PRINCE

PRINCE was a single-arm, multicentre phase 1b/2 trial led by the Peter MacCallum Cancer Centre, testing whether adding the checkpoint inhibitor pembrolizumab to 177Lu-PSMA-617 could improve on radioligand therapy alone in metastatic castration-resistant prostate cancer, a disease with generally low response to immunotherapy alone. Eligible men had progressed on an androgen receptor pathway inhibitor (prior docetaxel allowed) and had high PSMA expression on PET. Participants received up to six cycles of 177Lu-PSMA-617 every six weeks with pembrolizumab 200 mg every three weeks for up to 24 months. Co-primary endpoints were safety and PSA50 response rate.

Among 37 participants (73% docetaxel-pretreated, 100% ARPI-pretreated), a PSA decline of 50% or more was seen in 76%, and 46% had a PSA decline of 90% or more. In the subset with measurable disease, the objective response rate was 70%. Median overall survival was 20.8 months. Toxicity was consistent with the known profiles of each drug: xerostomia, fatigue and pruritus were common but mostly grade 1-2, while grade 3 immune-related adverse events (colitis, pancreatitis, myasthenia gravis, and others attributable to pembrolizumab) occurred in 30% of patients; there were no grade 4 events or treatment-related deaths.

PRINCE reports encouraging activity and manageable toxicity for the combination, broadly in line with 177Lu-PSMA-617 monotherapy benchmarks from VISION, and the authors conclude that radioligand therapy remains the principal driver of response with pembrolizumab possibly adding benefit in a biologically susceptible subset. It is a single-arm, non-randomised study, so it cannot establish incremental benefit from adding pembrolizumab.