Towards Improving the Efficacy of PSMA-Targeting Radionuclide Therapy for Late-Stage Prostate Cancer—Combination Strategies

PURPOSE OF REVIEW: [(177)Lu]Lu-PSMA-617 is a radiopharmaceutical that emits beta-minus radiation and targets prostate-specific membrane antigen (PSMA)-positive prostate cancer. Despite its clinical success, there are still patients not showing sufficient response rates. This review compiles latest studies aiming at therapy improvement in [(177)Lu]Lu-PSMA-617-naïve and -resistant patients by alternative or combination treatments. RECENT FINDINGS: A variety of agents to combine with [(177)Lu]Lu-PSMA-617 are currently under investigation including alpha radiation-emitting pharmaceuticals, radiosensitizers, taxane chemotherapeutics, androgen receptor pathway inhibitors, immune checkpoint inhibitors, and external beam radiation. Actinium-225 ((225)Ac)-labeled PSMA-targeting inhibitors are the most studied pharmaceuticals for combination therapy or as an alternative for treatment after progression under [(177)Lu]Lu-PSMA-617 therapy. SUMMARY: Alpha emitters seem to have a potential of achieving a response to PSMA-targeting radionuclide therapy in both initial non-responders or responders to [(177)Lu]Lu-PSMA-617 later developing treatment resistance. Emerging evidence for immunostimulatory effects of radiopharmaceuticals and first prospective studies support the combination of [(177)Lu]Lu-PSMA-617 and immune checkpoint inhibition for late-stage prostate cancer.