCT02952534) results demonstrated the efficacy of rucaparib 600 mg BID in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with a BRCA1 or BRCA2 (BRCA) or other DNA damage repair (DDR) gene alteration. OBJECTIVE: To present the final data from TRITON2. DESIGN, SETTING, AND PARTICIPANTS: TRITON2 enrolled patients with mCRPC who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was objective response rate (ORR; as per the modified Response Evaluation Criteria in Solid Tumor Version 1.1/Prostate Cancer Clinical Trials Working Group 3 criteria in patients with measurable disease by independent radiology review [IRR]); prostate-specific antigen (PSA) response rate (≥50% decrease from baseline [PSA50]) was a key secondary endpoint. RESULTS AND LIMITATIONS: As of July 27, 2021 (study closure), TRITON2 had enrolled 277 patients, grouped by mutated gene: BRCA (n = 172), ATM (n = 59), CDK12 (n = 15), CHEK2 (n = 7), PALB2 (n = 11), or other DDR gene (Other; n = 13). ORR by IRR was 46% (37/81) in the BRCA subgroup (95% confidence interval [CI], 35-57%), 100% (4/4) in the PALB2 subgroup (95% CI, 40-100%), and 25% (3/12) in the Other subgroup (95% CI, 5.5-57%). No patients within the ATM, CDK12, or CHEK2 subgroups had an objective response by IRR. PSA50 response rates (95% CI) in the BRCA, PALB2, ATM, CDK12, CHEK2, and Other subgroups were 53% (46-61%), 55% (23-83%), 3.4% (0.4-12), 6.7% (0.2-32%), 14% (0.4-58%), and 23% (5.0-54%), respectively. CONCLUSIONS: The final TRITON2 results confirm the clinical benefit and manageable safety profile of rucaparib in patients with mCRPC, including those with an alteration in BRCA or select non-BRCA DDR gene. PATIENT SUMMARY: Almost half of TRITON2 patients with BRCA-mutated metastatic castration-resistant prostate cancer had a complete or partial tumor size reduction with rucaparib; clinical benefits were also observed with other DNA damage repair gene alterations.

Outcomes of Second-Line Therapies in Patients With Metastatic de Novo and Treatment-Emergent Neuroendocrine Prostate Cancer: A Multi-Institutional Study.

BACKGROUND: De novo neuroendocrine prostate cancer (NEPC) and treatment-emergent neuroendocrine prostate cancer (T-NEPC) are rare diseases with a poor prognosis. After first-line platinum chemotherapy, there is no consensus on second-line treatments. PATIENTS AND METHODS: Patients with a pathologic diagnosis of de novo NEPC or T-NEPC between 2000 and 2020 who received first-line platinum and any second-line systemic therapy were selected and standardized clinical data was collected via the electronic health record at each institution. The primary endpoint was overall survival (OS) based on second-line therapy. Secondary endpoints included objective response rate (ORR) to second-line therapy, PSA response, and time on treatment. RESULTS: Fifty-eight patients (32 de novo NEPC, 26 T-NEPC) from 8 institutions were included. At de novo NEPC or T-NEPC diagnosis, the overall cohort had a median age of 65.0 years (IQR 59.2-70.3) and median PSA of 3.0 ng/dL (IQR 0.6-17.9). Following first-line platinum chemotherapy, 21 patients (36.2%) received platinum chemotherapy, 10 (17.2%) taxane monotherapy, 11 (19.0%) immunotherapy, 10 (17.2%) other chemotherapy, and 6 (16.2%) other systemic therapy. Among 41 evaluable patients, the ORR was 23.5%. The mOS after start of second-line therapy was 7.4 months (95% CI 6.1-11.9). CONCLUSIONS: In this retrospective study, patients with de novo NEPC or T-NEPC who received second-line therapy were treated with wide variety of treatment regimens, reflecting the lack of consensus in this setting. Most patients received chemotherapy-based treatments. Overall prognosis was poor and ORR was low in the second line regardless of treatment choice.

Clinical Outcomes of Stereotactic Radiosurgery-Related Radiation Necrosis in Patients with Intracranial Metastasis from Melanoma.

