AcTFirst: A phase 3 trial of 225 Ac-PSMA-617 plus ARPI versus standard of care in adults with PSMA-positive metastatic castration-resistant prostate cancer.

TPS5134 Background: In the VISION and PSMAfore trials, β-emitting radioligand therapy (RLT) with 177 LuLu-PSMA-617 ( 177 Lu-PSMA-617) shows superior efficacy and tolerable safety compared with standard of care (SoC) in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC). 225 AcAc-PSMA-617 ( 225 Ac-PSMA-617), an α-emitting agent, may offer an alternative treatment option to SoC in mCRPC because its higher linear energy transfer increases the likelihood of higher cytotoxicity in tumor cells. Methods: AcTFirst (NCT06855277) is a phase 3, open-label, multicenter, randomized study to evaluate the efficacy and safety of 225 Ac-PSMA-617 plus androgen receptor pathway inhibitor (ARPI) in patients with PSMA-positive mCRPC. Eligible participants are adults with PSMA positron emission tomography-positive mCRPC and progressive disease on androgen deprivation therapy plus one ARPI as their last treatment in the metastatic hormone-sensitive prostate cancer (mHSPC) or earlier setting. ARPI treatment received in the mHSPC setting can be continued until cycle 1. Key exclusion criteria include previous treatment with RLT or systemic anti-cancer therapy for mCRPC. Participants with homologous recombination repair gene-mutated mCRPC who had prior exposure to poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) for HSPC can be included. Participants with inadequate bone marrow, hepatic or renal function are excluded. Participants will be randomized to three treatment arms: 1) a combination of 225 Ac-PSMA-617 (up to six cycles) plus ARPI change (enzalutamide or abiraterone); 2) 225 Ac-PSMA-617 monotherapy (up to six cycles); or 3) investigator’s choice of SoC (ARPI change, taxane chemotherapy or 177 Lu-PSMA-617). Efficacy will be assessed using a hierarchical group sequential testing strategy for the primary and key secondary objectives. The primary endpoint is radiographic progression-free survival (rPFS) by conventional imaging for the combination and SoC arms. Key secondary endpoints are overall survival (OS) for the combination and SoC arms, rPFS by conventional imaging for the monotherapy and SoC arms, OS for the monotherapy and SoC arms, and rPFS by PSMA positron emission tomography/computed tomography imaging for the combination and SoC arms. Other outcomes of interest include safety, health-related quality of life and other patient-reported outcomes. As of January 2026, patient enrollment is ongoing. Clinical trial information: NCT06855277 .