Louise Emmett, MD, PhD, highlights early data on 225Ac-PSMA-617 in mCRPC

In this video, Louise Emmett, MD, PhD, MBChB, FRACP, discusses findings from the phase 1 AcTION trial, which evaluated the alpha-emitting radioligand therapy ²²⁵Ac-PSMA-617 in patients with metastatic castration-resistant prostate cancer (mCRPC).¹ These findings were presented at the 2026 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.

Emmett is a nuclear medicine physician at St Vincent's Hospital in Sydney, Australia and a professor at the University of New South Wales.

The AcTION study (NCT04597411) was designed to explore the safety and preliminary anti-tumor activity of ²²⁵Ac-PSMA-617. The phase 1 dose-escalation and expansion study enrolled 101 patients with PSMA-positive mCRPC across 3 cohorts: patients previously treated with chemotherapy and androgen receptor pathway inhibitors (ARPIs) (cohort A; n = 34), patients who were chemotherapy- and ARPI-naïve (cohort B; n = 27), and patients who had previously received ¹⁷⁷Lu-PSMA therapy (cohort C; n = 40).

The trial evaluated administered activities of 4, 6, 8, and 10 MBq of ²²⁵Ac-PSMA-617 given every 8 weeks for up to 6 cycles. Investigators identified 10 MBq as the recommended phase 2 dose across all 3 cohorts, with no dose-limiting toxicities observed and no maximum tolerated dose reached. The treatment demonstrated an acceptable safety profile, with no grade 4 or 5 treatment-related adverse events (AEs). Dry mouth emerged as the predominant AE, affecting more than 90% of patients across all groups and frequently persisting at the time of data cutoff.

Emmett highlighted the substantial antitumor activity observed across disease settings. In cohort A, which included patients previously treated with chemotherapy and ARPIs, the PSA50 response rate was 58.8%, increasing to 7.27% among patients treated at the highest dose level (n = 11). The most striking responses were seen in the earlier-line cohort (cohort B), where PSA50 and PSA90 response rates reached 85.2% and 100%, respectively. Activity was also observed in patients previously treated with prior ¹⁷⁷Lu-PSMA, with roughly half achieving a PSA50 response. Based on these findings, Emmett noted that ²²⁵Ac-PSMA-617 appears active across the mCRPC continuum, and the agent is now advancing into phase 3 evaluation through the ongoing AcTFirst and PSMAcTION trials.

REFERENCE

1. Emmett L, Sathekge MM, Crumbaker MA, et al. AcTION: Phase 1 study of [225Ac]Ac-PSMA-617 (225Ac-PSMA-617) in men with metastatic castration-resistant prostate cancer (mCRPC) with or without prior [177Lu]Lu-PSMA (177Lu-PSMA) radioligand therapy (RLT). J Clin Oncol. 44, 2026 (suppl 16; abstr 5010). doi:10.1200/JCO.2026.44.16_suppl.5010