First Patient Treated With PSMA-Targeted Actinium-225 Alpha Emitter in mCRPC

The first participant was dosed in a phase 1 clinical trial evaluating actinium (²²⁵Ac) rhPSMA-10.1 injection, an investigational alpha-emitting radiopharmaceutical targeting prostate-specific membrane antigen (PSMA), in patients with metastatic castration-resistant prostate cancer (mCRPC), according to a news release. The study sponsored by University College London (UCL) is being conducted at UCL Hospital, London.¹

The multicenter open-label phase 1/2 ACT-RESoLUTE trial (NCT07414940) is designed to evaluate safety, tolerability, antitumor activity, and radiation dosimetry of actinium (²²⁵Ac) rhPSMA-10.1 injection in participants with PSMA-positive mCRPC whose disease has progressed following prior therapy. Results are expected to characterize the adverse event profile and inform dose selection for subsequent studies.

“This study is an important step in advancing more precise treatment options for men with [mCRPC]. The combination of a highly targeted PSMA approach with the potent, short-range effects of an alpha-emitting radionuclide offers a promising strategy to deliver meaningful [antitumor] activity while limiting toxicity,” stated Gert Attard, MD, PhD, professor and director of the UCL Cancer Institute, in the news release.

Mechanism and Platform

Actinium (²²⁵Ac) rhPSMA-10.1 injection is based on Blue Earth Therapeutics’ radiohybrid PSMA (rhPSMA) platform, a proprietary 4-domain molecular architecture consisting of a PSMA-targeted receptor ligand, 2 labeling moieties capable of being radiolabeled with diagnostic isotopes such as ¹⁸F or ⁶⁸Ga for PET imaging or therapeutic isotopes for radioligand therapy, and a modifiable linker for pharmacokinetic optimization.

Alpha-emitting radionuclides such as actinium-225 deliver a high amount of energy over a short distance in tissue, causing irreparable DNA damage to targeted cancer cells while aiming to limit exposure to healthy tissue. When incorporated into a PSMA-targeting molecule such as rhPSMA-10.1, this approach is designed to deliver localized radiation directly to prostate cancer lesions, potentially offering a targeted treatment strategy for patients with advanced disease. Lutetium Lu 177 vipivotide tetraxetan (Pluvicto) is an approved radioligand therapy targeting PSMA in this setting.

Trial Design

The phase 1 portion of the trial will focus on dose finding and safety in patients with mCRPC who previously responded to lutetium Lu 177 vipivotide tetraxetan; a small number of patients are permitted to be naive to prior radioligand therapy. In phase 2, all patients must have previously responded to treatment with lutetium Lu 177 vipivotide tetraxetan. Patients must have PSMA-avid disease by PSMA-PET-CT scan, prior treatment with at least 1 but no more than 2 lines of taxane therapy or have been deemed ineligible or refused taxane therapy, and prior treatment with at least 1 second-generation androgen receptor pathway inhibitor. Patients cannot have received another prior radiotherapeutic for metastatic prostate cancer such as radium-223 dichloride (Xofigo).

The primary end point in phase 1 is the incidence of dose-limiting toxicities, whereas in phase 2 it is antitumor response as defined as reduction of prostate-specific antigen of at least 50% from baseline or objective radiographic response.

Development of Radiopharmaceuticals

Actinium (²²⁵Ac) rhPSMA-10.1 is the second agent from Blue Earth’s platform, following lutetium (¹⁷⁷Lu) rhPSMA-10.1 injection, which is currently in a phase 2 clinical trial, and together the 2 programs reflect the company’s strategy of developing both alpha- and beta-emitting radiopharmaceutical therapies using the same PSMA-targeting scaffold.

“Early-phase trials such as this are essential for determining safety, refining dose and guiding how these therapies can be integrated into personalized treatment pathways to improve outcomes for patients,” Attard stated in the news release.

REFERENCES

1. Blue Earth Therapeutics announces first participant dosed in Phase 1 clinical trial investigating Actinium (²²⁵Ac) rhPSMA-10.1 Injection in metastatic castration-resistant prostate cancer. News release. Blue Earth Therapeutics. July 9, 2026. Accessed July 10, 2026. https://tinyurl.com/52vctmna

2. ACTinium in Castrate-RESistant Prostate Cancer After LUTEtium (ACT-RESoLUTE). ClinicalTrials.gov. Updated May 8, 2026. Accessed July 10, 2026. https://clinicaltrials.gov/study/NCT07414940