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

BACKGROUND: [177Lu]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 [177Lu]Lu-PSMA-617. This study aims to evaluate the efficacy and safety of short-course enzalutamide priming with [177Lu]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 [177Lu]Lu-PSMA-617. Enzalutamide (160 mg/day) was administered orally for 7 days before and after [177Lu]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 [177Lu]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.