Background: Radiation necrosis (RN) is a clinically relevant complication of stereotactic radiosurgery (SRS) for intracranial metastasis (ICM) treatments. Radiation necrosis development is variable following SRS. It remains unclear if risk factors for and clinical outcomes following RN may be different for melanoma patients. We reviewed patients with ICM from metastatic melanoma to understand the potential impact of RN in this patient population. Methods: Patients who received SRS for ICM from melanoma at Mayo Clinic Arizona between 2013 and 2018 were retrospectively reviewed. Data collected included demographics, tumor characteristics, radiation parameters, prior surgical and systemic treatments, and patient outcomes. Radiation necrosis was diagnosed by clinical evaluation including brain magnetic resonance imaging (MRI) and, in some cases, tissue evaluation. Results: Radiation necrosis was diagnosed in 7 (27%) of 26 patients at 1.6 to 38 months following initial SRS. Almost 92% of all patients received systemic therapy and 35% had surgical resection prior to SRS. Patients with RN trended toward having larger ICM and a prior history of surgical resection, although statistical significance was not reached. Among patients with resection, those who developed RN had a longer period between surgery and SRS start (mean 44 vs 33 days). Clinical improvement following treatment for RN was noted in 2 (29%) patients. Conclusions: Radiation necrosis is relatively common following SRS for treatment of ICM from metastatic melanoma and clinical outcomes are poor. Further studies aimed at mitigating RN development and identifying novel approaches for treatment are warranted.

Performing Automatic Identification and Staging of Urothelial Carcinoma in Bladder Cancer Patients Using a Hybrid Deep-Machine Learning Approach.

Accurate clinical staging of bladder cancer aids in optimizing the process of clinical decision-making, thereby tailoring the effective treatment and management of patients. While several radiomics approaches have been developed to facilitate the process of clinical diagnosis and staging of bladder cancer using grayscale computed tomography (CT) scans, the performances of these models have been low, with little validation and no clear consensus on specific imaging signatures. We propose a hybrid framework comprising pre-trained deep neural networks for feature extraction, in combination with statistical machine learning techniques for classification, which is capable of performing the following classification tasks: (1) bladder cancer tissue vs. normal tissue, (2) muscle-invasive bladder cancer (MIBC) vs. non-muscle-invasive bladder cancer (NMIBC), and (3) post-treatment changes (PTC) vs. MIBC.

Randomized Phase III Study of Enzalutamide Compared With Enzalutamide Plus Abiraterone for Metastatic Castration-Resistant Prostate Cancer (Alliance A031201 Trial).

PURPOSE: Enzalutamide and abiraterone both target androgen receptor signaling but via different mechanisms. The mechanism of action of one drug may counteract the resistance pathways of the other. We sought to determine whether the addition of abiraterone acetate and prednisone (AAP) to enzalutamide prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the first-line setting. PATIENTS AND METHODS: Men with untreated mCRPC were randomly assigned (1:1) to receive first-line enzalutamide with or without AAP. The primary end point was OS. Toxicity, prostate-specific antigen declines, pharmacokinetics, and radiographic progression-free survival (rPFS) were also examined. Data were analyzed using an intent-to-treat approach. The Kaplan-Meier estimate and the stratified log-rank statistic were used to compare OS between treatments. RESULTS: In total, 1,311 patients were randomly assigned: 657 to enzalutamide and 654 to enzalutamide plus AAP. OS was not statistically different between the two arms (median, 32.7 [95% CI, 30.5 to 35.4] months for enzalutamide v 34.2 [95% CI, 31.4 to 37.3] months for enzalutamide and AAP; hazard ratio [HR], 0.89; one-sided P = .03; boundary nominal significance level = .02). rPFS was longer in the combination arm (median rPFS, 21.3 [95% CI, 19.4 to 22.9] months for enzalutamide v 24.3 [95% CI, 22.3 to 26.7] months for enzalutamide and AAP; HR, 0.86; two-sided P = .02). However, pharmacokinetic clearance of abiraterone was 2.2- to 2.9-fold higher when administered with enzalutamide, compared with clearance values for abiraterone alone. CONCLUSION: The addition of AAP to enzalutamide for first-line treatment of mCRPC was not associated with a statistically significant benefit in OS. Drug-drug interactions between the two agents resulting in increased abiraterone clearance may partly account for this result, although these interactions did not prevent the combination regimen from having more nonhematologic toxicity.

