Efficacy of Nivo3/Ipi1 in Molecularly Selected mCRPC

Anti-PD1 immune checkpoint blockade (ICB) is currently approved for use as monotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC) who have a tumor mutational burden (TMB) greater than 10 mutations per megabase (mut/Mb) or exhibit mismatch repair deficiency (MMRd). While dual anti-PD1/CTLA-4 therapy shows greater efficacy compared to monotherapy, the broader application of Nivolumab 1mg/kg and Ipilimumab 3mg/kg (Nivo1/Ipi3) in mCRPC is limited by associated toxicity.

Niven Mehra and the team aimed to explore the efficacy and safety of Nivo3/Ipi1 in patients with molecularly selected mCRPC.

They performed an inclusive analysis involving 69 molecularly selected patients with mCRPC having MMRd, non-synonymous TMB greater than 7 mut/Mb (hTMB), a BRCA2 mutation (BRCA2m), or biallelic inactivation of CDK12 (CDK12i).

Efficacy was assessed in cohort A, which comprised ICB-naïve patients with measurable disease as defined by RECIST1.1 (A1) and PCWG3 (A2). Safety evaluations were conducted in cohorts A and B, including patients who had received prior ICB monotherapy.

Patients were treated with Nivo3/Ipi1 every 3 weeks for 4 cycles, followed by Nivo at 480 mg every 4 weeks for up to 1 year. The primary endpoint was the disease control rate greater than 6 months (DCR>6), to exceed a DCR>6 of 22%.

About 69 patients initiated treatment between January 2021 and February 2024. The median age was 69 [range 50-82]. Cohort A included 65 patients, with 21 patients having MMRd (32%), 8 with hTMB (12%), 20 with BRCA2m (31%), and 16 exhibiting CDK12i (25%).

The median number of prior mCRPC treatments was 1 [range 0-5]. At the data cut-off, the median follow-up period was 12 months (mo) [range 1-42]. A DCR>6 was achieved in 38% (95% CI 27-51) of patients, with the highest rates observed in MMRd patients (81%), followed by hTMB (25%), CDK12i (19%), and BRCA2m patients (15%). The overall response rate (ORR), PSA50, and PSA90 responses were 38%, 47%, and 41%, respectively.

The median radiographic progression-free survival (rPFS) was 4.0 mo (95% CI, 3.5 to 12.0) in cohort A and 32.7 mo in patients with MMRd (95% CI, 21.8 to NR). Treatment-related adverse events (TRAEs) resulted in permanent discontinuation for 14 patients (20%). Grade ≥3 TRAEs occurred in 33 patients (48%) and included diarrhea and elevated transaminases, each affecting 10% of patients. There were 2 treatment-related deaths, specifically a bowel perforation, and euthanasia following grade 4 toxicity.

The study concluded that the trial of dual ICB in molecularly selected mCRPC successfully met its primary endpoint, demonstrating durable benefits across MMRd, hTMB, BRCA2m, and CDK12i subgroups. Outcomes for patients with MMRd were notably superior to those previously reported for ICB monotherapy.

The trial was sponsored by the Radboud University Medical Center.

Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/18

Clinical Trial: https://clinicaltrials.gov/study/NCT04717154

Mehra N, Wilpe S.V, Westdorp H, et al. (2024). “Nivolumab 3mg/kg and ipilimumab 1mg/kg (nivo3/ipi1) in molecularly selected patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).” Presented at ESMO 2024 (Abstract LBA72).