Phase 1/2 AlphaBet Trial: Promising Combination of Lutetium-177 PSMA-I&T and Radium-223 in Advanced Prostate Cancer

A novel therapeutic approach combining lutetium-177 ¹⁷⁷Lu-PSMA-I&T and radium-223 (²²³Ra) shows encouraging results for men with metastatic castration-resistant prostate cancer (mCRPC), as demonstrated in the recently reported AlphaBet trial published in The Lancet Oncology in October 2025.

This phase 1/2 AlphaBet study is the first to evaluate the safety, feasibility, and preliminary efficacy of the dual radionuclide therapy that targets both PSMA-expressing tumor cells (¹⁷⁷Lu-PSMA-I&T) and bone metastases (²²³Ra), addressing a critical need for therapies effective against bone-dominant disease.

The trial enrolled 36 patients with mCRPC and bone metastases, administering escalating doses of ¹⁷⁷Lu-PSMA-I&T combined with a fixed dose of ²²³Ra. Of these, 33 patients were evaluable for efficacy. The combination was well tolerated, with the most common adverse events including low-grade hematologic toxicities and mild xerostomia. Importantly, no dose-limiting toxicities were observed up to a ¹⁷⁷Lu dose of 55 kBq/kg.

Efficacy signals are promising, with over 50% of patients achieving a PSA decline of at least 50%, indicating a robust antitumor effect. This dual-radionuclide approach aims to enhance tumor control by combining targeted alpha therapy focusing on osseous disease with beta-emitting PSMA radioligand therapy addressing soft tissue and metastatic prostate cancer cells.

Presented at ESMO 2025, these results illustrate the potential of combination radionuclide therapy to improve outcomes in men with advanced prostate cancer with predominant bone involvement.

The AlphaBet trial’s encouraging safety and efficacy profile justifies further exploration in larger, randomized phase 3 studies to affirm the clinical benefits and optimize sequencing and dosing strategies for this promising combination.

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