Germline DNA damage repair variants and prognosis of patients with high-risk or metastatic prostate cancer

Abstract Purpose: Deleterious germline variants in certain DNA repair genes are risk factors for developing aggressive prostate cancer. The objective was to quantify their prognostic impact after prostate cancer diagnosis. Experimental Design: Men with prostate cancer, predominantly of European ancestry, were included from four cohorts with long-term follow-up. Pathogenic or likely pathogenic germline variants in 26 DNA repair genes were assessed in relation to metastasis-free survival in high-risk localized prostate cancer and to overall survival in metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). Results: Among 3,525 patients initially diagnosed with nonmetastatic prostate cancer, 2,594 had high-risk localized prostate cancer, 429 had mCSPC, and 502 had mCRPC at inclusion. BRCA2 variant carriers did not have worse metastasis-free survival in high-risk localized prostate cancer [hazard ratio (HR), 1.01; 95% confidence interval (CI), 0.69–1.46] or overall survival in mCSPC (HR, 0.46; 95% CI, 0.14–1.45) or mCRPC (HR, 0.60; 95% CI, 0.31–1.17) compared with noncarriers of DNA repair variants. Among 868 additional patients with de novo metastatic (M1) prostate cancer, BRCA2 variant carriers tended to have worse overall survival (HR, 1.59; 95% CI, 1.01–2.51). BRCA2 prognostic associations were not explained by radiation, PARP inhibitor, or platinum therapy. Results for other genes were limited in precision because variants were less common. Conclusions: Among patients with high-risk or metastatic prostate cancer who were initially diagnosed with and treated for nonmetastatic tumors, germline DNA repair variants in BRCA2 do not confer a substantially worse prognosis.