(UroToday.com) The 2025 ESMO annual meeting featured a prostate cancer trials in progress session and a presentation by Dr. Louise Emmett discussing PSMAcTION, a phase 2/3 randomized trial of 225Ac-PSMA-617 versus standard of care in patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who progressed on or after 177Lu-PSMA therapy.
Previously, PSMA-targeted radioligand therapy 177Lu-PSMA prolonged radiographic progression-free survival in patients with PSMA-positive mCRPC in the taxane-naive (PSMAfore}1 and post-taxane (VISION)2 settings. 225Ac has higher linear energy transfer and shorter tissue path length than 177Lu, resulting in a higher ratio of double- to single-stranded DNA breaks and potentially fewer off-target effects. 225Ac-PSMA-617 radioligand therapy has shown preliminary evidence of clinical efficacy in patients with mCRPC3 and may represent a viable treatment option in patients who have received previous lines of therapy.
PSMAcTION is an open-label, multicenter, phase 2/3 randomized trial to evaluate the efficacy and safety of 225Ac-PSMA-617 versus standard of care in adults with PSMA-positive mCRPC (confirmed by PSMA PET). Eligible patients have:
- Received androgen receptor pathway inhibitor and taxane therapy
- Progressed on or after 177Lu-PSMA radioligand therapy (≥ 1 cycle)
- ≥ 1 metastatic lesion on conventional imaging
- A castrate level of testosterone
- Adequate organ function
Exclusion criteria include ≥ grade 2 xerostomia, any prior 225Ac-radioligand therapy, other radionuclides ≤ 6 weeks before randomization, or investigational treatments ≤ 28 days before randomization. Xerostomia will be monitored throughout the trial. In phase 2, patients will be randomized to different 225Ac-PSMA-617 dose levels for ≤ 6 cycles to support the optimal dose for phase 3. The primary endpoints are biochemical response rate, safety, and tolerability. Secondary endpoints include radiographic progression-free survival and overall response rate:
In phase 3, ∼420 patients will be randomized to 225Ac-PSMA-617 for ≤ 6 cycles or investigator’s choice of standard of care (excluding PARP inhibitors and immunotherapy except sipuleucel-T). Cross over to 225Ac-PSMA-617 will not be permitted for any patient randomized to the standard of care arm. The dual primary endpoints are radiographic progression-free survival and overall survival. Secondary endpoints include progression-free survival, overall response rate, and safety. Safety follow-up will occur at 56 and 30 days (+7) after the last dose of 225Ac-PSMA-617 and standard of care, respectively, with long-term follow-up for up to 5 years.
An upcoming protocol amendment will aim to optimize eligibility criteria, study procedures, and operational aspects. As of August 2025, patient enrolment has commenced in 13 sites across 7 countries:
Clinical trial identification: NCT06780670
Presented by: Louise Emmett, MD, MBChB, FRACP, FAANMS, Professor, Director of Theranostics and Nuclear Medicine, St. Vincent’s Hospital Sydney, University of New South Wales, Sydney, Australia
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 European Society of Medical Oncology (ESMO) Annual Meeting, Berlin, Germany, Fri, Oct 17 – Tues, Oct 21, 2025.
References:
- Morris MJ, Castellano D, Herrmann K, et al. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naïve patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): A phase 3, randomized, controlled trial. Lancet 2024 Sep 28;404(10459):1227-1239.
- Sartor O, de Bono J, Chi KN et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 16;385(12):1091-1103.
- Sathekge MM, Lawal IO, Bal C, et al. Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): A multicentre, retrospective study. Lancet Oncol. 2024 Feb;25(2):175-183.