New Paradigms in Theranostics of Prostate Cancer: The Rise of α-Emitters and Next-generation Targets.

Radioligand therapy (RLT) with [177Lu]Lutetium-PSMA (prostate specific membrane antigen) has become a pillar of prostate cancer treatment; however, resistance and PSMA-negative disease remain as unmet needs. The α-emitting radionuclides represent a paradigm shift, with physical properties suited to overcome β-emitter resistance. [225Ac]Actinium-PSMA (prostate specific membrane antigen) has shown promising retrospective results, and ongoing trials are refining its sequencing and safety. Astatine-211 and lead-212 may further improve dosimetry and supply scalability. Beyond PSMA, emerging targets could extend theranostics to PSMA-negative and neuroendocrine diseases. Biomarker-stratified trials will be essential to personalize RLT in prostate cancer. PATIENT SUMMARY: This review highlights future directions in radioligand therapy for advanced prostate cancer, including α-therapy, and the identification of novel targets that may open new therapeutic options for prostate-specific membrane antigen-negative disease.