Keynote: The FLEX-MRT trial is evaluating whether a personalised, flexible dosing schedule of 177Lu-PSMA-617, including treatment holidays, can extend survival in men with advanced metastatic castration-resistant prostate cancer compared with the standard six-cycle regimen.
Keywords: 177Lu-PSMA-617 therapy, metastatic castration-resistant prostate cancer, flexible dosing schedule, treatment holidays, radiopharmaceutical therapy, survival outcomes
The FLEX-MRT study tests whether a patient-tailored schedule of 177Lu-PSMA-617 can improve outcomes in metastatic castration-resistant prostate cancer (mCRPC) compared with the currently approved fixed schedule. It is an investigator-initiated, single-centre, open-label, randomised phase 2 trial at UCLA (NCT06216249), aiming to enrol 90 men with mCRPC in a 1:1 ratio. The control arm follows the label: 7.4 GBq every six weeks for up to six cycles. The investigational arm permits up to twelve cycles and introduces planned “treatment holidays” for exceptional responders, with therapy re-started on progression.
Eligibility mirrors Pluvicto use: prior androgen receptor signalling inhibitor(s) and chemotherapy, PSMA PET meeting VISION criteria, ECOG 0–2, and adequate marrow and renal function. Prior 177Lu-PSMA-617 and recent myelosuppressive therapy are exclusions. The primary endpoint is two-year survival from the first treatment; secondary endpoints include overall survival, progression-free survival (radiographic, PSA, clinical, or disease progression to death), disease control rates, safety (as assessed by CTCAE), dosimetry, pain, performance status, and patient-reported outcomes.
Response assessment is integral to the adaptive design. During active treatment, each cycle is followed by quantitative post-therapy SPECT/CT (24–72 hours) to assess the relative change in PSMA-avid tumour burden and to perform single-time-point dosimetry. During treatment holidays, surveillance shifts to PSMA PET/CT every 12 weeks alongside PSA, using RECIP criteria. Patients achieving near-complete biochemical and imaging responses can pause therapy; if progression is detected, treatment resumes using the original cycle-1 SPECT/CT as the radiographic baseline for subsequent comparisons.
Safety is monitored through scheduled laboratory tests every three weeks during treatment and quarterly thereafter, up to 24 months, with an interim safety analysis conducted at 50% enrollment. Kidney dose constraints guide the total number of cycles; if the biologically effective dose to the kidneys would exceed 39 Gy, the regimen is curtailed. Concomitant androgen deprivation is allowed; other systemic anticancer therapies are restricted with defined washouts.
FLEX-MRT addresses two practical questions in PSMA-targeted radioligand therapy: whether extending beyond six cycles benefits suitable patients, and whether structured breaks for deep responders can reduce cumulative toxicity without sacrificing control. By coupling imaging-based response with dosimetry-informed limits, the trial aims to refine treatment intensity according to individual disease dynamics and organ tolerance, with two-year survival serving as the primary indicator of efficacy. Published online 28 August 2025, the protocol sets the stage for a more personalised approach to 177Lu-PSMA-617 in advanced mCRPC.
Reference: Holzgreve, A., Delker, A., Ells, Z., Brosch-Lenz, J., Unterrainer, L. M., Nikitas, J., Zhu, S., Contreras, M. M., Alam, H., Nabong, R. M., Lira, S., Vasilyev, A., Chen, L., Grogan, T., Elashoff, D., Meyer, C. A., Dahlbom, M., Czernin, J., & Calais, J. (2025). Randomised 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. Journal of Nuclear Medicine. https://doi.org/10.2967/jnumed.125.269495
Disclaimer
The information provided about the FLEX-MRT clinical trial is intended solely for general informational and educational purposes. It does not constitute medical advice, diagnosis, or treatment and should not be relied upon as a substitute for professional medical guidance. Participation in any clinical trial, including FLEX-MRT, involves potential benefits and risks that should be carefully considered in consultation with a qualified healthcare professional. Eligibility, treatment schedules, and outcomes will vary between individuals, and no guarantees of safety or efficacy are implied. The trial is being conducted in accordance with an approved research protocol, and participation is entirely voluntary. Readers should not make healthcare decisions based on this summary alone and are encouraged to seek advice from their own medical team. Neither the investigators nor the publisher accepts responsibility for any actions taken or not taken on the basis of the information contained herein.