First-line Systemic Treatment Options for Metastatic Castration-Sensitive Prostate Cancer: A Living Systematic Review and Network Meta-analysis.

Importance: The effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive prostate cancer (mCSPC) is unknown. Objective: To assess the comparative effectiveness of contemporary systemic treatment options for patients with mCSPC across clinically relevant subgroups. Data Sources: For this systematic review and meta-analysis, Ovid MEDLINE and Embase were searched from each database's inception (MEDLINE, 1946; Embase, 1974) through June 16, 2021. Subsequently, a "living" auto search was created with weekly updates to identify new evidence as it became available. Study Selection: Phase 3 randomized clinical trials (RCTs) assessing first-line treatment options for mCSPC. Data Extraction and Synthesis: Two independent reviewers extracted data from eligible RCTs. The comparative effectiveness of different treatment options was assessed with a fixed-effect network meta-analysis. Data were analyzed on July 10, 2022. Main Outcomes and Measures: Outcomes of interest included overall survival (OS), progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life. Results: This report included 10 RCTs with 11 043 patients and 9 unique treatment groups. Median ages of the included population ranged from 63 to 70 years. Current evidence for the overall population suggests that the darolutamide (DARO) triplet (DARO + docetaxel [D] + androgen deprivation therapy [ADT]; hazard ratio [HR], 0.68; 95% CI, 0.57-0.81), as well as the abiraterone (AAP) triplet (AAP + D + ADT; HR, 0.75; 95% CI, 0.59-0.95), are associated with improved OS compared with D doublet (D + ADT) but not compared with API doublets. Among patients with high-volume disease, AAP + D + ADT may improve OS compared with D + ADT (HR, 0.72; 95% CI, 0.55-0.95) but not compared with AAP + ADT, enzalutamide (E) + ADT, and apalutamide (APA) + ADT. For patients with low-volume disease, AAP + D + ADT may not improve OS compared with APA + ADT, AAP + ADT, E + ADT, and D + ADT. Conclusions and Relevance: The potential benefit observed with triplet therapy must be interpreted with careful accounting for the volume of disease and the choice of doublet comparisons used in the clinical trials. These findings suggest an equipoise to how triplet regimens compare with API doublet combinations and provide direction for future clinical trials.

Rucaparib or Physician's Choice in Metastatic Prostate Cancer.

BACKGROUND: In a phase 2 study, rucaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), showed a high level of activity in patients who had metastatic, castration-resistant prostate cancer associated with a deleterious BRCA alteration. Data are needed to confirm and expand on the findings of the phase 2 study. METHODS: In this randomized, controlled, phase 3 trial, we enrolled patients who had metastatic, castration-resistant prostate cancer with a BRCA1, BRCA2, or ATM alteration and who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI). We randomly assigned the patients in a 2:1 ratio to receive oral rucaparib (600 mg twice daily) or a physician's choice control (docetaxel or a second-generation ARPI [abiraterone acetate or enzalutamide]). The primary outcome was the median duration of imaging-based progression-free survival according to independent review. RESULTS: Of the 4855 patients who had undergone prescreening or screening, 270 were assigned to receive rucaparib and 135 to receive a control medication (intention-to-treat population); in the two groups, 201 patients and 101 patients, respectively, had a BRCA alteration. At 62 months, the duration of imaging-based progression-free survival was significantly longer in the rucaparib group than in the control group, both in the BRCA subgroup (median, 11.2 months and 6.4 months, respectively; hazard ratio, 0.50; 95% confidence interval [CI], 0.36 to 0.69) and in the intention-to-treat group (median, 10.2 months and 6.4 months, respectively; hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001 for both comparisons). In an exploratory analysis in the ATM subgroup, the median duration of imaging-based progression-free survival was 8.1 months in the rucaparib group and 6.8 months in the control group (hazard ratio, 0.95; 95% CI, 0.59 to 1.52). The most frequent adverse events with rucaparib were fatigue and nausea. CONCLUSIONS: The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a BRCA alteration. (Funded by Clovis Oncology; TRITON3 ClinicalTrials.gov number, NCT02975934.).

Differential responses to taxanes and PARP inhibitors in ATM- versus BRCA2-mutated metastatic castrate-resistant prostate cancer.

