Randomized Phase 2 Trial of an Extended and Flexible Dosing Schedule of 177Lu-PSMA Molecular Radiotherapy in Patients with Metastatic Castration-Resistant Prostate Cancer (FLEX-MRT): Study Protocol

[¹⁷⁷Lu]Lu-PSMA-617 radiopharmaceutical therapy has been approved for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) using a fixed dosing schedule of once every 6 wk for up to a total of 6 doses. We hypothesized that patients may benefit from a flexible and extended dosing schedule, up to 12 doses with potential "treatment holiday" periods. Objective: The objective of this study is to determine the 2-y survival rate of patients with mCRPC treated with an extended and flexible dosing schedule of [¹⁷⁷Lu]Lu-PSMA-617 therapy in comparison to patients treated with the standard fixed dosing schedule of a maximum of 6 treatment cycles once every 6 wk. Study Design: The FLEX-MRT trial is an investigator-initiated prospective phase 2, parallel group, randomized, controlled, open-label, single-center trial in men with mCRPC to determine the efficacy of a flexible and extended dosing schedule of [¹⁷⁷Lu]Lu-PSMA-617 therapy. Key inclusion criteria are patients eligible for Pluvicto (i.e., prior androgen receptor signaling inhibitors, prior chemotherapy, PSMA PET VISION criteria). Key exclusion criteria are prior [¹⁷⁷Lu]Lu-PSMA-617 therapy and less than 6 wk since last myelosuppressive therapy. The trial aims to centrally randomize 90 patients in a 1:1 ratio to 2 treatment arms. In the control arm, patients will be treated with the approved standard dosing schedule (n = 45). In the investigational arm, patients will be treated with up to 12 cycles and with potential treatment holidays depending on response (n = 45). Response assessment is based on SPECT/CT at each cycle and on PSMA PET/CT during treatment holiday periods (every 12 wk). Primary endpoint is the 2-y survival rate. Survival is calculated from the date of the first cycle of [¹⁷⁷Lu]Lu-PSMA-617 therapy. Secondary endpoints include safety by Common Terminology Criteria for Adverse Events and dosimetry and determination of overall and progression-free survival (evidence of progression as defined by radiographic, prostate-specific antigen level, or clinical progression, or death from any cause).