Clinical Impact of Germline Pathogenic Variants in High-risk Prostate Cancer Treated with Radiotherapy

Background Pathogenic and likely pathogenic (P/LP) germline variants in cancer susceptibility genes (CSGs) are detected in 5–10% of patients with prostate cancer, but their clinical impact in high-risk disease remains unclear. Objective This study aimed to assess the prevalence of P/LP variants in CSGs among patients with high-risk prostate cancer and their association with oncologic outcomes in patients treated with radiotherapy. Methods We conducted a retrospective study of 600 men with high-risk prostate cancer. Germline DNA was analyzed using a 19-gene panel, and gene-level variant prevalence was compared with non-cancer control cohorts using Fisher’s exact test. Time-to-event analyses were performed in the 390 patients treated with radiotherapy as primary curative intent. The primary endpoint was overall survival (OS), assessed by Kaplan-Meier and multivariable Cox regression. Secondary endpoints included biochemical recurrence, distant metastasis, prostate cancer–specific mortality (PCSM), and second primary malignancies, analyzed using cumulative incidence functions and Fine-Gray competing-risk models. Key findings and limitations P/LP variants were identified in 8.0% of patients ( n = 48). CHEK2 , ATM , and BRCA2 variants were significantly enriched in patients compared with non-cancer control cohorts. BRCA1/BRCA2 carriers had worse OS (10-yr OS rate: 19% vs 57%; p = 0.021) and higher cumulative incidence of biochemical recurrence events (10-yr cumulative incidence: 57% vs 28%; p = 0.048), distant metastases (57% vs 18%; p = 0.004) and PCSM (33% vs 4.3%; p = 0.001) compared with non-carriers. CHEK2 carriers showed heterogeneous family cancer histories and a higher incidence of second primary malignancies (47% vs 15%; p = 0.003). ATM carriers showed no metastatic progression or PCSM during follow-up. Limitations include the single-institution design and small gene-specific subgroups. Conclusions and clinical implications Germline P/LP variants are prevalent in high-risk prostate cancer and define gene-specific subgroups with distinct oncologic outcomes, supporting the role of germline genetic testing in risk stratification and treatment decision-making.