Phase 2 Trial: Adaptive PSMA-PET–Guided 177Lu-DOTA-HYNIC-panPSMA (TLX597-Tx) in mHSPC

The OPTIMAL-e trial is a phase 2 pilot study testing adaptive, PSMA-PET–guided radioligand therapy (RLT) with 177Lu-DOTA-HYNIC-panPSMA (TLX597-Tx) in men with metastatic hormone-sensitive prostate cancer (mHSPC), on top of standard androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARPI). Conducted at St Vincent’s Hospital in Sydney, it is single-arm, open-label, and nonrandomized, designed primarily to assess PSA response rates, the depth and durability of responses, and the safety of dose intensification in this earlier disease setting.

What makes OPTIMAL-e distinctive is its adaptive dosing strategy: TLX597-Tx is continued while PSMA-PET shows persisting PSMA-avid disease, paused when imaging reveals a substantial reduction in PSMA-expressing tumor burden, and resumed if PSA rises in conjunction with reappearance of PSMA targets on PET. The goal is to maintain disease control while reducing cumulative radioligand exposure, potentially limiting long-term marrow and organ toxicity and keeping patients in a low-volume metastatic state for longer. TLX597-Tx itself is a small-molecule PSMA-targeting radiopharmaceutical delivering lutetium-177 β‑radiation to PSMA-overexpressing lesions, being developed in parallel with the antibody-based TLX591-Tx, which is already in phase 3 trials for mCRPC.

The rationale for moving TLX597-Tx into hormone-sensitive disease builds on dosimetry and safety data from the OPTIMAL-PSMA study in mCRPC, which showed that higher activity per cycle could be delivered while maximizing dose to tumor relative to organs at risk using an intensified schedule. It also leverages emerging evidence that 177Lu-PSMA-RLT is feasible and safe in low-volume mHSPC, where tumor burden is lower and PSMA expression often robust, and that flexible, response-based dosing may improve the therapeutic index compared with fixed-cycle regimens.

Source.

Clinical trial.