Background: Aberrations of the DDR pathway have been shown to be prognostic of survival and predictive of PARP inhibition in PCa. Additionally, germline mutations in DDR genes are linked to PCa susceptibility. Here, we report the germline DDR mutation frequencies in an EA PCa cohort, and their associations with clinicopathological indices and outcomes. Methods: We utilized a prospectively recruited cohort of 891 EA patients, with centrally assessed Gleason’s score (GS) by an expert pathologist. Germline mutation profiling was performed by whole exome sequencing (100X) using the Illumina Novaseq (CA). Following joint genotyping, common variants of ≥1% were filtered, and only variants defined as pathogenic (P)/likely pathogenic (LP) in ClinVar or predicted to be P by CADD or REVEL were retained. We used a 32 DDR gene-set for tests of association with clinicopathological indices, biochemical relapse-free rate (bRFR), and distant metastasis-free survival (DMFS). Results: Median follow up was 54 (33-83) mo; median age at diagnosis was 70 (64-74) y. 741 (84%) men had localized PCa, 65 (7%) had N+M0, and 80 (9%) had M1 disease. Among those with localized PCa, 417 (56%) were stratified as NCCN high/very high. 5-year DMFS was 100%, 96%, 86%, and 74% for NCCN low, intermediate, high/very high, and N+M0 PCa, respectively. 31 (3.5%) men in our cohort harbored a P/LP variant in at least one of the 32 DDR genes; P/LP variants were most frequently observed for BRCA2 (N=11[1.2%]), ATM (N=6[0.7%]), and RAD50 (N=5[0.6%]). P/LP variants were more frequent in men with N+M0/M1 compared with those with localized PCa (29% vs 16%, P=0.05), and in men with GS 9-10 vs 6-8 tumors (43% vs 20%, P=0.002). Presence of P/LP DDR variants were significantly associated with bRFR (HR 2.44 [95% CI:1.0-6.1], P=0.049) in M0 patients treated with RT+/-hormonal therapy on univariable and multivariable analyses. Conclusions: Herein, we observed lower frequencies of germline DDR P/LP mutations in our EA PCa cohort than other published Chinese cohorts (Wei, et al. 2018; Wei, et al. 2020). Nonetheless, there was a strong trend for increased incidence of DDR mutations with more advanced PCa. Men with DDR mutations were more likely to fail treatment than men without.

Abbreviations: RG, Risk grouping based on NCCN Guidelines; GS, Gleason’s score; P/LP, pathogenic/likely pathogenic DDR variants.