The INSPIRE trial, a phase II study, investigated the efficacy of nivolumab and ipilimumab combination therapy in molecularly selected patients with metastatic castration-resistant prostate cancer (mCRPC). The results, presented at ESMO, highlight the potential of dual checkpoint inhibitors in specific patient subgroups, particularly those with mismatch repair deficiency.
The trial focused on four subgroups of mCRPC patients: mismatch repair deficiency, high tumor mutational burden (TMB), CDK12 inactivation, and BRCA2 mutations. These subgroups represent approximately 15% of mCRPC patients. Patients were treated with nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) for up to four cycles, followed by nivolumab monotherapy for 10 cycles. The primary endpoint was disease control rate at six months, with secondary endpoints including objective response, biochemical response, progression-free survival (PFS), overall survival (OS), and toxicity.
Key Findings
The study screened almost 500 patients, with 69 initiating the protocol. The primary endpoint was met, with 38% of patients in Cohort A achieving disease control at six months. However, efficacy varied significantly across the molecular subtypes. The mismatch repair-deficient group showed an 81% disease control rate, while the high TMB, CDK12 inactivation, and BRCA2-mutated subgroups had rates of 25%, 19%, and 15%, respectively.
In the mismatch repair-deficient subgroup, 75% of patients with RECIST measurable disease experienced an objective response (all partial responses), and the median PFS was 32.7 months, compared to four months in the entire cohort. PSA90 responses were observed in 86% of mismatch repair-deficient patients, demonstrating deep and durable responses.
Clinical Implications
Niven Mehra, MD, PhD, from Radboud University Medical Centre, emphasized the importance of early molecular testing to identify patients who could benefit from checkpoint inhibitor therapy, particularly those with mismatch repair deficiency. He noted that while monotherapy with checkpoint inhibitors is reimbursed in some regions, the INSPIRE trial suggests that dual checkpoint inhibitors may offer superior efficacy in this specific subgroup.
"This trial showed clearly in the molecularly selected subgroup that there was efficacy... clear efficacy was seen in the mismatch repair-deficient subgroup with the dual checkpoints, demonstrating a disease control of 81%, objective responses of 75%, and PSA90 responses of 86%, reflecting a PFS of 33 months with a median follow-up of 19 months," said Dr. Mehra.
Moving Forward
The findings from the INSPIRE trial underscore the need for early testing and treatment of mismatch repair-deficient prostate cancer with dual checkpoints. Neeraj Agarwal, MD, FASCO, from the Huntsman Cancer Institute, highlighted the significance of these biomarker-targeted studies in mCRPC, a population with high unmet needs.
Dr. Mehra suggested that the data from INSPIRE, along with other trials like the NEPTUNES trial and CheckMate 650, might be sufficient to encourage regulatory bodies to consider reimbursement for dual checkpoint inhibitors in this setting. He also noted that some patients treated with dual checkpoints have remained disease-free for several years, suggesting the potential for cure in some cases.
Call to Action
Both Dr. Mehra and Dr. Agarwal emphasized the importance of comprehensive genomic profiling at the time of initial diagnosis of metastatic disease to identify targetable mutations, including mismatch repair deficiency, homologous recombination repair mutations, and PTEN deficiency. Early testing ensures that treatment decisions can be informed by the patient's specific molecular profile, potentially leading to improved outcomes.
