Carboplatin in patients with metastatic castration-resistant prostate cancer (mCRPC) harbouring somatic or germline homologous recombination repair (HRR) gene mutations: Protocol for a phase II single-arm trial.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) remains an unmet medical challenge. Approximately 20-25% of patients with mCRPC harbour a deleterious germline or somatic mutation in the homologous recombination repair (HRR) pathway genes, which is involved in the repair of double-stranded DNA damage. Half of these mutations are germline, while the remaining are exclusively somatic. While poly ADP ribose polymerase (PARP) inhibitors, like olaparib and rucaparib, are effective in this subgroup, their widespread use is limited due to the associated high cost, especially in resource-constrained settings. Notably, platinum agents like carboplatin have exquisite sensitivity to cells with defective DNA repair machinery; this mechanism is known as synthetic lethality. Carboplatin, a conventional, inexpensive chemotherapeutic agent, offers a potential alternative treatment in such patients. Several retrospective small case series support this hypothesis. However, there are no prospective clinical trials of carboplatin in patients with mCRPC with HRR mutations.

OBJECTIVE: The primary objective is to assess the objective response rate of three weekly carboplatin treatments in patients with mCRPC harbouring deleterious mutations in the HRR pathway genes and previously treated with a taxane and/or a novel antiandrogen agent. Secondary objectives include progression-free survival, health-related quality of life, and safety profile of carboplatin.

METHODS: 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. In this single-arm phase II study, we will screen approximately 200 patients to enroll 49 patients, and carboplatin (dosing at the area under curve = 5) will be administered every three weeks until progression or intolerable side effects. The primary endpoint will be assessed as the proportion of patients with a reduction of serum PSA by more than 50% from enrollment. Secondary outcomes include progression-free survival - soft-tissue disease progression [by Response Criteria Evaluation in solid tumors , 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 (NCI CTCAE version 5.0).

RESULTS: The trial started enrollment in September 2023. This trial is ongoing, and 12 patients have been recruited to date All 49 participants will be enrolled according to plan.

CONCLUSIONS: This prospective phase II trial represents a critical step towards addressing the therapeutic gap in mCRPC patients harboring HRR pathway mutations, particularly in demographic regions with limited access to PARP inhibitors. Outcomes from this study will inform clinical practice and guide future phase III randomized trials, ultimately improving patient outcomes globally.

CLINICALTRIAL: Clinical Trials Registry of India (CTRI/2023/04/051507).