Theranostic applications of PSMA-targeted radiopharmaceuticals: From molecular design to clinical translation and emerging paradigms

Theranostics is an innovative concept in nuclear medicine that combines molecular imaging with targeted radionuclide therapy. PSMA is the best-studied and most clinically utilized oncological theranostic target, as it is a protein that is highly and differentially expressed in late-stage prostate cancer. This review comprises a comprehensive appraisal of PSMA-targeted radiopharmaceuticals and emphasizes their physiological basis, molecular blueprint, clinical imaging, and treatment utilization. A narrative review of peer-reviewed literature was conducted, encompassing preclinical studies, prospective clinical trials, meta-analyses, and real-world evidence on PSMA-targeted imaging and radionuclide therapy. Emphasis was placed on clinically validated positron emission tomography tracers and therapeutic agents, including beta- and alpha-emitting radiopharmaceuticals. PSMA-targeted positron emission tomography imaging with gallium-68 and fluorine-18-labelled tracers provides excellent diagnostic performance in both staging and restaging scenarios and is therefore pivotal for patient selection in radioligand therapy. PSMA radioligand therapy with ¹ ⁷⁷Lu-PSMA-617 has demonstrated substantial benefits in progression-free and overall survival in metastatic castration-resistant prostate cancer, while maintaining a good safety profile. Nevertheless, treatment response is variable, mainly due to differences in PSMA expression, disease biology, and dosimetric factors. Recent data from the past few years also indicate that personalized dosimetry, the use of alpha-emitting compounds, and combinations of treatment regimens, such as Poly(ADP-ribose) polymerase (PARP) inhibitor and immunotherapy, could further improve clinical outcomes; however, challenges such as long-term toxicity and shortages of radionuclides must be addressed. PSMA-targeted theranostics are a clinically proven platform for precision oncology. Subsequent developments will rely on biologically guided patient stratification, treatment personalization, refined dosimetry, careful clinical evaluation of novel radiopharmaceuticals, and long-term safety assessment.