Predictors and Real-World Use of Prostate-Specific Radioligand Therapy: PSMA and Beyond

PSMA is a transmembrane protein that is markedly overexpressed in prostate cancer, making it an excellent target for imaging and treating patients with prostate cancer. Several small molecule inhibitors and antibodies of PSMA have been radiolabeled for use as therapeutic agents and are currently under clinical investigation. PSMA-based radionuclide therapy is a promising therapeutic option for men with metastatic prostate cancer. The phase II TheraP study demonstrated superior efficacy, lower side effects, and improved patient-reported outcomes compared with cabazitaxel. The phase III VISION study demonstrated that radionuclide therapy with β-emitter ¹⁷⁷Lu-PSMA-617 can prolong survival and improve quality of life when offered in addition to standard-of-care therapy in men with PSMA-positive metastatic castration-resistant prostate cancer whose disease had progressed with conventional treatments. Nevertheless, up to 30% of patients have inherent resistance to PSMA-based radionuclide therapy, and acquired resistance is inevitable. Hence, strategies to increase the efficacy of PSMA-based radionuclide therapy have been under clinical investigation. These include better patient selection; increased radiation damage delivery via dosimetry-based administered dose or use of α-emitters instead of β-emitters; or using combinatorial approaches to overcome radioresistance mechanisms (innate or acquired), such as with novel hormonal agents, PARP inhibitors, or immunotherapy.