A new Phase III clinical trial is underway to evaluate the efficacy of ²²⁵Ac-PSMA-617 (AAA817) in combination with androgen receptor pathway inhibitors (ARPI) for treating prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC). This study aims to determine whether this combination therapy can improve radiographic progression-free survival (rPFS) compared to standard-of-care treatments, which include either a change in ARPI or taxane-based chemotherapy.

Eligible participants are adult males with PSMA-positive mCRPC who have been treated with an ARPI as their most recent therapy but have not received taxane-containing chemotherapy in the mCRPC setting, nor any prior PSMA-targeting radioligand therapy. The trial plans to administer up to six cycles of 225-Ac-PSMA-617 at a dose of 10 Megabecquerel (MBq) ±10%, alongside an ARPI chosen by the investigator. The primary objective is to assess the improvement in rPFS compared to the investigator’s choice of standard-of-care treatments.

225-Ac-PSMA-617 is a targeted alpha therapy that binds to PSMA-expressing tumor cells, delivering alpha radiation directly to the cancerous cells, thereby minimizing damage to surrounding healthy tissue. Previous studies have demonstrated its potential efficacy in treating mCRPC, particularly in patients who have exhausted other treatment options.

This trial represents a significant step in exploring advanced therapeutic options for mCRPC patients, aiming to provide more effective treatments with potentially improved survival outcomes.

Actinium-225-labeled PSMA-617 (225-Ac-PSMA-617) has been investigated in several Phase I and II studies for the treatment of metastatic castration-resistant prostate cancer (mCRPC). These studies have demonstrated promising efficacy and manageable safety profiles.​

A notable Phase I study published in 2018 involved chemotherapy-naïve patients with advanced prostate cancer. The study reported that 225Ac-PSMA-617 treatment led to significant prostate-specific antigen (PSA) declines, with 87% of patients experiencing any PSA decrease and 66% showing a decline greater than 50%. The median overall survival (OS) was reported as 12.5 months, and progression-free survival (PFS) was 9.1 months.

Clinical trial.