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OPTIMAL-PSMA Trial Launches to Test Whether Dose-Intensified Lu-PSMA-597 Improves Outcomes in mCRPC
OPTIMAL-PSMA is an ongoing phase 2 randomized controlled trial enrolling 120 patients that is designed to determine whether a dose-intensified regimen of [177Lu]Lu-PSMA-597 produces deeper PSA responses — specifically a 90% or greater PSA decline — compared with the current standard dosing schedule in metastatic castration-resistant prostate cancer; no efficacy or safety results are yet available, as this publication describes the trial protocol only.
What Was Studied
The trial investigates whether compressing and intensifying the early dosing schedule of [177Lu]Lu-PSMA-597, a novel PSMA-targeting radiopharmaceutical characterized by low nontarget organ uptake, can achieve greater depth of response — measured as a 90% or greater decline in PSA — and improve survival outcomes relative to the conventional approach of administering the agent every six weeks. The rationale centers on whether front-loaded dosing during the induction phase, followed by maintenance cycles, might better exploit tumor radiosensitivity and delay disease progression in this heavily pre-treated population.
How It Was Studied
OPTIMAL-PSMA is a phase 2, open-label, two-arm, multicenter randomized controlled trial with a 2:1 allocation ratio, enrolling a total of 120 patients with mCRPC. Eligible participants must have demonstrated disease progression following androgen receptor pathway inhibitor therapy, must have already received docetaxel chemotherapy or be considered medically unfit for it, and must show PSMA-avid disease confirmed by PET/CT imaging. Patients assigned to the dose-intensified arm (arm 1) receive [177Lu]Lu-PSMA-597 at 7.5 or 8.5 GBq — with the higher dose contingent on an interim safety assessment — on days 1, 3, and 15, followed by additional doses at weeks 10, 20, and 30, totalling six doses. The comparator arm (arm 2) follows the standard-of-care schedule of 7.5 GBq administered every six weeks for a maximum of six doses, continued until the patient is no longer deriving clinical benefit. Clinical and laboratory safety monitoring occurs three times weekly, with CT and bone scans at eight weeks and then every twelve weeks until radiographic progression.
What Was Observed
- This publication is a protocol report; no efficacy data are yet available. The primary endpoint — a 90% or greater PSA decline — will be evaluated upon trial completion, and results have not been reported.
- The trial incorporates serial circulating tumor DNA sampling matched with SPECT/CT dosimetry at multiple time points, alongside PSMA PET imaging at baseline and week 8, to correlate biological effective dose with clinical outcomes across both dosing regimens.
- Key secondary endpoints specified in the protocol include the safety profile of the intensified regimen, a 50% or greater PSA decline, radiographic and PSA progression-free survival, and overall survival — none of which have yet been reported.
Why This Matters
If the dose-intensified schedule proves safe and more effective, the results of this trial could directly redefine how PSMA-targeted radiopharmaceutical therapy is sequenced and scheduled for patients with mCRPC, a population with limited remaining treatment options following androgen receptor pathway inhibitors and chemotherapy. Beyond the dosing question, the embedded translational program — linking serial circulating tumor DNA dynamics to SPECT/CT-derived dosimetry and PSMA PET response — may yield novel predictive biomarkers capable of identifying which patients are most likely to benefit from intensified treatment approaches.
How to Read This Result
As a protocol paper with no efficacy or safety outcomes yet reported, all conclusions about the relative merits of dose-intensified versus standard [177Lu]Lu-PSMA-597 remain entirely prospective and unconfirmed; the moderate quality signal and open-label design further mean that definitive interpretation must await full trial results.
Limitations
The abstract does not explicitly report study limitations.