A phase I study of [225Ac]Ac-PSMA-XT, a novel alpha-particle–emitting radioligand therapy, in patients with metastatic castration-resistant prostate cancer.

5063 Background: Targeted alpha therapy (TAT) is an emerging modality for metastatic castration-resistant prostate cancer (mCRPC), offering the potential for precise tumor cell eradication with limited off-target exposure. [225Ac]Ac-PSMA-XT (XT381) is a PSMA-targeted alpha-emitting radiopharmaceutical designed to deliver high linear energy transfer radiation. This single-center, open-label Phase I study (NCT07135102) in China aims to assess the safety, tolerability, and preliminary efficacy of [225Ac]Ac-PSMA-XT in heavily pretreated mCRPC. Methods: Patients with PSMA-positive mCRPC (confirmed by THERP trial criteria, ≥1 lesion with SUV max > 20 on PSMA PET/CT imaging, and all measurable lesions with SUV max > liver SUV mean ) who progressed after ≥1 line of androgen receptor pathway inhibitor were enrolled. A standard "3 + 3" design was used across five dose levels (25, 50, 75, 100 and 125 kBq/kg), with up to 6 cycles administered every 6 weeks. Primary endpoints were safety/tolerability (CTCAE v5.0). Key secondary endpoints inclued PSA50 response (≥50% decline), radiographic progression-free survival (rPFS), objective response rate (ORR) by RECIST 1.1, and disease control rate (DCR). Enrollment has completed through the 75 kBq/kg cohort, the 100 kBq/kg cohort is ongoing. Results: As of December 12, 2025, 12 paitents were dosed (cohorts 25-100 kBq/kg, n = 3 each). All patients received at least one dose of [225Ac]Ac-PSMA-XT. No dose-limiting toxicities have been observed. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 2 patients. The most common TRAEs were xerostomia and grade 1-2 hematologic toxicities, including anemia (55.6%, 5/9), leukopenia (44.4%, 4/9), lymphopenia (22.2%, 2/9), neutropenia (11.1%, 1/9), and thrombocytopenia (11.1%, 1/9). Among 9 evaluable patients (≥6 weeks follow-up), 7 (77.8%) achieved a PSA50 response, and 4 (44.4%) achieved a PSA90 response. The 6-month progression-free survival (PFS) rate was 71.4 (5/7). In 5 patients with RECIST-measurable disease, ORR was 60% (3 partial responses). Overall DCR was 67%. Conclusions: [225Ac]Ac-PSMA-XT shows a favorable and manageable safety profile with no DLTs observed up to 100 kBq/kg. Early efficacy signals are highly encouraging, with deep PSA declines and durable disease control observed in this heavily pretreated mCRPC population. These data support continued dose escalation and further development of this alpha-emitting PSMA-targeted therapy. Clinical trial information: NCT07135102 .