Precision Oncology with PSMA-Targeted α-Particle Therapy of mCRPC

Prostate-specific membrane antigen (PSMA) has been firmly established as a clinically relevant biomarker in imaging and targeted radionuclide therapy (theranostics) of prostate cancer, particularly in the metastatic castrate-resistant state. Numerous investigations from around the world in both academic and pharma settings are focused on research and development of safe and effective PSMA-based theranostic agents. Encouraging results from retrospective studies using the β-particle emitting 177Lu-PSMA-617 radioligand therapy prompted prospective phase II and phase III randomized clinical trials with recently published favorable results of the VISION trial. While these pivotal investigations continue, there has also been major growing interest in the potential clinical utility of α-particle PSMA-targeted therapeutic agents. After a brief review of PSMA biology, imaging with positron emission tomography, and current experience with targeted β-particle (177Lu) therapy, this article summarizes the preclinical and early clinical studies that have evaluated the PSMA-targeted agents conjugated properly to α-particle radiolabels including 225Ac, 213Bi, 227Th, 212Pb, and 149Tb.