225Ac-PSMA-617 for Therapy of Prostate Cancer

Prostate-specific membrane antigen (PSMA)-targeting radio-ligand therapy with beta-emitting (177)Lutetium 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 Ac-225-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, Ac-225-PSMA-617 is really more efficiently than Lu-177-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 Lu-177-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 Ac-225/Lu-177-PSMA "cocktail"-regimens improved the tolerability of Ac-225-PSMA-617 TAT, reducing the risk for development dry-mouth syndrome. This opens new avenues for future application in earlier stage disease. (C) 2020 Elsevier Inc. All rights reserved.