Adding a checkpoint inhibitor to PSMA radioligand therapy

Radiation-induced cell death can expose tumour antigens and trigger immune responses, but immune checkpoints such as PD-1 can suppress that response. The PRINCE trial (NCT03658447, Peter MacCallum Cancer Centre) tested whether adding the PD-1 inhibitor pembrolizumab to 177Lu-PSMA-617 could improve outcomes in metastatic castration-resistant prostate cancer, a disease in which checkpoint inhibitors alone have limited activity. In this single-arm phase 1b/2 study of 37 patients, up to six cycles of 177Lu-PSMA-617 were given with pembrolizumab every three weeks for up to 24 months. The trial reported a PSA50 response rate of 76% and PSA90 of 46%, notably higher than the roughly 46% (VISION) and 66% (TheraP) PSA50 rates reported with 177Lu-PSMA-617 alone in other trials, and median radiographic progression-free survival of 11.2 months with median overall survival of 17.8 months.

The combination was not free of added toxicity: 35% of patients experienced grade 3 treatment-related adverse events, including grade 3 immune-related events in 30% of patients (colitis, myasthenia gravis, acute kidney injury, oral mucositis among them), and 14% of patients discontinued pembrolizumab because of immune-related toxicity, though all patients were able to continue 177Lu-PSMA-617. Because PRINCE was single-arm with no concurrent comparator, the reported PSA response rates cannot be directly attributed to the addition of pembrolizumab rather than to differences in patient selection between trials. A second combination trial, testing the CTLA-4-directed antibody ONC-392 alongside 177Lu-PSMA-617 (NCT05682443), is exploring an alternative checkpoint target in the same disease setting.