PSMA Therapy Grey Zones: Actinium, Lutetium, or Terbium for the Future of Radioligand therapy?

Radioligand therapy targeting the prostate-specific membrane antigen (PSMA) has been established as a key treatment for PSMA-positive metastatic castration-resistant prostate cancer following the approval of [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu). However, variable responses, resistance, uncertain treatment sequencing, and limited efficacy in selected biological settings remain major clinical challenges. This narrative perspective reviews the rationale for radionuclide selection in PSMA-targeted therapy.

A nonsystematic review of PubMed/MEDLINE and EMBASE was performed, updated to April 2026, prioritizing registered trials and multicenter studies.

¹⁷⁷Lu remains the clinical benchmark owing to randomized evidence, favorable logistics, posttherapy imaging, and a well-defined safety profile. Its β-emission crossfire effect is useful in bulky or heterogeneous disease but may be less effective against micrometastatic or PSMA-low/aggressive clones. Actinium-225-based targeted α-therapy offers high linear energy transfer radiation and may overcome β-emitter resistance, although side effects, imaging limitations, and supply constraints remain concerns. Terbium-161 (¹⁶¹Tb) may provide a valid alternative with potential advantages in small-volume disease.

Early data with ¹⁶¹Tb- and Lead-212-based PSMA therapies are promising but require prospective comparative validation. Future progress will depend on matching radionuclide properties to tumor biology rather than identifying a universally superior isotope.