Metastatic castration-resistant prostate cancer (mCRPC) typically exhibits resistance to immune checkpoint inhibitors (ICIs). However, a subset of mCRPC patients displays a more immunogenic profile. This study examines efficacy and safety of dual ICI therapy in molecularly selected mCRPC.
This single-arm, phase II trial, included 69 molecularly selected mCRPC patients with mismatch repair deficiency (MMRd), non-synonymous tumour mutational burden ≥7.1 muts/Mb (hTMB), a BRCA2 mutation (BRCAm), or biallelic CDK12 inactivation (CDK12i). Efficacy was assessed in ICI-naïve patients (cohort A) with RECIST1.1 (A1) and PCWG3 (A2) measurable disease. Safety was evaluated in cohorts A and B (prior ICI monotherapy). Treatment included nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for 4 cycles, followed by nivolumab 480 mg every 4 weeks for up to 1 year. The primary endpoint was disease control rate beyond 6 months (DCR>6), aiming to surpass a DCR>6 of 22%.
Patients initiated treatment between January 2021 and February 2024. Cohort A included 65 patients. Of these, 21 had MMRd (32%), 8 hTMB (12%), 20 BRCAm (31%), and 16 CDK12i (25%). DCR>6 was achieved in 38% (95% CI 27-51), and was highest in MMRd (81%), followed by hTMB (25%), CDK12i (19%), and BRCAm (15%). Objective and PSA50 response rates in cohort A were 38% (95% CI 22-55) and 47% (95% CI 34-60), respectively. Median progression-free survival was 4.0 months (95% CI 3.5-12.0) in cohort A, and 32.7 months (95% CI 21.8-NR) in MMRd patients. Treatment-related adverse events (TRAEs) led to permanent discontinuation in 14 of 69 patients (20%). Grade ≥3 TRAEs occurred in 48% of patients, with diarrhoea and elevated transaminases each in 10%. There was one treatment-related death due to a bowel perforation and a second following euthanasia after grade 4 toxicity.
This trial of dual ICIs in molecularly selected mCRPC met its primary endpoint, showing DCR>6 in 40% of patients. Dual ICIs exhibited modest responses in the hTMB, BRCAm and CDK12i subgroups, but demonstrated exceptional efficacy in MMRd.
Annals of oncology : official journal of the European Society for Medical Oncology. 2024 Sep 10 [Epub ahead of print]
S van Wilpe, I S H Kloots, P H J Slootbeek, M den Brok, H Westdorp, M D Franken, M Coskunturk, T Osinga, H Bloemendal, G Adema, R J Smeenk, J Nagarajah, J van Ipenburg, L I Kroeze, M J L Ligtenberg, J Schalken, W R Gerritsen, N Mehra
Medical Oncology Department, Radboud university medical center Nijmegen, Nijmegen, The Netherlands., Department of Radiation Oncology, Radboud university medical center, Nijmegen, The Netherlands., Department of Medical Imaging, Radboud university medical center, Nijmegen, The Netherlands., Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands., Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands; Department of Radiation Oncology, Radboud university medical center, Nijmegen, The Netherlands., Urology Department, Radboud university medical center, Nijmegen, The Netherlands., Medical Oncology Department, Radboud university medical center Nijmegen, Nijmegen, The Netherlands. Electronic address: .