A Narrative Review of Recent Advances in Prostate-Specific Membrane Antigen (PSMA)-Based Diagnostics and Theranostics

Prostate-specific membrane antigen (PSMA) has emerged as a pivotal target in the management of prostate cancer, revolutionizing both diagnostic and therapeutic landscapes. This narrative review explores recent advances in PSMA-based theranostics, focusing on the superior diagnostic accuracy of PSMA-PET imaging for staging and restaging compared to conventional modalities. It highlights how PSMA-PET improves detection rates, particularly at low PSA levels, and facilitates precise patient selection for targeted therapies. The review then details the paradigm shift brought by PSMA-directed radioligand therapy (RLT), particularly with Lutetium-177 (¹⁷⁷Lu-PSMA-617), which has demonstrated significant survival benefits in metastatic castration-resistant prostate cancer (mCRPC) patients in landmark trials like VISION and TheraP. The potential of the more potent alpha-emitter Actinium-225 (²²⁵Ac-PSMA-617) for treating advanced disease is also discussed. Despite these promising results, clinical implementation faces challenges, including tumor heterogeneity in PSMA expression, the emergence of treatment resistance, and off-target toxicities such as xerostomia and myelosuppression. Furthermore, issues of global accessibility, cost-effectiveness, and a lack of standardized response criteria remain significant hurdles. In conclusion, PSMA theranostics represent a transformative approach in prostate cancer care. Future efforts must focus on refining biomarker-driven patient selection, developing novel ligands to overcome resistance, and establishing standardized protocols to ensure equitable and optimal clinical adoption.