Clinical Outcome of Prostate Cancer Patients with Germline DNA Repair Mutations: Retrospective Analysis from an International Study

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 gBRCAI/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+ = 83 mo, gDDRm- = 83 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.& para;& para;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. (C) 2018 European Association of Urology. Published by Elsevier B.V.