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

Abstract

Up to 30% of patients with metastatic castration-resistant prostate cancer (mCRPC) have DNA damage repair (DDR) gene alterations, mainly in <i>BRCA2</i>. PARP inhibitors (PARPi) are standard treatments for <i>BRCA1/2</i>-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. 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 (<i>BRCA1</i>, <i>BRCA2</i>, <i>CDK12</i>, <i>ATM</i>, <i>CHEK2</i>, <i>PALB2</i>, or <i>FANCA</i>), 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. 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 (<i>P</i> < .0001). Objective responses occurred in 37.5% in BRCA, 11% in DDR+ non-BRCA, and 13% in DDR- patients (<i>P</i> = .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 (<i>P</i> = .015), whereas the median clinical/radiographic PFS was 4.7 months, 2.8 months, and 2 months, respectively (<i>P</i> = .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 (<i>P</i> = .013). Single-agent platinum agents show significant anticancer activity in <i>BRCA</i>-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.