[ 177 Lu]Lu‐PSMA‐617 Plus Short‐Course Priming With Enzalutamide in Metastatic Castration‐Resistant Prostate Cancer: A Single‐Arm Phase 2 Trial (Lu‐PRIME)

Abstract

ABSTRACT Background [ 177 Lu]Lu‐PSMA‐617 has been an approved treatment modality for metastatic castration‐resistant prostate cancer (mCRPC). Recent studies have shown PSMA upregulation following enzalutamide, which may enhance the outcomes with [ 177 Lu]Lu‐PSMA‐617. This study aims to evaluate the efficacy and safety of short‐course enzalutamide priming with [ 177 Lu]Lu‐PSMA‐617 in mCRPC patients. Methods This investigator‐initiated, single‐arm phase 2 trial recruited men with mCRPC, having progressed on ≥one line of taxane and androgen‐receptor pathway inhibitors (ARPIs), and fit for [ 177 Lu]Lu‐PSMA‐617. Enzalutamide (160 mg/day) was administered orally for 7 days before and after [ 177 Lu]Lu‐PSMA‐617 (7.4 GBq/cycle, up to 6 cycles, at 6–8 week intervals). The primary end‐point was proportion of patients achieving ≥ 50% decline in prostate‐specific antigen (PSA50‐response rate, PSA50‐RR). A sample size of 20 patients was calculated using Simon's two‐stage design with at least 12/20 PSA50‐responses required for rejection of null hypothesis. Secondary end‐points included objective radiographic response rate (ORR), PSA progression‐free survival (PSA‐PFS), radiographic PFS (rPFS), overall survival (OS), and adverse events (AEs). Results Between May 2023 and January 2025, 20 mCRPC patients (median age 67 years) were enrolled. The PSA50‐RR was 40% (8/20, 95% CI: 19–64), thus the null hypothesis was not rejected. The ORR was 25% (5/20, 95% CI: 10–49). Over a median follow‐up of 24 months, median PSA‐PFS, rPFS, and OS were 4.0 months (95% CI: 3.0–7.5), 4.0 months (95% CI: 4.0–7.5), and 12.6 months (95% CI: 6.2–17.0), respectively. Grade 3 AEs were observed in four patients (20%, 95% CI: 6–44). Conclusion The addition of short‐course enzalutamide to [ 177 Lu]Lu‐PSMA‐617 did not meaningfully improve treatment outcomes of taxane and ARPI‐exposed mCRPC patients in this trial. Trial Registration Clinical Trials Registry‐India, CTRI/2023/05/053301. Registered 31 May 2023.