225Ac-PSMA-Trillium achieves high PSA responses in phase 1 PAnTHa trial

Data from the phase 1 PAnTHa study (NCT06217822) showed promising safety and strong antitumor activity for the investigational alpha-emitting radioligand therapy ²²⁵Ac-PSMA-Trillium in men with metastatic castration-resistant prostate cancer (mCRPC), supporting advancement to dose expansion and future phase 3 evaluation.¹

The data were presented at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California.

Beginning his presentation, Fred Saad, CQ, MD, FRCS, FCAHS, explained, “Currently available RLTs [radioligand therapies] radium[-223 (Xofigo)] and PSMA [prostate-specific membrane antigen] lutetium [Pluvicto] have proven to be both efficacious and safe. Developing alpha-emitting PSMA-targeting agents are based on the theoretical benefits of delivering higher linear energy, with shorter penetration, compared to beta emitters.” Saad is a professor and chairman of the department of surgery as well as the head of GU oncology at the University of Montreal.

The study population consisted of adult men with ECOG Performance Status of 0 or 1, confirmed mCRPC, at least 1 PSMA-positive metastases, prior treatment with an androgen receptor pathway inhibitor, prior treatment with 1 or 2 taxanes, and no prior radionuclide therapy. ²²⁵-Ac-PSMA-Trillium was administered on the first day of a 6-week cycle (4 cycles maximum) over a period of 18 weeks. Doses administered ranged from 70 kBq/kg to 150 kBq/kg; 3 to 4 patients were treated per dose level.

“If no DLT [dose-limiting toxicity] was observed, additional backfill patients were added to the individual dose levels in order to establish the recommended dose for the expansion part of the study,” Saad said.

The primary objectives included safety, efficacy, and the establishment of the recommended dose for expansion. Exploratory analyses included baseline PSMA-PET SUVmean and longitudinal circulating tumor DNA (ctDNA).

The dose expansion phase consisted of 3 groups:

• group A: Patients in this group had 1 or 2 prior taxanes in the castration-resistant setting and not received prior radionuclides.

• group B: Patients in this group had not received prior taxane chemotherapy since castration resistance and had not received prior radionuclides.

• group C: Patients in this group had received 1 or 2 prior taxanes as well as prior treatment with ¹⁷⁷Lu-PSMA.

Saad reported that baseline patient characteristics were similar among the dosage levels. Median follow-up was 7.2 months (range, 2.5-18.2 months). Eighty-percent of patients completed 4 cycles of treatment; median number of cycles received was 4.

Regarding safety, “The safety profile of the drug was manageable, with no DLTs at any of the dose levels and no deaths, with almost no patients requiring dose modifications up until the 150 [kBq/kg] dose, where 3 of 13 patients had a dose reduction. Overall, only 6% of patients discontinued treatment due to an adverse event,” Saad said.

Xerostemia was observed in 86% of patients; in 56%, xerostemia was grade 1. There were no grade 3 or 4 adverse events [AEs] reported. Other common AEs included fatigue, nausea, and decreased appetite.

“Biochemical responses were seen at all dose levels, with an overall PSA50 response of 62% and a PSA90 response of 40%. At the 125 [kBq/kg]-dose, PSA50 was actually 83% and PSA90 was 67%. Measurable response was 50% in the overall patient population, with 71% overall response in the 125 [kBq/kg]-dose. Given the safety and efficacy results, it was decided to move forward with the 125 [kBq/kg]-dose for the expansion part of the study,” Saad said. He also noted that PSA50 responses were seen in all basedline SUVmean groups.

Turning to ctDNA analyses, Saad commented, “We performed exploratory ctDNA analyses that showed declines at all dose levels and corresponded nicely to PSA responses. Of note, at the 125 [kBq/kg]-dose, there was an 89% decline in ctDNA, and 36% of patients had ctDNA clearance, further confirming the choice moving forward with the 125 [kBq/kg]-dose.”

Closing his presentation, Saad said, “In conclusion, the study using Trillium actinium PSMA showed a PSA response of 62% and an overall response rate of 50%, with 93% of patients having PSA responses with SUVs of above 10. Based on the overall response of 71% and PSA50 of 83% with the 125 [kBq/kg]-dose, this is going forward and is ongoing in the expansion part of the study. The expansion part includes patients that are mCRPC post-chemotherapy, prior to chemotherapy, and post-lutetium, and these findings from the phase 1 study will inform the phase 3 trial in mCRPC.”

REFERENCES

1. 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. Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium. February 26-28, 2026. San Francisco, California. Abstract 19. https://meetings.asco.org/meetings/2026-asco-genitourinary-cancers-symposium/334/16932

2. Parker C, Lewington V, Shore N, et al. Targeted alpha therapy, an emerging class of cancer agents: A review. JAMA Oncol. 2018;4(12):1765-1772. doi:10.1001/jamaoncol.2018.4044

3. Tafreshi NK, Doligalski ML, Tichacek CJ, et al. Development of targeted alpha particle therapy for solid tumors. Molecules. 2019;24(23):4314. doi:10.3390/molecules24234314