Search

Introduction: The homologous recombination repair (HRR) pathway is a frequently mutated pathway in advanced prostate cancer. The clinical course of patients with HRR gene alterations who have metastatic hormone sensitive prostate cancer (mHSPC) has not been fully characterized. Here, we examine the outcomes of men with mHSPC with HRR alterations., Methods: We conducted a single-center retrospective analysis of men with mHSPC who underwent next generation sequencing. The primary objective was to assess the time from diagnosis of mHSPC to metastatic castrate resistance prostate cancer (mCRPC) in patients with pathogenic HRR alterations compared to individuals lacking these alterations. Key secondary objectives included time to mCRPC in prespecified cohorts, PSA response, and overall survival., Results: 151 men with mHSPC were identified for the study. 24% (N = 37) had pathogenic HRR gene alterations detected with the most common alterations found in BRCA2 (n = 15), ATM (n = 10), and CDK12 (n = 7). Time to mCRPC was significantly decreased in patients with HRR gene alterations versus those without such alterations (12.7 vs. 16.1 months, HR 1.95, P = .02). In multivariate analysis, the effect of HRR gene alterations on time to CRPC remained significant when adjusting for age, mHSPC therapy, the volume of disease, the presence of visceral metastases, and PSA (adjusted HR 1.69, P = .02). Stratified by specific HRR gene alteration, patients with BRCA2 or CDK12 had significantly decreased time to mCRPC compared to other HRR alterations., Conclusion: HRR gene alterations are associated with the worse outcomes in mHSPC with significantly shorter time to mCRPC. Given the established role of Poly (ADP-ribose) Polymerase (PARP) inhibitors in mCRPC, these data highlight an opportunity to examine PARP inhibitors earlier in the clinical course for prostate cancer patients. Ongoing prospective studies will further validate the role of PARP inhibitors in mHSPC patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: There has been considerable interest in ctDNA next generation sequencing platforms to assess genomic alterations in mCRPC given its accessibility and identification of temporal genomic data., Patientsand Methods: In this retrospective analysis, we analyzed 63 patients who underwent ctDNA genomic profiling during their mCRPC disease course using a CLIA-certified commercial assay. The primary objective was to assess the feasibility of commercial ctDNA analysis in a real world mCRPC cohort. Key secondary objectives included assessment of the landscape of pathogenic ctDNA alterations and the prognostic significance of ctDNA detection on overall survival (OS)., Results: Among the cohort, at the time of ctDNA collection, median age was 70 years, and 47.6% (N = 30/63) had bone-only metastases. ctDNA was detected in the majority of patients with at least 1 pathogenic alteration detected in 90.5% (N = 57/63) of individuals. The most common alterations detected were in AR, TP53, and PIK3CA. Actionable alterations with FDA-approved therapies were found in 15.8% (N = 10) of the cohort. The presence of ≤ 1 versus > 1 alteration on ctDNA analysis was strongly associated with inferior OS with a median OS of 26.1 versus 8.8 months, respectively (HR = 7.0, 95% CI, 2.2-23.1, P < .001). In multivariate analysis, the number of detected alterations remained a significant predictor for OS. Lastly, there was weak correlation between Prostate-Specific Antigen (PSA), and ctDNA characteristics., Conclusion: ctDNA is a viable next generation sequencing (NGS) platform in mCRPC and can be utilized to identify actionable alterations. The presence and extent of ctDNA alterations appear to be prognostic of OS in mCRPC., (Copyright © 2021. Published by Elsevier Inc.)