Advances With 225Ac-DOTATATE Targeted Alpha Therapy in Somatostatin Receptor Positive Neuroendocrine Tumors.

Abstract

²²⁵Ac-DOTATATE-based targeted alpha therapy (TAT) is emerging as a transformative option in the management of advanced, well-differentiated, somatostatin receptor (SSTR)-positive neuroendocrine tumors (NETs), particularly in patients refractory to conventional β-emitter peptide receptor radionuclide therapy (PRRT). This review synthesizes current evidence from preclinical models and early-phase clinical studies, highlighting its therapeutic promise in terms of potent antitumor efficacy and favorable toxicity profile. We discuss the radiobiological and mechanistic advantages of α-particle therapy while also addressing key limitations such as radionuclide supply constraints, recoil-induced daughter redistribution, challenges in dosimetry, and regulatory hurdles. Emerging strategies including improved chelators, SSTR antagonists, and tandem or combination therapies are described. Key ongoing trials have also been summarized. As ²²⁵Ac-DOTATATE-based TAT progresses toward mainstream clinical integration, multidisciplinary collaboration across academia, industry, and regulatory bodies will be essential to refine protocols, optimize safety, and expand access.