PSMA-targeted radioligand therapy with 177Lu-PSMA-617 has been shown to improve survival outcomes in select pre-treated mCRPC patients; however, disease control is typically short-term. PSMA may be targeted with antibodies or small molecules that have significant differences in their kinetics and biodistribution:
- Monoclonal antibodies (mAb): Large molecules with long circulation times and non-specific exposure to the bone marrow (e.g., 225Ac-J591)
- Small molecules: Small enough to target PSMA expression in the kidneys, salivary/lacrimal glands, and small bowel (e.g., 177Lu-PSMA)
This was a post hoc analysis of three prospective clinical trials:
- Phase I dose-escalation trial of 225Ac-J591 in mCRPC patients (NCT03276572)1
- Pilot study of PSMA-targeted radionuclide therapy (TRT) re-treatment utilizing 225Ac-J591 (NCT04576871)
- Fractionated or multiple dose 225Ac-J591 for mCRPC (NCT04506567)2
The trial inclusion criteria were as follows (two trials allowed prior PSMA-TRT, one trial mandated):
- Progressive mCRPC after ≥1 ARPI and chemotherapy (or chemotherapy ineligible/refused).
- ECOG 0-2, intact organ function.
- Pre-treatment 68Ga-PSMA-11 PET was performed, but not utilized for eligibility
The patient demographics are summarized below. The median patient age and PSA were 72 years and 164 ng/ml, respectively. The most common sites of metastases were bone (97%) and lymph nodes (75%), with 25% of patients having liver metastases. The median SUVmean was 8.2, with a median total tumor volume of 427.
With regards to previous systemic therapies received, 57% had received ≥2 prior ARPIs, 70.3% chemotherapy, 41% prior immunotherapy, 24% Radium-223, and 14% a prior PARP inhibitor.
From an efficacy standpoint, a PSA50 and PSA90 response was observed in 22/37 (41%) and 3/37 (8%) patients, respectively, receiving 225Ac-J591 following 177Lu-PSMA therapy.
None of the baseline characteristics evaluated were shown to be significantly associated with the odds of achieving a PSA50 response. The changes in the circulating tumor cell (CTC) counts and PSMA PET parameters with 225Ac-J591 following 177Lu-PSMA therapy. The median progression-free survival (PFS) was 3.7 months, and the median overall survival (OS) was 10.9 months. The most common adverse events were nausea, xerostomia, and anorexia (all Grade 1–2).
Dr. Arham concluded as follows:
- 225Ac-J591 shows efficacy in mCRPC patients following prior 177Lu-PSMA therapy
- This sequential therapy is associated mostly with low-grade adverse events
- Multicenter trials are currently underway to validate these findings, including CONVERGE-01 (NCT06549465) which was presented at ASCO GU 2025 (trials in progress)
Written by: Rashid K. Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2025 American Urological Association (AUA) annual meeting held in Las Vegas, NV, Saturday, April 26 - Tuesday, April 29, 2025
Related content: Combining Alpha and Beta Emitters in PSMA-Targeted Prostate Cancer Therapy - Scott Tagawa
- Tagawa ST, Milowsky MI, Morris MJ, et al. Prostate-specific membrane antigen–targeting alpha emitter via antibody delivery for metastatic castration-resistant prostate cancer: a phase I dose-escalation study of 225Ac-J591. J Nucl Med. 2019; 60(7):1233-1240.
- Nauseef JT, Sun MP, Thomas C, et al. A phase I/II dose-escalation study of fractionated 225Ac-J591 for progressive metastatic castration-resistant prostate cancer in patients with prior treatment with 177Lu-PSMA. J Clin Oncol. 2023; 41(6_suppl):TPS288.