News Brief

AUA 2025: Evaluating 225Ac-J591 PSMA-Targeted Radionuclide Therapy in mCRPC Patients Previously Treated with 177Lu-PSMA

Published Date: April 28, 2025
By News Release

At the 2025 American Urologic Association (AUA) Annual Meeting in Las Vegas (April 26–29), Dr. Abdul Baseet Arham presented results from a post hoc analysis assessing the safety and efficacy of 225Ac-J591, a PSMA-targeted alpha-emitting radioligand therapy, in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously undergone treatment with 177Lu-PSMA therapy.

While 177Lu-PSMA-617, a beta emitter, has demonstrated survival benefits in pre-treated mCRPC patients, its effects are often short-lived. PSMA-targeting agents differ in design: monoclonal antibodies like 225Ac-J591 are large molecules with prolonged circulation times and may expose bone marrow to radiation, whereas small molecules like 177Lu-PSMA can reach additional tissues, including kidneys, glands, and the gastrointestinal tract.

The key rationale for this study was that alpha emitters like 225Ac, with higher linear energy transfer, could produce greater DNA damage over a shorter range compared to beta emitters. Given PSMA expression often persists after prior PSMA therapy, researchers theorized that 225Ac-J591 might offer continued benefit even after 177Lu-based treatment.

Study Design and Patient Characteristics

This analysis drew on data from three prospective clinical trials:

  • A Phase I dose-escalation study of 225Ac-J591 (NCT03276572)

  • A pilot trial of PSMA-targeted alpha therapy re-treatment (NCT04576871)

  • A study of fractionated/multi-dose 225Ac-J591 in mCRPC (NCT04506567)

Participants included patients with progressive mCRPC following at least one androgen receptor pathway inhibitor (ARPI) and chemotherapy (or those who were ineligible for or declined chemotherapy). Eligible patients had ECOG performance status 0–2 and adequate organ function. Though 68Ga-PSMA-11 PET was performed pre-treatment, it wasn’t used as an inclusion criterion.

Among 37 patients evaluated:

  • Median age: 72 years

  • Median PSA: 164 ng/mL

  • Bone metastases: 97%

  • Lymph node metastases: 75%

  • Liver metastases: 25%

  • Median PSMA SUVmean: 8.2

  • Median total tumor volume: 427

In terms of treatment history:

  • 57% had ≥2 prior ARPIs

  • 70.3% received chemotherapy

  • 41% had prior immunotherapy

  • 24% were treated with Radium-223

  • 14% received a PARP inhibitor

Efficacy and Safety Outcomes

After treatment with 225Ac-J591, a PSA50 response (≥50% decline in PSA) was observed in 41% of patients (22/37), and a PSA90 response in 8% (3/37). No baseline characteristics, including prior treatments or metastasis locations, were statistically associated with PSA50 response likelihood.

Additional evaluations of circulating tumor cells (CTCs) and PSMA PET imaging parameters were performed post-treatment. Median progression-free survival (PFS) was 3.7 months, while overall survival (OS) reached 10.9 months.

Most adverse events reported were mild to moderate (Grade 1–2), with nausea, xerostomia, and anorexia being the most common.

Conclusion and Future Directions

Dr. Arham concluded that 225Ac-J591 demonstrates promising efficacy in patients with mCRPC who previously received 177Lu-PSMA, with a manageable safety profile dominated by low-grade side effects. Ongoing multicenter trials, including CONVERGE-01 (NCT06549465), are set to further investigate this treatment approach.