PSMA may be targeted by monoclonal antibodies or small molecules, which have different kinetics and biodistribution profiles and, therefore, different predicted toxicities. Radionuclides include both alpha and beta emitters. What is the difference between alpha and beta emitters? Alpha emitters are associated with higher linear energy transfers over a shorter range, compared to beta emitters, offering distinct therapeutic advantages with pre-clinical and dosimetric rationale for combining these two classes of emitters. These radionuclides can be complexed with antibody ligands (e.g., J591), which are larger in size, target tissue via blood vessels, and are associated with off-tumor side effects (i.e., bone marrow, liver). Conversely, small molecules include PSMA-617 and PSMA-I&T, which are smaller in size, thus lasting for hours in the bloodstream, rapidly penetrate tissues, and are associated with side effects in other organs that express PSMA (i.e., kidney, salivary/lacrimal glands, small intestine).
This study was a post hoc analysis of four separate early phase prospective clinical trials.1-4 All trials included adult mCRPC patients who had received ≥1 androgen receptor pathway inhibitor (ARPI) and a prior taxane (or unfit/refused) and received either:
- 225Ac-J591 single agent therapy
- 225Ac-J591 in combination with either 177Lu or pembrolizumab + an ARPI
A brief overview of the 4 trials is illustrated below:
- Phase I trial of single dose 225Ac-J591
- Phase I trial of fractionated or multiple dose 225Ac-J591
- Phase I dose-escalation trial of 225Ac-J591 + 177Lu-PSMA-I&T
- Phase I/II trial of 225Ac-J591 + pembrolizumab + an ARPI
The baseline patient characteristics, stratified by receipt of single agent or combination therapy, are summarized below. The baseline PSA was 84 ng/ml for patients receiving single agent therapy versus 20 ng/ml in the combination therapy-treated patients. Single agent-treated patients were more likely to have received chemotherapy (68% versus 43%) and 177Lu-PSMA (34% versus 10%).
From an efficacy standpoint, a PSA50 response was observed in 57% of patients who received 225Ac combination therapy and 48% of patients who received single agent 225Ac (p=0.4).
In multivariable analysis, the baseline PSMA PET SUVmean was a significant predictor of a PSA50 response.
Both progression-free survival (5.7 versus 3.9 months) and overall survival (20.6 versus 11.2 months) favored the combination approach (p<0.01 for both).
On multivariable analyses, a high Halabi risk and receipt of prior chemotherapy were both significant predictors of worse progression-free and overall survivals among 225Ac-treated patients (single agent and combination).
The incidence of grade 3 and 4 adverse events was non-significantly worse with combination therapy (Grade 3: 33% vs 20%; Grade 4: 20% vs 16%; p=0.2).
There was an increased incidence of xerostomia (OR: 2.98, 95% CI: 1.05–9.88) and elevated LFTs (OR: 1.8, 95% CI: 0.71-4.80) with combination therapy, whereas neutropenia (OR: 0.37, 95% CI: 0.13–0.93) was observed less frequently with combination therapy.
Dr. Corzo concluded as follows:
- 225Ac-J591 combination therapy demonstrated a higher PSA50 response rate compared to monotherapy (57% versus 48%), albeit not statistically significant different
- Progression-free and overall survivals were superior in the combination therapy groups, with HRs of 0.61 (p=0.02) and 0.54 (p=0.03), respectively
- Acute adverse events were generally low grade in nature
- This study supports the feasibility and potential clinical benefit of combination PSMA-targeted Alpha therapy
Presented by: Valentina Marulanda Corzo, MD, Postdoctoral Research Fellow in Radiology, Division of Molecular Imaging and Therapeutics, Weill Cornell Medicine, New York, NY
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
References:
- 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.
- Tagawa ST, Sun MSP, Nauseef JT, et al. Phase I dose-escalation results of prostate-specific membrane antigen-targeted radionuclide therapy (PSMA-TRT) with alpha-radiolabeled antibody 225Ac-J591 and beta-radioligand 177Lu-PSMA I&T. J Clin Oncol. 2023; 41: 16_Suppl.
- Sun MP, Nauseef JT, Palmer J, et al. Phase I results of a phase I/II study of pembrolizumab and AR signaling inhibitor (ARSI) with 225Ac-J591. J Clin Oncol. 2023; 41: 6_Suppl.