Activity of Platinum Monotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer and DNA Damage Repair Gene Alterations

PURPOSE Up to 30% of patients with metastatic castration-resistant prostate cancer (mCRPC) have DNA damage repair (DDR) gene alterations, mainly in BRCA2 . PARP inhibitors (PARPi) are standard treatments for BRCA1/2 -altered patients with mCRPC, and evidence for platinum agents is limited. This study assesses single-agent platinum therapy in patients with mCRPC with and without DDR alterations. METHODS This multicenter, retrospective study included patients with mCRPC with known DDR status treated with platinum monotherapy. DDR-positive (DDR+) patients had deleterious germline or somatic alterations in DDR genes ( BRCA1 , BRCA2 , CDK12 , ATM , CHEK2 , PALB2 , or FANCA ), whereas DDR-negative (DDR–) patients had no such alterations. Prostate-specific antigen (PSA) response, progression-free survival (PFS, PSA/clinical/radiographic), and overall survival (OS) were assessed in DDR+ and DDR– groups. RESULTS Among 129 patients, 81 had DDR+ and 48 had DDR– cancers. A PSA decline of ≥50% was demonstrated in 48% in BRCA, 9% in DDR+ non-BRCA, and 13% in DDR– patients ( P < .0001). Objective responses occurred in 37.5% in BRCA, 11% in DDR+ non-BRCA, and 13% in DDR– patients ( P = .017). No response was reported in DDR+ patients who had received previous PARPi (n = 16). The median PSA response was 5 months for BRCA, 2 months for DDR+ non-BRCA, and 1.7 months for DDR– patients, respectively ( P = .015), whereas the median clinical/radiographic PFS was 4.7 months, 2.8 months, and 2 months, respectively ( P = .2). In PARPi-naïve patients, the median OS was 13.7 months for BRCA, 8.7 months for DDR+ non-BRCA, and 6.1 months for DDR– patients ( P = .013). CONCLUSION Single-agent platinum agents show significant anticancer activity in BRCA -mutated patients with mCRPC without previous PARPi exposure. With their low cost and broad availability, platinum agents offer a practical alternative, particularly in regions where PARPi are inaccessible.