Phase 2 Prospective Trial of Retreatment with [ ¹⁷⁷ Lu]Lu-PSMA-617 Molecular Radiotherapy for Metastatic Castration-Resistant Prostate Cancer—RE-LuPSMA

[177Lu]Lu-PSMA-617 radiopharmaceutical therapy has been approved for the treatment of patients with metastatic castration-resistant prostate cancer for up to 6 cycles. Unfortunately, this treatment is not curative and patients experience relapse, even after initially favorable responses. When this occurs, patients have limited treatment options. Readministration of [177Lu]Lu-PSMA-617 in patients who previously benefited from therapy and had limited toxicity seems to be a promising option, with retrospective studies reporting favorable outcomes. Methods: RE-LuPSMA is an investigator-initiated, single-arm, single-center, open-label, phase 2 clinical trial designed to study the efficacy and safety of rechallenge therapy using [177Lu]Lu-PSMA-617 in patients whose disease progressed after responding well to a previous regimen of [177Lu]Lu-PSMA-617. This study plans to enroll 40 patients with progressive metastatic castration-resistant prostate cancer who previously completed 4–6 cycles of [177Lu]Lu-PSMA-617 with a favorable response (i.e., ≥50% decrease in prostate-specific antigen [PSA] level at any point during the first [177Lu]Lu-PSMA-617 regimen). After the first regimen of [177Lu]Lu-PSMA-617, patients must meet VISION trial criteria on a prostate-specific membrane antigen (PSMA) PET/CT scan within 8 wk of the planned first cycle of rechallenge therapy. After enrollment, participants will receive up to 6 additional cycles of [177Lu]Lu-PSMA-617 (7.4 GBq every 6 wk). The primary endpoint is 12-mo overall survival (OS), measured from the start of rechallenge therapy. The study will have 80% power to detect a difference between the null hypothesis of 50% OS at 12 mo and the study hypothesis of 71% OS at 12 mo. Secondary endpoints include adverse-event rates, PSA response rates (proportion of patients with a decrease of 50% or greater in PSA level), biochemical progression-free survival (defined as the time until PSA level increases 25% and 2 ng/mL above the nadir), radiographic progression-free survival, and quality-of-life changes (measured using Functional Assessment of Cancer Therapy–Radionuclide Therapy and Brief Pain Inventory–Short Form). Enrollment began in August 2024, with a planned study duration of 45 mo.