A Phase 2, Open-Label, Randomized Controlled Trial Evaluating Safety and Efficacy of Dose-Intensified Versus Standard...

OPTIMAL-PSMA aims to determine the safety and efficacy of a dose-intensified (intense induction followed by a maintenance period) regimen of [¹⁷⁷Lu]Lu-PSMA-597 compared with the standard-of-care regimen (every 6 wk for up to 6 doses) in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: OPTIMAL-PSMA is a phase 2, open-label, 2-arm, multicenter, randomized controlled trial of [¹⁷⁷Lu]Lu-PSMA-597, a novel prostate-specific membrane antigen (PSMA) peptide with low nontarget organ dosimetry. A total of 120 patients with mCRPC will be enrolled and randomized 2:1 to receive either a dose-intensified regimen (arm 1) or the standard-of-care regimen (arm 2) of [¹⁷⁷Lu]Lu-PSMA-597. Eligible participants must have mCRPC with disease progression after androgen receptor pathway inhibitor therapy, have received or are not considered medically fit for docetaxel chemotherapy, and demonstrate PSMA-avid disease on PET/CT. Participants assigned to arm 1 will receive early intensified [¹⁷⁷Lu]Lu-PSMA-597 dosing (7.5 or 8.5 GBq on the basis of an interim safety assessment) on days 1, 3, and 15 and during weeks 10, 20, and 30 (6 doses). All participants in arm 2 will receive the standard dose of 7.5 GBq of [¹⁷⁷Lu]Lu-PSMA-597 administered every 6 wk until they are no longer clinically benefiting, for a maximum of 6 doses. Clinical and laboratory safety assessments will be conducted 3 times weekly, with diagnostic CT and bone scans performed at 8 wk and then every 12 wk until radiographic progression. Translational studies incorporate serial multiple-time-point circulating tumor DNA matched with SPECT/CT dosimetry at each time point and PSMA PET at baseline and 8 wk for correlation with clinical outcomes. The primary endpoint is a 90% or greater decline in prostate-specific antigen (PSA) level. Key secondary endpoints include the safety of intensified dosing, a 50% or greater decline in PSA level, radiographic and PSA progression-free survival, and overall survival. Translational endpoints include evaluation of serial circulating tumor DNA, biologic effective dose with intensified versus standard dosing of [¹⁷⁷Lu]Lu-PSMA-597, and evaluation of serial SPECT/CT and PSMA PET/CT for treatment response. Conclusion: OPTIMAL-PSMA will determine whether a dose-intensified regimen of [¹⁷⁷Lu]Lu-PSMA-597 is safe and improves depth of response and survival outcomes compared with the standard dosing regimen. The results of this study may redefine the optimal treatment scheduling for PSMA-targeted radiopharmaceutical therapy for patients with mCRPC.