LBA72 - Nivolumab 3mg/kg and ipilimumab 1mg/kg (nivo3/ipi1) in molecularly selected patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)

Background

Anti-PD1 immune checkpoint blockade (ICB) is currently approved as monotherapy for mCRPC pts with a tumor mutational burden (TMB) of >10 mutations per megabase (mut/Mb) or mismatch repair deficiency (MMRd). Dual anti-PD1/CTLA-4 appears more effective than monotherapy, but wide applicability of nivo1/ipi3 in mCRPC is constrained by its toxicity. This study investigates the efficacy and safety of nivo3/ipi1 in molecularly selected mCRPC.

Methods

This single arm, phase II trial, included 69 molecularly selected mCRPC pts with MMRd, non-synonymous TMB >7 mut/Mb (hTMB), a BRCA2 mutation (BRCA2m) or biallelic inactivation of CDK12 (CDK12i). Efficacy was evaluated in cohort A, which included ICB-naïve pts with RECIST1.1 (A1) and PCWG3 (A2) measurable disease. Safety was evaluated in cohorts A and B (prior ICB monotherapy). Pts were treated with nivo3/ipi1 Q3W for 4 cycles, followed by nivo 480 mg Q4W up to 1 year. Primary endpoint was disease control rate > 6 months (DCR>6), aiming to surpass a DCR>6 of 22%.

Results

Pts initiated treatment (Tx) between Jan 2021 and Feb 2024. Median age was 69 [range 50-82]. Cohort A consisted of 65 pts. 21 pts had MMRd (32%), 8 hTMB (12%), 20 BRCA2m (31%) and 16 CDK12i (25%). Median number of prior mCRPC Txs was 1 [range 0-5]. At data cut off, the median follow up was 12 months (mo) [range 1-42]. DCR>6 was reached in 38% (95% CI 27-51) and was highest in MMRd pts (81%), followed by hTMB (25%), CDK12i (19%) and BRCAm pts (15%). ORR, PSA50 and PSA90 responses were 38%, 47% and 41%, resp. Median rPFS was 4.0 mo (95% CI, 3.5 to 12.0) in cohort A and 32.7 mo in MMRd pts (95% CI, 21.8 to NR). Tx-related AEs (TRAEs) led to permanent discontinuation in 14 pts (20%). Grade ≥3 TRAEs occurred in 33 pts (48%) and included diarrhea and elevated transaminases (each in 10% of pts). There were 2 Tx-related deaths, i.e. a bowel perforation and euthanasia following grade 4 toxicity.

Conclusions

This trial of dual ICB in molecularly selected mCRPC met its primary endpoint. Durable benefit was seen across MMRd, hTMB, BRCA2m and CDK12i subgroups. Outcomes to dual ICB in pts with MMRd appear superior than what was previously reported for ICB monotherapy.

Clinical trial identification

NCT04717154.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Bristol Meyers Squibb.

Disclosure

N. Mehra: Financial Interests, Personal, Advisory Board: Pfizer, MSD, AstraZeneca, Astellas, JNJ, Bayer; Financial Interests, Institutional, Advisory Board: Janssen; Financial Interests, Institutional, Other, An predictive biomarker IP is being validated / no income / no royalties: EUROSTAR grant for predictive biomarker in urothelial cancer; Financial Interests, Institutional, Funding: Astellas, Pfizer; Financial Interests, Personal and Institutional, Funding: Janssen; Financial Interests, Institutional, Coordinating PI: BMS, Janssen, BMS; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS; Non-Financial Interests, Leadership Role, Head of the Prostate Cancer Working group: Dutch Uro-Oncology Study Group; Non-Financial Interests, Principal Investigator, co-PI / multi-dharma sponsored: Prospective Bladder Cancer Infrastructure (Netherlands); Non-Financial Interests, Leadership Role: Castration-resistant Prostate Cancer Registry; Non-Financial Interests, Principal Investigator, RWD registry de novo mHSPC: TripleAIM1 / Janssen. M. Franken: Financial Interests, Institutional, Invited Speaker: Servier; Financial Interests, Institutional, Other, Congress: Ipsen; Financial Interests, Institutional, Advisory Board: Astellas. J. Nagarajah: Financial Interests, Institutional, Research Funding: Advanced Accelerator Applications, ABX; Financial Interests, Institutional, Advisory Role: Curium, Point Biopharma, Bayer, Pfizer; Financial Interests, Institutional, Other, Travel support: Bayer. M. Ligtenberg: Financial Interests, Institutional, Advisory Board: AstraZeneca, GSK, Janssen Pharmaceuticals; Financial Interests, Institutional, Other, educational activities: Roye Congressen, Uitgeverij Jaap. All other authors have declared no conflicts of interest.