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.