JMIR Publications

ABSTRACT

Background:

Metastatic castration-resistant prostate cancer (CRPC) is an incurable disease and 25-30% of patients harbour deleterious/likely deleterious mutations in the homologous recombination repair (HRR) pathway. In these patients, poly ADP ribose polymerase (PARP) inhibitors are effective and improve overall survival. These agents act by ‘synthetic lethality’, wherein tumour cells with defective HRR are unable to repair DNA damage when treated with PARP inhibitors. However, these drugs are inaccessible to most patients in low- and middle-income countries. Interestingly, carboplatin is an inexpensive chemotherapeutic drug that also utilizes ‘synthetic lethality’. Retrospective studies have demonstrated an encouraging response rate with carboplatin in this subset of mCRPC patients. However, no prospective clinical trial has been conducted to elucidate the role of carboplatin in patients with mCRPC harbouring deleterious mutations in the HRR pathway.

Objective:

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.

Methods:

Patients diagnosed with mCRPC harbouring HRR pathway mutations previously treated with docetaxel or novel antiandrogen agents (abiraterone or enzalutamide) or both will be eligible. In this single-arm phase II study, we will screen approximately 200 patients to enrol 49 patients, and carboplatin will be administered every three weeks until progression. The primary outcome is to assess the objective response rate as the proportion of patients with more than 50% serum PSA decline. Secondary outcomes include progression-free survival (PFS) - soft-tissue disease progression [by RECIST, version 1.1] and bone lesion progression (by Prostate Cancer Clinical Trials Working Group 3 criteria), health-related quality of life during carboplatin treatment (FACT-P questionnaire and EORTC questionnaire) and safety profile of carboplatin (NCI CTCAE version 5.0)

Results:

The project has been funded in March 2022. Data collection started on 20 th September 2023. As of November 2023, we enrolled 2 out of 49 patients.The results will be published in July 2025.

Conclusions:

This prospective phase II clinical trial will provide data on the efficacy of carboplatin in patients with mCRPC. If the study provides positive results, a phase III randomized study will be conducted. Clinical Trial: The trial is registered prospectively with the Clinical Trials Registry of India (CTRI/2023/04/051507)