The alpha prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy 225Ac-J591 demonstrated promising clinical efficacy and safety in patients with metastatic castration-resistant prostate cancer (mCRPC), according to data from a first-in-human phase 1 dose escalation trial (NCT03276572) of the agent.1
The trial included 32 patients with progressive mCRPC that were resistant to or refused other treatment options. In total, 22 participants received 1 dose of 225Ac-J591 at 1 of the 7 dose escalation levels assessed followed by 10 patients receiving expansion at the highest dose level.
Overall, 78% of patients included in the study had previous treatment with at least 2 androgen receptor pathway inhibitors, 63% had previous treatment with chemotherapy, and 46.9% had been previously treated with 177Lu-PSMA. The median patient age was 70 years. The primary end points were the determination of dose-limiting toxicity (DLT) and a recommended phase 2 dose (RP2D).2
Only 1 DLT (4.5%) was observed in a patient from cohort 6 (80 KBq/kg; grade 4 anemia and thrombocytopenia), though no DLTs were observed in cohort 7. At the time of the data cutoff, a maximum tolerated dose (MTD) had not yet been reached. Therefore, the RP2D was determined to be 93.3 KBq/kg, the highest dose level assessed in the study.
The majority of high-grade adverse events (AEs) were hematologic. The investigators also noted that higher-grade hematologic AEs were associated with higher administered radioactivity. Nonhematologic AEs were generally low-grade, with grade 3 AEs only occurring in 1 patient.
Declines in PSA levels and circulating tumor cell control (CTC) were also observed among 71.9% and 75% of patients, respectively. Overall, 46.9% of patients (n = 15) experienced at least a 50% PSA decline at any point, with 34.4% (n = 11) having a confirmed PSA50 response. Further, 59.1% (n = 13) of patients experienced a protocol-defined CTC count response (defined as a drop from 5 or greater CTCs to 4 or less, or a count remaining at 4 or less CTCs at 12 weeks).
The median progression-free survival was 5.6 months (95% CI, 3.7-7.9) and the median overall survival was 10.7 months (95% CI, 6.5-17.2) among all patients. Only Cancer and Leukemia Group B prognostic grouping was found to be associated with survival (HR, 3.94; P = .04) upon multivariable analysis.
The investigators noted that because an MTD had not been reached, a follow-up phase 1/2 study (NCT04506567) is underway to determine the MTD of multiple or fractionated dosing of 225Ac-J591 with or without previous 177Lu-PSMA.
The authors concluded, “In conclusion, to our knowledge, in this initial first-in-human trial using a single-dose of 225Ac-J591, we found reversible toxicity and good antitumor activity in men with pretreated progressive mCRPC despite not selecting patients by PSMA PET and with 47% having had previous 177Lu-PSMA.”1
1. Tagawa ST, Thomas C, Sartor AO, 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 Clin Oncol. 2023:JCO2300573. doi:10.1200/JCO.23.00573
2. National Institutes of Health US National Library of Medicine ClinicalTrials.gov. Phase I trial of 225Ac-J591 in patients with mCRPC. Last updated November 2, 2023. Accessed November 7, 2023. https://clinicaltrials.gov/study/NCT03276572