Prostate-Specific Membrane Antigen (PSMA)-Targeted Radionuclide Therapies for Prostate Cancer

Purpose of review: Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) is a promising investigational treatment for metastatic castration-resistant prostate Cancer (mCRPC). This review describes the available data with PSMA TRT.

Recent findings: Conjugates used for PSMA TRT include Antibodies or small molecules PSMA-radiolabeled with beta (most commonly 177Lu) or alpha emitters (commonly 225Ac). 177Lu-J591 demonstrated accurate targeting of known metastatic sites, based on post-treatment scintigraphy, in study populations that were not selected for PSMA expression, with evidence of dose-response and dose-limiting myelosuppression. Early phase studies of 177Lu-PSMA-617 have demonstrated favorable adverse event profiles and signs of clinical activity as evidenced by PSA responses and other short-term outcomes. A phase II randomized study of 177Lu-PSMA-617 showed a superior PSA50 response rate (66 vs 37%) over cabazitaxel in patients with docetaxel-pretreated, progressive mCRPC selected by PSMA and FDG PET/CT scans. PSMA TRT is emerging as a promising investigational therapy for mCRPC. The first randomized data with 177Lu-PSMA-617 (phase 2) have been presented, and the first phase 3 trial has completed accrual with radiographic progression-free and overall survival as dual primary endpoints. Multiple additional phase 3 trials of PSMA-TRT are starting and studies investigating optimal patient selection and combination therapy continue.

Metastatic castration resistant prostate cancer; Monoclonal antibodies; Prostate specific membrane antigen; Radioligand therapy; Small molecules; Targeted therapies.