PRINCE: Phase I trial of ¹⁷⁷Lu-PSMA-617 in combination with pembrolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC).

5017 Background: The VISION and TheraP trials have established the safety and efficacy of 177 Lu-PSMA-617 in mCRPC with a 50% PSA response rate (PSA50-RR) of 46% and 66% and median progression free survival (PFS) of 8.7 and 5.1 months, respectively. More effective treatments are required as disease progression remains universal. Immunotherapy has limited single-agent efficacy in mCRPC. We hypothesise that by potentially inducing immunogenic cell death, 177 Lu-PSMA-617 may act synergistically with pembrolizumab, an anti-programmed death 1 inhibitor, to enhance the depth and durability of response. PRINCE is a Phase I trial evaluating the safety and efficacy of this combination. Methods: mCRPC patients with high PSMA expression (SUVmax ≥ 20 in an index lesion, SUVmax > 10 for all lesions ≥ 10mm), and no FDG+ve/PSMA-ve lesions on paired baseline PET/CT screening, received up to 6 cycles of 177 Lu-PSMA-617 (starting at 8.5 GBq, reducing by 0.5 GBq with each cycle) every 6 weeks in conjunction with 200mg of pembrolizumab every 3 weeks for up to 2 years. Response evaluation was undertaken as per PCWG3 and RECIST criteria. Co-primary endpoints were safety and PSA50-RR. Secondary endpoints included PSA-PFS, radiographic PFS (rPFS), overall survival (OS), and patient reported outcomes (PROs). This analysis was undertaken after the last patient had 12 months follow-up. Results: 37 patients (median age 72 years; prior docetaxel 73%; prior androgen receptor targeted agent 100%) received a median of 5 cycles (range: 2 to 6) of 177 Lu-PSMA-617 and 12 doses (range: 6 to 19) of pembrolizumab. The median follow up was 16 months. PSA50-RR was 76% (28/37 [95% CI 59-88]) and 7/10 (70%) patients with RECIST-measurable disease had a partial response. Median rPFS, PSA-PFS and OS was 11.2 months (95% CI: 5.1-14.1), 8.2 months (95% CI: 5.1-11.2) and 17.8 months (95% CI:13.4-not estimable). 12-month rPFS and OS was 38% (95% CI: 22-54) and 83% (95% CI: 67-92), respectively. Common (≥10%) treatment-related adverse events (TRAE) were mainly Grade (G) 1-2, including xerostomia (78%), fatigue (43%), pruritus (27%), nausea (27%), rash (24%), diarrhoea (14%), anorexia (16%), thrombocytopenia (16%), elevated ALT (11%), arthralgia (11%) and a flare in bone pain (11%). Haematologic TRAEs included G2-3 anaemia (8%), G1-2 thrombocytopenia (16%), and G1 neutropenia (3%). G3 immune-related AEs occurred in 10 (27%) patients with no dominant manifestation. 5 (14%) patients discontinued pembrolizumab due to toxicity. PROs including BPI-SF and FACT-P were stable throughout the study. Conclusions: The combination of 177 Lu-PSMA-617 and pembrolizumab had promising activity. Toxicities were generally consistent with those of single-agent 177 Lu-PSMA-617 and pembrolizumab and were not clearly augmented by combination use. No new safety concerns were observed. Clinical trial information: NCT03658447.