UPDATE: ProstACT Global Phase 3 Trial for TLX591 Dosed The First Patient

ProstACT Global is a pivotal randomized Phase 3 study testing the PSMA-targeted radiopharmaceutical TLX591 (lutetium‑177 rosopatamab tetraxetan) in metastatic castration‑resistant prostate cancer. The trial has just moved into its randomized expansion phase, with the first patient in this part dosed at a specialized prostate cancer center in Melbourne, marking a key transition from safety/dosimetry work to large‑scale efficacy evaluation.​

TLX591 is a lutetium‑177–labeled humanized monoclonal antibody against PSMA (rosopatamab) rather than a small‑molecule ligand. After binding to PSMA‑expressing tumor cells, the antibody is internalized and retains the beta‑emitting isotope within malignant tissue for prolonged periods, delivering sustained radiation to metastases. Early‑phase trials, including the ProstACT SELECT Phase 1 study, showed encouraging PSA responses with a tolerable hematologic safety profile, providing the rationale for Phase 3.​

The Phase 3 program has two parts. Part 1 enrolled about 30 patients to characterize safety, biodistribution, and dosimetry for TLX591 when layered on top of modern standard therapies. With that portion completed, Part 2 is now randomizing roughly 490 men with metastatic castration‑resistant disease in a 2:1 ratio to TLX591 plus standard of care versus standard of care alone, where standard of care includes agents such as abiraterone, enzalutamide or docetaxel. The design explicitly aims to measure the incremental benefit of adding TLX591 to real‑world treatment rather than using a placebo control.​

Radiographic progression‑free survival is the primary endpoint, with overall survival and other clinical outcomes as key secondary measures. Patients will be followed for at least five years from first dose to capture both long‑term benefit and late safety signals associated with lutetium‑177–based antibody therapy. The study is enrolling in Australia, New Zealand and Canada, with regulatory approvals already obtained in several additional regions, and further geographic expansion planned once the Part 1 data have been reviewed by major regulators.​

A central differentiator of TLX591 versus peptide‑based PSMA radioligands is its biodistribution and clearance. The antibody’s large size leads to minimal uptake in salivary and lacrimal glands, which is expected to substantially reduce the risk of dry mouth and dry eye, chronic toxicities that are common with small‑molecule PSMA therapies. In addition, TLX591 is predominantly cleared via the liver, and long‑term follow‑up in earlier studies has not shown the kidney toxicity frequently observed with small‑molecule PSMA radioligands. If confirmed in Phase 3, these features would represent a meaningful tolerability advantage in a heavily pretreated population.​

The dosing schedule is deliberately simple: a fractionated regimen of two infusions 14 days apart with a fixed total radioactivity dose, in contrast to multi‑cycle schedules extending over many months for current small‑molecule PSMA agents. Phase 1 data indicate that this regimen achieves strong tumor uptake and sustained lesion visibility for up to two weeks post‑infusion while keeping hematologic toxicity within manageable limits, and non‑hematologic treatment‑related events were mainly low grade. This supports the feasibility of combining TLX591 with androgen receptor pathway inhibitors or chemotherapy without excessive overlapping toxicity.​

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