Background: Enrichment of germline PVs in metastatic castration resistant prostate cancer (mCRPC), compared to localized disease, has directly informed genetic testing guidelines. The prevalence and prognostic/predictive associations of such variants are not well characterized in the mHSPC state, in particular the effect of susceptibility mutations related to DNA damage and repair (DDR) pathways. Methods: We performed whole exome sequencing of germline DNA derived from whole blood available from patients (pts) in the phase III CHAARTED trial (NCT00309985) of androgen deprivation therapy (ADT) versus ADT plus docetaxel (ADT+D). After filtering for low coverage, variant annotation and effect prediction, PVs from a curated list of 588 prostate cancer-associated genes were reviewed. The prognostic effect of PVs was evaluated within each treatment arm. Endpoints of time to CRPC (ttCRPC), time to clinical progression (ttClinPD), and overall survival (OS) were estimated by Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated by Cox models evaluating association of endpoints with biomarkers/arm. Multivariable analysis adjusted for metastatic timing and volume. Results: Of 137 pts, 135 had unique germline exomes that passed downstream analysis. Most pts had synchronous (66.7%) and high-volume (62.2%) disease. This biomarker cohort showed benefit of adding docetaxel to ADT (ttCRPC: HR 0.55, 95% CI 0.37-0.82; OS: HR 0.68, 95% CI 0.44-1.07). In total, 61 PVs were detected; 49 pts (36.3%) harbored at least 1 PV in 41 different genes. The most frequently-mutated gene was BRCA2 (6.67%). In addition, PVs were found in DDR-associated genes including PALB2 (1.48%), CHEK2 (1.48%), BRCA1 (0.74%) and PMS2 (0.74%) for an overall prevalence of 11.1% (15/135). Pts with BRCA2 PV on ADT alone had shorter ttCRPC compared with men without the PV (UVA: HR 2.67, 95% CI 0.93-7.63, log rank p=0.057; MVA: HR 2.59, 95% CI 0.91-7.39, p=0.074). There was no evidence of a difference in the ADT+D arm (UVA: HR 1.00, 95% CI 0.31-3.25, log rank p=0.1). Supportive data was observed for ttClinPD in ADT arm (HR 2.85, 95% CI 1.01-8.08, log rank p=0.04). Metastatic volume and timing were not significantly associated with germline BRCA1/2 or DDR PVs. Conclusions: The prevalence of germline BRCA1/2 and DDR PVs in mHSPC is similar to mCRPC and BRCA2 PV may confer worse outcomes on ADT alone. This supports the need for genetic testing at diagnosis of mHSPC.

wt: wild-type; mt: mutated.