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

Curr Oncol Rep. 2023 Nov;25(11):1363-1374. doi: 10.1007/s11912-023-01458-6. Epub 2023 Oct 20.


Purpose of review: [177Lu]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 [177Lu]Lu-PSMA-617-naïve and -resistant patients by alternative or combination treatments.

Recent findings: A variety of agents to combine with [177Lu]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 (225Ac)-labeled PSMA-targeting inhibitors are the most studied pharmaceuticals for combination therapy or as an alternative for treatment after progression under [177Lu]Lu-PSMA-617 therapy. Alpha emitters seem to have a potential of achieving a response to PSMA-targeting radionuclide therapy in both initial non-responders or responders to [177Lu]Lu-PSMA-617 later developing treatment resistance. Emerging evidence for immunostimulatory effects of radiopharmaceuticals and first prospective studies support the combination of [177Lu]Lu-PSMA-617 and immune checkpoint inhibition for late-stage prostate cancer.

Keywords: Combination therapy; Lutetium-177-PSMA-617; Metastatic castration-resistant prostate cancer; Prostate-specific membrane antigen; Radioligand therapy.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Male
  • Pharmaceutical Preparations
  • Prospective Studies
  • Prostate-Specific Antigen
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / radiotherapy
  • Radioisotopes* / therapeutic use
  • Radiopharmaceuticals / therapeutic use
  • Treatment Outcome


  • Radioisotopes
  • Prostate-Specific Antigen
  • Radiopharmaceuticals
  • Pharmaceutical Preparations