Prospective phase 2 trial of PSMA-targeted molecular RadiothErapy with 177Lu-PSMA-617 for metastatic castration-reSISTant Prostate Cancer (RESIST-PC): efficacy results of the UCLA cohort.

The objective of this study was to determine prospectively the efficacy profile of 2 activity regimens of 177Lu-PSMA therapy in patients with progressive metastatic castrate-resistant prostate cancer (mCRPC): 6.0 vs. 7.4 GBq. Methods: RESIST-PC (NCT03042312) was a prospective multicenter phase 2 trial. Patients with progressive mCRPC after ≥ 1 novel androgen-axis drug, either chemotherapy naïve or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, and sufficient PSMA expression by PSMA PET were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq) and received up to 4 cycles every 8 wk. The primary endpoint was the efficacy of 177Lu-PSMA measured by the prostate-specific antigen (PSA) response rate (RR) after 2 cycles (≥50% decline from baseline). Secondary endpoints included the PSA RR (≥50% decline) at any time (best response), and overall survival (OS). Results: The study was closed at enrollment of 71/200 planned patients because of sponsorship transfer. We report here the efficacy of the University of California Los Angeles cohort results only (n = 43). The PSA RRs after 2 cycles and at any time were 11/40 (28%, 95% CI 15-44), 6/13 (46%, 95% CI 19-75), and 5/27 (19%, 95% CI 6-38), and 16/43 (37%, 95% CI 23-53), 7/14 (50%, 95% CI 23-77), and 9/29 (31%, 95% CI 15-51) in the whole cohort, the 6.0-GBq group, and the 7.4-GBq group, respectively (P = 0.12 and P = 0.31). The median OS was 14.0 mo (95% CI 10.1-17.9), 15.8 (95% CI 11.8-19.4), and 13.5 (95% CI 10.0-17.0) in the whole cohort, the 6.0-GBq group, and the 7.4 GBq group, respectively (P = 0.87). OS was longer in patients who experienced a PSA decline ≥ 50% at any time than in those who did not: median, 20.8 versus 10.8 mo (P = 0.005). Conclusion: In this prospective phase 2 trial of 177Lu-PSMA for mCRPC, the median OS was 14 mo. Despite the heterogeneous study population and the premature study termination, the efficacy profile of 177Lu-PSMA appeared to be favorable and comparable with both activity regimens (6.0 vs. 7.4 GBq). Results justify confirmation with real-world data matched-pair analysis and further clinical trials to refine and optimize the 177Lu-PSMA therapy administration scheme to improve tumor radiation dose delivery and efficacy.