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

Abstract

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.

Keywords: BRCA; Biomarkers; DNA repair; Genomics; Germline; Precision medicine; Prostate cancer.