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

TPS291 Background: Approximately 20-25% of patients with metastatic castration resistant prostate cancer (mCRPC) harbour a germline or somatic mutation in the homologous recombination repair (HRR) pathway genes, which are involved in the repair of double stranded DNA damage. While polyadenosine 5’diphosphoribose [poly (ADP-ribose)] polymerase inhibitors, such as olaparib and rucaparib, are effective in this subgroup, their widespread use is limited due to the associated high cost, especially in resource-constrained settings. Platinum agents like carboplatin have exquisite sensitivity to cells with defective DNA repair machinery. Carboplatin, a conventional, inexpensive chemotherapeutic agent offers a potential alternative treatment in such patients. Several retrospective small case series support this hypothesis. However, there has been no prospective study evaluating the role of carboplatin in this subset of patients. Methods: This is an Investigator-initiated, prospective phase II, single-arm clinical trial in which patients diagnosed with mCRPC harbouring HRR pathway mutations previously treated with docetaxel or novel antiandrogen agents (abiraterone, enzalutamide, apalutamide, or darolutamide) or both will be eligible. Genes involved directly or indirectly in the HRR pathway will be tested by Next Generation Sequencing (NGS).We will screen approximately 200 patients to enroll 49 patients, and carboplatin (dosing at the area under curve=5) will be administered every 3 weeks until progression or intolerable side effects. The primary endpoint will be assessed as the proportion of patients with a reduction of serum prostate-specific antigen by more than 50% from enrolment. Using Simon’s two-stage design, 24 patients will be enrolled initially in the first stage. If at least 6 or more patients achieve a response, the trial will continue until enrolment of a total of 49 patients. Secondary outcomes include progression-free survival—soft-tissue disease progression (by response evaluation criteria in solid tumours, version 1.1, and bone lesion progression using Prostate Cancer Clinical Trials Working Group 3 criteria), health-related quality of life during carboplatin treatment using the Functional Assessment of Cancer Therapy—Prostate questionnaire and the European Organisation for Research and Treatment of Cancer questionnaire and safety profile of carboplatin (National Cancer Institute’s Common Terminology Criteria for Adverse Events version 5.0). The trial started enrolment in September 2023. The prespecified activity goal for the first stage of accrual was met; the second stage of accrual began in July 2024. This trial is ongoing and 30 patients have been recruited to date. All 49 participants will be enrolled according to plan. Clinical trial information: CTRI/2023/04/051507 .