Actinium-225 Demonstrates Safety and Responses in mCRPC

The α-emitting radionuclide actinium-225 (²²⁵AC-PSMA-Trillium) was well tolerated and demonstrated biochemical and radiographic responses in patients with metastatic castration-resistant prostate cancer (mCRPC), according to findings of the phase 1 dose-escalation PAnTHA study (NCT06217822). Data were presented during the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium.

In the 50 patients, the PSA50 response rate (defined as a ≥ 50% decline in prostate-specific antigen [PSA] from baseline) was 62%, and the PSA90 response rate was 40%. The overall response rate (ORR) in confirmed responses only was 42%, whereas in both confirmed and unconfirmed responses, the rate was 50%. Further, investigators reported a disease control rate (DCR) of 79%.

In particular, patients who received a dose level of 125 kilobecquerels (kBq)/kg had a PSA50 response rate of 83% and a PSA90 response rate of 67%. Among confirmed responses only, the ORR was 43%, and among confirmed and unconfirmed, the ORR was 71%. DCR was 71%.

Notably, PSA responses were observed across all dose levels, with 93% of patients with a mean PSA greater than 10 achieving a PSA50 response. Exploratory circulating tumor DNA (ctDNA) analyses revealed declines at all dose levels that corresponded closely with the PSA responses. At the 125 kBq/mg dose, an 89% decline in ctDNA was observed, and 36% of patients achieved ctDNA clearance.

The safety profile of the drug was manageable with no dose-limiting toxicities (DLTs) and no deaths. Lymphopenia and anemia were the only grade 3 or higher treatment-emergent adverse events (TEAEs) reported in more than 2% of patients. The most common TEAEs were xerostomia (56% grade 1; 30% grade 2), fatigue (40% grade 1; 14% grade 2), and nausea (38% grade 1; 8% grade 2; and 2% grade 3).

“Given the safety and efficacy results, it was decided to move ahead with the 125 kBq/kg dose for the expansion part of the study,” lead author Fred Saad, MD, said during the presentation of data. Saad is a professor of surgery/urology, director of genitourinary oncology, and director of the Molecular Oncology Research Lab at the Montreal Cancer Institute, University of Montreal, Canada.

Study Design

The PAnTHA study enrolled patients with mCRPC whose disease had worsened after treatment with at least 1 androgen receptor pathway inhibitor and 1 taxane chemotherapy.

The study used a dose-escalation design. Small groups of 3 to 4 patients were treated at increasing dose levels: 75, 101.25, and 150 kBq/kg. Patients could receive up to 4 infusions, which were spaced 6 weeks apart.

If no DLTs were observed at a given level, additional backfill patients were enrolled at that same dose. This was done to gather more safety data and help determine the optimal recommended dose for the next, larger expansion phase of the study.

The primary objectives of the study were safety, efficacy, and the establishment of a recommended dose for expansion.

Patient Characteristics

In the overall population, the median age was 70.5 years (range, 46-85), 90% experienced bone metastases, and the median PSA was 43 µg/L (range, 0.1-5500). The median follow-up time was 7.2 months (range, 2.5-18.2), and 80% of patients completed 4 cycles, which was also the median number of cycles received.

Saad shared the experience of 2 patients during the trial. At the 125-kBq/kg dose, 1 patient experienced nearly complete clearance of visible disease after just 2 treatment cycles, accompanied by a durable decline in PSA to almost undetectable levels. Similarly, another patient showed almost complete disappearance of visible lesions, along with a significant and sustained PSA reduction that remained very low for more than a year.

“These results show a PSA response of 62%. For patients with high PSMA expression, the rate was 93%. At the 125-kBq/kg dose, the ORR was 71% and the PSA50 response rate was 83%,” Saad concluded.

DISCLOSURES: Saad disclosed that he has received honoraria from Abbvie, Advanced Accelerator Applications, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, GSK, Janssen Oncology,Knight Therapeutics, Merck, Myovant Sciences, Novartis, Pfizer, Sanofi, Sumitomo Dainippon Pharma Oncology, and Tolmar. He has served in a consulting or advisory role to AbbVie, Advanced Accelerator Applications, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, GSK, Janssen Oncology, Knight Therapeutics, Merck, Myovant Sciences, Novartis, Pfizer, Sanofi, Sumitomo Dainippon Pharma Oncology, and Tolmar. He has received research funding for Abbvie (Inst), Advanced Accelerator Applications (Inst), Astellas Pharma (Inst), AstraZeneca (Inst), Bayer (Inst), Bristol Myers Squibb (Inst), Janssen Oncology (Inst), Merck (Inst), Novartis (Inst), Pfizer (Inst), Point Therapeutics (Inst), and Sanofi (Inst).

REFERENCE

Saad F, Hotte SJ, Jayaram A, et al. First-in-human assessment of actinium-225-prostate-specific membrane antigen (225Ac-PSMA)-Trillium (BAY 3563254) in mCRPC: dose-escalation results of the phase 1 PAnTHa study. J Clin Oncol. 2026;44(suppl 7):19. doi:10.1200/JCO.2026.44.7_suppl.19