225Ac-PSMA-617 for Therapy of Prostate Cancer.

Prostate-specific membrane antigen (PSMA)-targeting radio-ligand therapy with beta-emitting 177Lutetium has already been investigated in several early phase dosimetry studies, demonstrated promising results in phase-2, and recently the first phase-3 trial finished recruitment. In contrast, PSMA-targeting alpha-particle therapy (TAT) has only been evaluated in few preclinical experiments, preliminary dosimetry attempts and some retrospective observational studies, yet. First clinical experience with 225Ac-PSMA-617 demonstrates promising antitumor activity with a 63%-70% PSA>50%-response rate, 10-15 months duration of response and complete remissions in approximately ten percent of patients, some of them with enduring relapse-free survival. Nevertheless, without comparative trials there is no prove whether, applied in identical clinical situations, 225Ac-PSMA-617 is really more efficiently than 177Lu-PSMA-617 or vice versa. However, there is some good rationale, that PSMA-TAT might have advantages in particular clinical indications. This includes patients with diffuse type red-marrow infiltration by reducing off-target radiation to surrounding cells; ablation of micrometastases after favorable response to other previous therapy or someday in early stage disease. Also treatment escalation of patients, either with poor response to 177Lu-PSMA or harboring adverse prognostic biomarkers, appears promising. In preclinical research, alpha-radiation demonstrated stronger induction of abscopal effects than beta-radiation; favoring its usage as a combination partner with immunotherapies. So, further evaluation of PSMA-TAT is definitely warranted. Recently, de-escalated treatment protocols and application of 225Ac/177Lu-PSMA "cocktail"-regimens improved the tolerability of 225Ac-PSMA-617 TAT, reducing the risk for development dry-mouth syndrome. This opens new avenues for future application in earlier stage disease.