Abstract
[177Lu]Lu-PSMA-617 is an approved therapy for metastatic castration-resistant prostate cancer (mCRPC); however, response rates vary significantly, particularly among patients with low prostate-specific membrane antigen (PSMA) expression on PSMA PET. This multicenter, open-label phase 2 trial evaluates the efficacy and safety of an intensified Lu-PSMA treatment schedule in patients with mCRPC and a whole-body tumor SUVmean of less than 10 on [68Ga]Ga-PSMA-11 PET, a subgroup associated with poorer outcomes with the conventional treatment schedule. Methods: Eligible participants (n = 45) with mCRPC, prior exposure to androgen receptor pathway inhibitor therapy, and progressive disease (defined by the Prostate Cancer Working Group 3 criteria) must have PSMA-positive lesions without PSMA-negative sites and a whole-body tumor SUVmean of less than 10 on [68Ga]Ga-PSMA-11 PET within 3 mo of enrollment. Participants will receive up to 6 cycles of [177Lu]Lu-PSMA-617 (7.4 GBq per cycle; cumulative dose, 44 GBq) administered at an intensified cadence (days 1 and 8, days 50 and 57), followed by 2 standard cycles every 6 wk. The primary endpoint is prostate-specific antigen (PSA) progression-free survival, with safety as a key secondary endpoint, assessed in accordance with the Common Terminology Criteria for Adverse Events version 5.0. A continuous safety monitoring rule allows early termination if grade 3 or higher adverse hematologic events (excluding lymphopenia) exceed predefined thresholds established by historical data. Additional secondary endpoints include PSA response, radiographic progression-free survival, overall survival, and patient-reported outcomes (Functional Assessment of Cancer Therapy-Prostate, Brief Pain Inventory-Short Form). Exploratory analyses include radiation dosimetry and plasma biomarker assessments. Participants achieving a marked response (≥90% PSA decline to Conclusion: By modulating treatment intensity using baseline PSMA expression, this trial aims to improve outcomes in patients predicted to have lower response rates under the standard schedule while maintaining acceptable toxicity.