Dose optimisation and PSMA receptor intensification with 177 Lu-PSMA-597 in metastatic castration-resistant prostate cancer (mCRPC): The randomised phase II OPTIMAL-PSMA trial.

TPS293 Background: 177 LuLu-PSMA is a targeted radionuclide beta therapy in metastatic prostate cancer that affords excellent quality of life compared to chemotherapy in men who have few available options. However, its impact in improving overall survival (OS) has been limited using current dosing regimens, with an OS improvement of 4 months compared to a standard-of-care (SoC) that excluded chemotherapy. A phase 1 dose escalation study previously found 22Gbq dose of 177 LuPSMA-617 over 15 days to be safe and tolerable, but randomised data compared to conventional dosing are lacking. The objective of OPTIMAL-PSMA is to directly compare a dose intensification regimen to a SoC comparator using a novel PSMA peptide 177 LuLu-PSMA-597, evaluating dosimetry, safety and efficacy. Methods: This open label, single centre, phase 2 trial randomises 120 participants 2:1 to either dose-intensified 177 LuPSMA-597 or SoC 177 Lu-PSMA-597 every 6 weeks for a total of 6 doses. Treatment continues until the pt is no longer clinically benefitting. The primary endpoint is PSA90% response rate(PSA90). The sample size provides 80% power to detect a 24.5% increase in PSA90 with an assumed 20% of participants achieving the primary endpoint in the SoC arm with a sample size of 120 participants (80:40) recruited over 18 months. Secondary endpoints include safety, dosimetry, rPFS, overall survival, and PSMA-PET response at 8 weeks. The target population is progressive mCRPC post androgen receptor pathway inhibition therapy. In the experimental arm 7.5GBq (8.5Gbq after patient 40) is administered on days 1, 3 and 15, then weeks 10, 20 and 30. In the SoC arm 7.5Gbq is administered at baseline and weeks 6, 12, 18, 24 and 30. Translational bloods for circulating tumour DNA genomic and epigenomic analysis are undertaken on both arms at each treatment timepoint. A PSMA-PET is undertaken at baseline and week 8 in both arms. Safety assessments including bloods are undertaken 3-weekly with diagnostic CT and bone scan every 12-weeks. As of October 2025, 33 participants have been randomised. An independent data safety monitoring assessment of the first 10 experimental patients identified no safety concerns and recommended a planned increased dose to 8.5Gbq in the experimental arm. 177 Lu-SPECT and PSMA PET quantitation will be used to assess both treatment response and compare biologic effective dose delivered with a dose intensified versus SoC 177 LuPSMA administration. Clinical trial information: ACTRN12625000971437 .