JMIR Publications

ABSTRACT

Background:

Despite the favourable outcomes in early-stage prostate cancer cases, a subset of patients (15-20%) present with distant metastasis, often involving bones, nonregional lymph nodes, and liver. Patients with metastatic prostate cancer are treated with androgen deprivation therapy (ADT) with additional chemotherapeutic agents and/or novel antiandrogen agents. These patients eventually develop resistance to ADT, and this state, known as castration-resistant prostate cancer (CRPC), is incurable, despite the advent of newer therapies. The therapeutic landscape for mCRPC involves chemotherapeutic agents, novel antiandrogen agents, and radioligand therapies. Pritchard et al.(1) reported that 11.8% of men with metastatic prostate cancer harbour deleterious germline mutations, primarily in BRCA2, followed by ATM, CHEK2, BRCA1, RAD51D and PALB41 genes. Subsequent studies evaluated the prevalence of deleterious somatic mutations within the homologous recombination repair (HRR) pathway in 25-30% of patients with mCRPC . PARP inhibitors employ a strategy of synthetic lethality, inhibiting the base excision repair pathway, leading to the accumulation of unrepaired DNA breaks within HRR-deficient tumour cells, culminating in cancer cell death(2)(3)(4). Olaparib, a PARP inhibitor, demonstrated an impressive 88% response rate in mCRPC patients with HRR gene abnormalities, in contrast to a minimal 3% response in those without these mutations (5)(6). The pivotal PROfound trial further supported these findings, leading to FDA approval for patients with mCRPC harbouring HRR gene mutations(7). Similar efficacy was observed with other PARP inhibitors, including rucaparib and talazoparib(8)(9). However, most patients with mCRPC harbouring HRR gene mutations residing in low- and middle-income countries (LMICs) do not have access to PARP inhibitors. Interestingly, HRR-deficient tumours also exhibit increased sensitivity to platinum-based chemotherapeutic agents due to their reliance on the HRR pathway for DNA double-strand break repair, a vulnerability exploited by platinum-containing treatments that have previously been observed in breast and ovarian tumours (10) (11). Initial studies involving carboplatin in unselected mCRPC patients showed encouraging efficacy, particularly within the subset carrying HRR gene alterations(12)(13)(14). However, these studies are limited by several biases associated with retrospective studies. Despite a strong scientific rationale and encouraging preliminary data from real-world studies, no prospective study has been reported to assess the role of carboplatin in this subset of patients.

Objective:

The primary objective of this study is to assess the PSA response rate of three weekly carboplatin treatments (AUC 5) in patients with mCRPC harbouring deleterious mutations in the HRR genes and previously treated with a taxane and/or a novel antiandrogen (proportion of patients with more than 50% serum PSA decline) The secondary objectives are to compare the effect of oral gabapentin with placebo on: 1. 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) 2. Health-related quality of life during carboplatin treatment (FACT-P questionnaire and EORTC questionnaire) 3. Safety profile of carboplatin (NCI CTCAE version 5.0)

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:

This is a trial protocol. Results will be available after completion of trial

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)