Adrien Holzgreve, Astrid Delker, Zachary Ells, Julia Brosch-Lenz, Lena M. Unterrainer, John Nikitas, Shaojun Zhu, Maria M. Contreras, Hamzah Alam, Rejah M. Nabong, Stephanie Lira, Arseniy Vasilyev, Lillian Chen, Tristan Grogan, David Elashoff, Catherine A. Meyer, Magnus Dahlbom, Johannes Czernin, Jérémie Calais
- [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[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).
Radiopharmaceutical therapy (RPT) with [177Lu]Lu-PSMA-617 was approved both by the U.S. Food and Drug Administration and the European Medicines Agency in 2022 for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) following the VISION trial (1,2). The VISION trial demonstrated that 177Lu-PSMA RPT can improve overall survival, radiographic progression-free survival (PFS), prostate-specific antigen (PSA) response, quality of life, and bone pain in patients with progressing mCRPC in comparison to the standard of care (2,3). However, even after a good response to [177Lu]Lu-PSMA-617 therapy, patients will eventually relapse and further treatment opportunities are limited. Hence, further optimization of the treatment is warranted.
Following the VISION trial design, [177Lu]Lu-PSMA-617 was approved by the Food and Drug Administration for patients with mCRPC on a fixed dosing schedule: up to 6 doses (cycles) of [177Lu]Lu-PSMA-617 at an injected activity of 7.4 GBq, administered at a time interval of 6 wk.
Retreatment (after an interval without 177Lu-PSMA, with or without other therapy) and extended regimen (>6 cycles) of 177Lu-PSMA therapy have been performed successfully outside of the United States with favorable efficacy and toxicity profiles (4–9). There are no guidelines for the optimum number of cycles of 177Lu-PSMA in patients who show good response. Because of the approved drug label and insurance coverage, 177Lu-PSMA is usually discontinued after a maximum number of 6 cycles. Moreover, some patients experience a complete or almost complete response (CR) before the last cycle 6 (e.g., after cycle 2). It is unclear whether these patients benefit from the subsequent remaining treatment cycles. In these patients with no visible lesions anymore on PET or SPECT or with limited or minimal residual lesions, the risk–benefit ratio may not be in favor of administering the subsequent treatment cycles. 177Lu-PSMA therapy may be saved for later time points, when the disease becomes again visible and large enough to be treated with β-radiation. A treatment holiday could reduce patients’ exposure to the therapy and prevent unnecessary toxicity when treatment seems to be already maximally effective, with potentially no further benefit expected from further treatment cycles. The concept of treatment holidays in patients experiencing a complete or almost CR before the last cycle 6 (e.g., after cycle 2) has been reported by Emmett et al. and Seifert et al. (7,10).
In the randomized phase 2 trial FLEX-MRT (ClinicalTrials.gov identifier: NCT06216249), we aimed at assessing prospectively the concept of a flexible and extended (>6 cycles) regimen of 177Lu-PSMA RPT that includes potential treatment holiday periods, and up to 12 cycles.…
