Phase 1/2 ACRES Trial: Pioneering 225Ac-rhPSMA-10.1 for Post-Lutetium mCRPC

The ACRES trial represents a promising step forward in targeted alpha therapy for metastatic castration-resistant prostate cancer (mCRPC), focusing on Actinium-225-labeled radiohybrid PSMA-10.1 (225Ac-rhPSMA-10.1) in patients who have largely progressed after Lutetium-177 PSMA therapy. This multi-site, open-label Phase 1/2 study addresses an urgent need in advanced prostate cancer, where effective post-Lu-PSMA options remain limited despite approvals like Pluvicto.

The rhPSMA-10.1 platform stands out for its “radiohybrid” design, allowing the same molecule to switch between diagnostic PET isotopes (e.g., 68Ga/18F) and therapeutics like beta-emitting 177Lu or alpha-emitting 225Ac, optimizing tumor targeting while minimizing off-target effects. Actinium-225 delivers high-energy alpha particles over a short range (50-100 μm), potentially overcoming Lu-177 resistance by enhancing cell-killing potency in PSMA-expressing lesions.

Eligible men must have histologically confirmed prostate adenocarcinoma (including neuroendocrine features), castration-resistant disease with rising PSA per PCWG3 or radiographic progression, and PSMA-avid metastases on screening PET-CT. Key priors include at least one ARPI, one to two taxane lines (or refusal/ineligibility), and, crucially, prior 177Lu-PSMA (up to six cycles) with a physician-assessed response, except in Phase 1 where the first three participants per dose level can be Lu-naïve.

Clinical trial.