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The investigational PSMA-targeted compound 225Ac-J591 demonstrated promising clinical activity with a tolerable safety profile in patients with metastatic castration-resistant prostate cancer (mCRPC), according to results from a phase 1 trial presented during the 2021 ASCO Annual Meeting.1
The findings showed that nearly 70% of patients treated with 225Ac-J591 had a PSA decline, and about 44% of the population reached a PSA decline of more than 50%.
“In summary, 225Ac-J591 was well tolerated, with preliminary evidence of efficacy in a heavily pretreated patient population. This first-in-human, single-dose, phase 1 study has led to several additional phase 1 and 2 studies that have either begun, or will be initiating enrollment shortly after the ASCO Annual Meeting,” said first study author Scott T. Tagawa, MD, a professor of Medicine and Urology at Weill Cornell Medicine, and an attending physician at NewYork-Presbyterian/Weill Cornell Medical Center.
225Ac-J591 is a novel compound that combines J591, a monoclonal antibody that recognizes PSMA, with actinium-225 (225Ac), a potent alpha-emitter.
The data shared at the ASCO meeting were from a cohort of 32 men with progressive mCRPC who had previously received 1 or more androgen receptor (AR)-pathway inhibitors, such as abiraterone acetate (Zytiga) or enzalutamide (Xtandi). Eligible patients should also have received prior chemotherapy. There was no limit on the number of prior treatments, and prior radium-223 (Xofigo) and PSMA-targeted radionuclide therapies (TRTs; eg, 177Lu-PSMA) were allowed. Baseline ECOG performance status for all patients was 0 to 2. Patients received baseline 68Ga-PSMA-11 PET imaging, but PSMA status was not used as a study enrollment criterion.
Baseline characteristics included a median patient age of 69.5 years (range, 52-89) and median a PSA of 149.1 ng/mL (range, 4.8-7168). Prognostic groups per CALGB criteria were low (n = 1), intermediate (n = 8), and high (n = 23). Sites of metastases included bone (n = 31), lymph node (n = 28), liver (n = 6), and lung (n = 5). Overall, 25 (78.1%) patients had received 2 or more prior AR-pathway inhibitors. Other prior treatments included chemotherapy (n = 20), radium-223 (n = 9), sipuleucel-T (Provenge; n = 12), and PSMA-TRTs (n = 14).
In the dose-escalation phase of the study, there was 1 patient who had dose-limiting toxicity, which was grade 4 thrombocytopenia and grade 4 anemia. However, there was no maximum-tolerated dose and the recommended phase 2 dose of the compound is 93.3 KBq/Kg.
Overall, 68.8% of patients had at least some level of PSA decline and 43.8% had a PSA decline of over 50%. Further, of 22 patients with paired circulating tumor cell (CTC) counts at baseline and 12 weeks (CellSearch test), 11 had a CTC decrease (40%-100% decline), 5 were stable, and 4 were increased.
The median biochemical progression-free survival in the whole population was 5. 1 months and the median overall survival was 11.1 months.
“Most treatment-emergent adverse events (TEAEs) were low-grade and improved with time,” said Tagawa. The most common grade 1/2 TEAEs were fatigue (75%), thrombocytopenia (62.5%), anemia (50%), pain (43.8%), nausea (43.8%), neutropenia (28.1%), xerostomia (37.2%), and transaminitis (9.4%).
Grade 3 TEAEs included fatigue (12.5%), thrombocytopenia (3.6%), anemia (9.4%), pain (3.1%), neutropenia (6.3%), and transaminitis (3.1%). Grade 4 TEAEs were thrombocytopenia (9.4%), anemia (3.1%), and neutropenia (3.1%).
1. Tagawa ST, Sun M, Sartor AO, et al. Phase I study of 225Ac-J591 for men with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 39, 2021 (suppl 15; abstr 5015). 10.1200/JCO.2021.39.15_suppl.5015.