Ipilimumab plus nivolumab elicits response in molecularly selected mCRPC patients

Use of dual immune checkpoint inhibitors (ICIs), nivolumab and ipilimumab, exhibits responses in some molecularly selected patients with metastatic castration-resistant prostate cancer (mCRPC), including those with mismatch repair deficiency (dMMR), nonsynonymous tumour mutational burden ≥7.1 muts/Mb (hTMB), a BRCA2 mutation (BRCAm), or biallelic CDK12 inactivation (CDK12i).

“The study met its primary endpoint, demonstrating a 6-month disease control rate (DCR) of 38 percent in the efficacy population,” the investigators said. “Responses were particularly robust in patients with dMMR and underscore the need for early testing and earlier treatment of dMMR mCRPC with dual ICIs.”

Sixty-nine mCRPC patients were enrolled in this single-arm, phase II trial. The investigators assessed efficacy in ICI-naïve patients (cohort A) with RECIST 1.1 (A1) and Prostate Cancer Working Group 3 (A2) measurable disease. They also assessed safety in cohorts A and B (those with prior ICI monotherapy).

In the trial, the participants received nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for four cycles, followed by nivolumab 480 mg every 4 weeks for up to 1 year. They started treatment between January 2021 and February 2024. DCR beyond 6 months (DCR >6), with a rate of >22 percent, was the primary endpoint.

Disease control

Sixty-five patients were included in cohort A, of whom 21 had dMMR (32 percent), eight had hTMB (12 percent), 20 had BRCAm (31 percent), and 16 had CDK12i (25 percent). [Ann Oncol 2024;35:1126-1137]

The primary endpoint was achieved in 38 percent of patients (95 percent confidence interval [CI], 27‒51). DCR >6 was highest in dMMR (81 percent), followed by hTMB (25 percent), CDK12i (19 percent), and BRCAm (15 percent). Objective response rate was 38 percent (95 percent CI, 22‒55), with 47 percent (95 percent CI, 34‒60) achieving a 50-percent decline in prostate-specific antigen levels.

In cohort A, the median progression-free survival was 4.0 months (95 percent CI, 3.5‒12.0), while that in dMMR patients was 32.7 months (95 percent CI, 21.8‒not reached).

Fourteen patients (20 percent) experienced treatment-related adverse events (TRAEs) that led to discontinuation, while nearly half of the participants (48 percent) had grade ≥3 TRAEs, with diarrhoea and elevated transaminases each in 10 percent. Two treatment-related deaths occurred, one due to a bowel perforation and a second following euthanasia after grade 4 toxicity.

“Dual ICIs exhibited modest responses in the hTMB, BRCAm, and CDK12i subgroups, but demonstrated exceptional efficacy in dMMR,” the investigators said.

Predictors

Beyond dMMR, no predictive biomarkers are available yet for response to dual ICIs. This study shows benefit in up to 20 percent of patients with advanced mCRPC with BRCAm and CDK12i, precluding the use of genomic alterations for patient selection to ICIs.

“Translational analyses from this study and other studies with dual ICIs may shed more light on genomic correlates associated with response,” the investigators said. [J Clin Oncol 2023;41:22; Clin Cancer Res 2021;27:566-574; J Clin Oncol 2024;42:5013; Prostate 2021;81:326-338]

“These include frameshift mutation burden in dMMR, tandem duplication signatures and fusion load in CDK12i, and genomic instability correlates in BRCAm,” they added.

Moreover, using other types of biomarkers, including the composition of the immune infiltrate, must be further studied to improve patient selection for ICIs, according to the investigators.