Carboplatin in patients with metastatic castration-resistant prostate cancer harboring somatic or germline homologous recombination repair gene mutations: phase II single-arm trial (CIPHER)

Background Homologous recombination repair (HRR) gene alterations in metastatic castration-resistant prostate cancer (mCRPC) confer vulnerability to DNA-damaging therapies. Although poly (ADP-ribose) polymerase inhibitors improve outcomes in biomarker-selected patients, limited access due to high cost restricts their use in resource-limited health care settings. Platinum chemotherapy targets HRR-altered tumor cells and could be a feasible option but there are limited prospective data on its use in genomically selected mCRPC. Patients and methods This phase II, single-arm study was conducted in men with mCRPC harboring deleterious somatic or germline HRR alterations previously treated with docetaxel and/or a novel androgen receptor pathway inhibitor. Carboplatin was administered every 3 weeks (dose calculated at area under the curve 5) until progression or intolerable toxicity. The primary endpoint was confirmed prostate-specific antigen (PSA) 50 response (≥50% decline from baseline). Secondary endpoints included radiographic progression-free survival (rPFS), safety (Common Terminology Criteria for Adverse Events, version 5.0), and health-related quality of life (the Functional Assessment of Cancer Therapy-Prostate questionnaire and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 with the prostate cancer–specific PR25 module). Results Thirty-nine patients received carboplatin. A confirmed PSA50 response was observed in 41.0% (95% confidence interval 25.6-57.9) of patients. The median rPFS was 4.53 months. The median time to objective response was 3.48 months and the median duration of response was 6.93 months. Durable responses were observed in patients with breast cancer susceptibility gene 1/2 alterations. Treatment-emergent adverse events occurred in 97.4% of patients, with grade ≥3 events occurring in 59.0% of patients, predominantly hematologic. Overall quality of life was largely preserved, with modest deterioration in social functioning, incontinence aid, and hormonal symptom domains. Conclusions Single-agent carboplatin produced encouraging PSA responses with predictable toxicity in HRR-altered mCRPC. Carboplatin represents a pragmatic option in selected patients with HRR-altered mCRPC, especially in resource-constrained settings.