BACKGROUND: PARP (poly(ADP-ribose) polymerase) inhibitors (PARPi) are now standard of care in metastatic castrate-resistant prostate cancer (mCRPC) patients with select mutations in DNA damage repair (DDR) pathways, but patients with ATM- and BRCA2 mutations may respond differently to PARPi. We hypothesized that differences may also exist in response to taxanes, which may inform treatment sequencing decisions. METHODS: mCRPC patients (N = 158) with deleterious ATM or BRCA2 mutations who received taxanes, PARPi, or both were retrospectively identified from 11 US academic centers. Demographic, treatment, and survival data were collected. Kaplan-Meier analyses were performed and Cox hazard ratios (HR) were calculated for progression-free survival (PFS) as well as overall survival (OS), from time of first taxane or PARPi therapy. RESULTS: Fifty-eight patients with ATM mutations and 100 with BRCA2 mutations were identified. Fourty-four (76%) patients with ATM mutations received taxane only or taxane before PARPi, while 14 (24%) received PARPi only or PARPi before taxane. Patients with ATM mutations had longer PFS when taxane was given first versus PARPi given first (HR: 0.74 [95% confidence interval [CI]: 0.37-1.50]; p = 0.40). Similarly, OS was longer in patients with ATM mutations who received taxane first (HR: 0.56 [CI: 0.20-1.54]; p = 0.26). Among patients with BRCA2 mutations, 51 (51%) received taxane first and 49 (49%) received PARPi first. In contrast, patients with BRCA2 mutations had longer PFS when PARPi was given first versus taxane given first (HR: 0.85 [CI: 0.54-1.35]; p = 0.49). Similarly, OS was longer in patients with BRCA2 mutations who received PARPi first (HR: 0.75 [CI: 0.41-1.37]; p = 0.35). CONCLUSIONS: Our retrospective data suggest differential response between ATM and BRCA2 mutated prostate cancers in terms of response to PARPi and to taxane chemotherapy. When considering the sequence of PARPi versus taxane chemotherapy for mCRPC with DDR mutations, ATM, and BRCA2 mutation status may be helpful in guiding choice of initial therapy.

Emergence of BRCA Reversion Mutations in Patients with Metastatic Castration-resistant Prostate Cancer After Treatment with Rucaparib.

BACKGROUND: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved in the USA for the treatment of patients with BRCA1 or BRCA2 (BRCA) mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC). BRCA reversion mutations are a known mechanism of acquired resistance to PARP inhibitors in multiple cancer types, although their impact and prevalence in mCRPC remain unknown. OBJECTIVE: To examine the prevalence of BRCA reversion mutations in the plasma of patients with BRCA+ mCRPC after progression on rucaparib. DESIGN, SETTING, AND PARTICIPANTS: Men with BRCA+ mCRPC enrolled in Trial of Rucaparib in Prostate Indications 2 (TRITON2) were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected at the end of treatment after confirmed progression before May 5, 2020, was queried for BRCA reversion mutations using next-generation sequencing (NGS). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The association of clinical efficacy and postprogression genomics was measured in 100 patients with BRCA+ mCRPC treated with rucaparib. RESULTS AND LIMITATIONS: No baseline BRCA reversion mutations were observed in 100 BRCA+ patients. NGS identified somatic BRCA reversion mutations in 39% (39/100) of patients after progression. Reversion rates were similar for BRCA2 and BRCA1, irrespective of germline or somatic status, but higher in samples with a high tumor DNA fraction. Most patients with reversions (74%, 29/39) had two or more reversion mutations occurring subclonally at lower allele frequencies than the original BRCA mutations. The incidence of BRCA reversion mutations increased with the duration of rucaparib treatment. The frequency of reversion mutations was higher in patients with an objective (58%) or a prostate-specific antigen (69%) response compared with those without either (39% and 29%, respectively). CONCLUSIONS: These findings suggest that BRCA reversion mutations are a significant mechanism of acquired resistance to rucaparib in patients with BRCA+ mCRPC, with evidence of subclonal convergence promoting systemic resistance. PATIENT SUMMARY: Men with BRCA mutated metastatic castration-resistant prostate cancer enrolled in TRITON2 were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected after radiographic or prostate-specific antigen progression before May 5, 2020, was analyzed by next-generation sequencing and queried for BRCA reversion mutations.