[Lu]Lu-PSMA-617 in combination with pembrolizumab for treatment of metastatic castration resistant prostate cancer (PRINCE): a single-arm, phase 1b/2 study.

[BACKGROUND] Lutetium-177 [Lu]-prostate-specific membrane antigen (PSMA)-617 improves overall survival and progression-free survival in metastatic castration resistant prostate cancer (mCRPC), whereas immune checkpoint inhibitors (ICIs) have limited activity. Preclinical evidence suggests radioligand therapy might induce immunogenic cell death that can be enhanced with ICIs. This study evaluates the activity and adverse event profile associated with multiple doses of [Lu]Lu-PSMA-617 with pembrolizumab.

[METHODS] PRINCE was a multicentre, single-arm, phase 1b/2 trial of [Lu]Lu-PSMA-617 and pembrolizumab. Eligible participants were aged 18 years or older, had mCRPC, an Eastern Cooperative Oncology Group performance status of 0-1, previous androgen receptor pathway inhibitor therapy with previous docetaxel allowed, and high PSMA expression. Participants received up to six cycles of [Lu]Lu-PSMA-617 intravenously every 6 weeks with 200 mg of pembrolizumab intravenously every 3 weeks for up to 24 months. Co-primary endpoints were safety and 50% prostate-specific antigen (PSA) response rate. All participants who received treatment were included in the analysis. The trial is registered with ClinicalTrials.gov, NCT03658447, and has been completed.

[FINDINGS] Between Aug 22, 2019 and Dec 16, 2020, 37 participants (median age 72 years, IQR 67-76; 27 [73%] docetaxel pretreated) received a median of six cycles (IQR 4-6) of [Lu]Lu-PSMA-617 and a median of 12 cycles (IQR 6-24) of pembrolizumab. Median follow up was 30 months (IQR 28-31). A decline in PSA of 50% or greater from baseline was observed in 28 (76%, 95% CI 59-88) of the 37 participants. Common treatment-related adverse events were grade 1-2. Grade 3 adverse events included anaemia in one (3%) participant and immune-related adverse events in 11 (30%) participants, including two cases each of fatigue (5%), colitis (5%), and increased serum amylase (5%), and one case (3%) each of pancreatitis, pneumonitis, type 1 diabetes, nephritis, myasthenia gravis, and mucosal pemphigus attributable to pembrolizumab. One participant had co-occurring myasthenia gravis and colitis. There were no grade 4 adverse events or treatment-related deaths.

[INTERPRETATION] Multicycle [Lu]Lu-PSMA-617 and pembrolizumab showed encouraging activity with manageable toxicity that was consistent with [Lu]Lu-PSMA-617 or pembrolizumab, and the combination might provide durable clinical benefit in a subset of patients.

[FUNDING] Victorian Cancer Agency, Merck Sharp & Dohme, and Novartis.