Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide

Background: Inherited DNA-repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood. Objective: To investigate the clinical significance of germlineDNA-repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving next-generation hormonal therapy (NHT), with a particular emphasis on BRCA/ATM mutations. Design, setting, and participants: We interrogated 50 genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT with abiraterone or enzalutamide. Outcome measurements and statistical analysis: We assessed the impact of germline DNA-repair gene mutation status on >= 50% and >= 90% PSA responses, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Survival outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses. Results and limitations: Among 172 mCRPC patients included, germline mutations (in any DNA-repair gene) were found in 12% (22/172) of men, and germline BRCA/ATM mutations specifically in 5% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs no mutations) with respect to PSA-PFS (hazard ratio [HR] 0.47; p = 0.061), PFS (HR 0.50; p = 0.090), and OS (HR 0.28; p = 0.059). In propensity score-weighted multivariable analyses, outcomes were superior in menwith germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95% confidence interval [CI] 0.25-0.92; p = 0.027), PFS (HR 0.52, 95% CI 0.28-0.98; p = 0.044), and OS (HR 0.34, 95% CI 0.12-0.99; p = 0.048), but not in men with non-BRCA/ATM germline mutations (all p > 0.10). These results require prospective validation, and our conclusions are limited by the small number of patients (n = 9) with BRCA/ATM mutations. Conclusions: Outcomes to first-line NHT appear better in mCRPC patients harboring germline BRCA/ATM mutations (vs no mutations), but not for patients with other non-BRCA/ATM germline mutations. Patient summary: Patients with metastatic castration-resistant prostate cancer and harboring germline mutations in BRCA1/2 and ATM benefit from treatment with abiraterone and enzalutamide. (C) 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.