Radionuclide Combination Strategies in Prostate Cancer: Insights from the AlphaBet Trial.

Abstract

The integration of [¹⁷⁷Lu]Lu-prostate-specific membrane antigen (PSMA) therapy into the treatment paradigm for advanced prostate cancer has improved survival and quality of life; however, resistance and disease progression remain inevitable. Radionuclide combination strategies, particularly α-/β-emitter pairings, aim to overcome biological and dosimetric limitations of [¹⁷⁷Lu]Lu-PSMA monotherapy. The AlphaBet trial demonstrated the feasibility and safety of combining the bone-seeking α-emitter radium-223 with [¹⁷⁷Lu]Lu-PSMA in metastatic castration-resistant prostate cancer, underpinned by complementary spatial targeting and radiophysical properties. Ongoing studies are evaluating other novel combinations to overcome resistance, earlier integration to define optimal sequencing, and biomarker-driven approaches to refine patient selection. For patients, these strategies may enable more effective and durable treatments by combining different types of targeted radiation or systemic therapies; however, further studies are needed to confirm long-term benefits and safety.