First-in-human assessment of actinium-225-prostate-specific membrane antigen ( 225 Ac-PSMA)-Trillium (BAY 3563254) in mCRPC: Dose-escalation results of the phase 1 PAnTHa study.

19 Background: PSMA is a validated target in the treatment of mCRPC. We investigated 225 Ac-PSMA-Trillium, a novel PSMA-targeting molecule which comprises a highly specific PSMA-binding motif, an albumin-binding domain to optimize the agent’s pharmacokinetic profile, and a Macropa chelator complexed with the alpha-emitter 225 Ac. We present results of the global, Phase 1 PAnTHa (NCT06217822) study, assessing safety and efficacy of 225 Ac-PSMA-Trillium in patients (pts) with mCRPC. Methods: PAnTHa consists of dose-escalation and dose-expansion parts; the former is reported here. Pts had mCRPC with metastases overexpressing PSMA on positron emission tomography (PET) imaging (uptake >liver in ≥1 lesion), ≥1 prior androgen receptor pathway inhibitor (ARPI) and (if eligible) 1 or 2 prior taxanes, and no prior radiopharmaceutical. 225 Ac-PSMA-Trillium was given intravenously every 6 weeks for up to 4 doses. Dose escalation used a 2-stage joint TITE-CRM design with ≥3 pts per dose level; ≤9 further pts could be added to any dose level considered tolerable with evidence of antitumor activity. The dose-escalation primary objectives were to determine the safety, tolerability and recommended dose for expansion (RDE) of 225 Ac-PSMA-Trillium. Dose-limiting toxicities (DLTs) were assessed in cycles 1–3. Exploratory analyses included baseline PSMA PET mean Standardized Uptake Value (SUVmean) and longitudinal circulating tumor DNA (ctDNA). Results: At data cut-off (18 Sept 2025), 50 patients had received ≥1 dose of 225 Ac-PSMA-Trillium (range: 75 to 150 kBq/kg; 12–13 pts/cohort). Median age was 71 years, 84% had bone metastases, 48% had measurable disease; 58% and 20% had received 1 or 2 prior taxanes, respectively; all received ≥1 prior ARPI. There were no DLTs or treatment-related deaths. Treatment-emergent adverse events (TEAEs) occurred in 98% of pts, most commonly dry mouth (76%; 52% grade Gr 1, 24% Gr 2, 0 Gr ≥3). Other common TEAEs were fatigue (48%) and nausea (44%). Overall, 38% had Gr ≥3 TEAEs, most commonly lymphopenia (20%), 16% had serious TEAEs and 4% discontinued treatment due to TEAEs. The overall response rate per PCWG3 criteria across all doses in pts with measurable disease at baseline (n=24) was 46% and the disease control rate was 83%. Based on safety and preliminary antitumor activity data, 125 kBq/kg was selected as the RDE. Respective PSA50 and PSA90 response rates were 58% and 36% overall, and 83% and 58% at the RDE. PSA responses were seen in 14 out of 15 pts with high PSMA expression at baseline (SUVmean >10). A dose-dependent trend in ctDNA clearance was seen up to the RDE by the start of the second cycle. Conclusions: 225 Ac-PSMA-Trillium was well-tolerated with no DLTs. PSA50 response rates were 83% at the RDE and 93% in all pts with SUVmean >10. These promising data support the further investigation of the molecule. Clinical trial information: NCT06217822 .