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

Abstract

[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).

Keywords: PSMA; RPT; SPECT/CT; [177Lu]Lu-PSMA-617; mCRPC; metastatic castration-resistant prostate cancer; prostate-specific membrane antigen; radiopharmaceutical therapy; therapy response assessment; treatment holidays.

FIGURE 1.

Study design. FLEX-MRT trial will randomize 90 patients in 1:1 ratio to investigational arm treated with extended and flexible dosing schedule and control arm treated with approved standard dosing schedule. Primary endpoint is 2-y survival rate. ARSI = androgen receptor signaling inhibitor; CTx = chemotherapy; QOL = quality of life.

FIGURE 2.

Investigational arm. Patients in investigational arm are treated with up to 12 cycles including potential “treatment holidays” depending on response. Response assessment is based on SPECT/CT and PSA at each cycle during treatment periods. C = treatment cycle; RR = relative response/response rate.

FIGURE 3.

Treatment holidays. Patients with exceptional response in investigational are put on “treatment holidays.” Response assessment during treatment holiday periods is based on PSMA PET/CT and PSA every 12 wk. RECIP = response evaluation criteria in PSMA PET/CT; RR = relative response/response rate; VOL = volume.