Radionuclide Therapy in Prostate Cancer: From Standalone to Combination PSMA Theranostics

Despite significant advances in therapeutic developments for prostate cancer over the last 2 decades, metastatic prostate cancer remains a lethal disease. Prostate-specific membrane antigen (PSMA), which is markedly overexpressed in prostate cancer cells and metastatic sites but has low normal-tissue expression, has emerged as an important theranostic target for this disease. Both β-emitting and α-emitting PSMA-targeted radionuclide therapy (RNT) are in clinical development. Several of these agents have already shown promising activity; however, a subset of patients have primary resistant disease, and secondary resistance invariably occurs. Further, the effect of these therapies on healthy organs limits their therapeutic window. Elucidating the biology of PSMA and characterizing the pharmacokinetic and pharmacodynamic properties of PSMA-targeted RNT and mechanisms of resistance will facilitate therapeutic approaches aimed at improving efficacy and safety. In this review, we provide an overview of existing PSMA-targeting RNT and novel RNT combinatorial approaches, such as those with novel hormonal agents, poly-[adenosine diphosphate-ribose]-polymerase inhibitors and immunotherapy, currently under investigation.