patient care perspectives

Radioligand Therapy for Metastatic Castration-Resistant Prostate Cancer

by Daniel J. George, MD

Overview

Newer radiopharmaceuticals on the horizon include several that target prostate-specific membrane antigen (PSMA)–expressing tumors. Such therapies have shown promise in metastatic castration-resistant prostate cancer (mCRPC), with some demonstrating overall survival (OS) benefits, and may change the treatment landscape in the future.

Expert Commentary

Daniel J. George, MD

Professor of Medicine and Surgery
Divisions of Medical Oncology and Urology
Director, Genitourinary Oncology
Duke Cancer Institute
Duke University Medical Center
Durham, NC

“The future is bright. This will likely change our landscape and how we think about managing prostate cancer therapeutically with these radionuclide-based approaches. The idea is that having PSMA-positive tumors is a phenotype.”

Daniel J. George, MD

Targeted alpha therapy for bone metastases in CRPC predates the PSMA-directed radioligand therapies that are now in development. Radium-223 has shown an improvement in OS, and I think that this helped to usher in the idea of systemic radiotherapy, or radionuclide therapy, more broadly. Radium-223 certainly adds to the treatment armamentarium for our patients who have a bone-dominant phenotype, typically defined by symptomatic bone metastases and no known visceral metastatic disease.

Newer radiopharmaceuticals on the horizon include several agents that target PSMA-expressing tumors. Most recently, we saw preliminary data with the targeted radioligand therapy lutetium-177 (177Lu)–PSMA-617 from the phase 3 VISION trial at the 2021 American Society of Clinical Oncology Annual Meeting. 177Lu-PSMA-617 showed an OS benefit in patients with mCRPC who had already been through several lines of therapy. 

I suspect that there will be other PSMA-based radioligand therapies that make it to phase 3. And there are already therapies that are in early development that will also utilize PSMA ligand with other radioisotopes, including alpha particles such as actinium-225 (eg, 225Ac-PSMA-617). So, the future is bright. This will likely change our landscape and how we think about managing prostate cancer therapeutically with these radionuclide-based approaches. The idea is that having PSMA-positive tumors is a phenotype, just as visceral metastasis or bone metastases-predominant disease is a phenotype. The imaging space continues to evolve as well. 18F-DCFPyL, a commercially available PSMA positron emission tomography (PET), was recently approved by the US Food and Drug Administration, and there will potentially be other PSMA labels out there in the future. 

It really is a new era of precision medicine, and I say that because these approaches would involve a companion diagnostic, such as a positive PSMA PET scan or gallium-68 PSMA PET scan. Patients with PSMA-positive mCRPC were included in the VISION trial. To me, that is a critical space; in the post-chemotherapy setting, we have not really had a study showing a substantial survival benefit in patients who had progressed on 1 or 2 chemotherapy agents. There also may be opportunities to move the drug to earlier in the disease in patients with this phenotype that we can define by the PSMA PET. There are studies that are being launched today and that will launch soon that will evaluate this drug in the prechemotherapy space and in the metastatic hormone-sensitive space. I think that these are important disease states for which this agent should be evaluated.

References

Awang ZH, Essler M, Ahmadzadehfar H. Radioligand therapy of metastatic castration-resistant prostate cancer: current approaches. Radiat Oncol. 2018;13(1):98. doi:10.1186/s13014-018-1037-7

Juzeniene A, Stenberg VY, Bruland ØS, Larsen RH. Preclinical and clinical status of PSMA-targeted alpha therapy for metastatic castration-resistant prostate cancer. Cancers (Basel). 2021;13(4):779. doi:10.3390/cancers13040779

Labriola MK, Atiq S, Hirshman N, Bitting RL. Management of men with metastatic castration-resistant prostate cancer following potent androgen receptor inhibition: a review of novel investigational therapies. Prostate Cancer Prostatic Dis. 2021;24(2):301-309. doi:10.1038/s41391-020-00299-9

Morris MJ, De Bono JS, Chi KN, et al; VISION Trial Investigators. Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol. 2021;39(suppl 18):LBA4. doi:10.1200/JCO.2021.39.15_suppl.LBA4

Satapathy S, Sood A, Das CK, Mittal BR. Evolving role of 225Ac-PSMA radioligand therapy in metastatic castration-resistant prostate cancer—a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2021 Mar 21. doi:10.1038/s41391-021-00349-w

von Eyben FE, Bauman G, von Eyben R, et al. Optimizing PSMA radioligand therapy for patients with metastatic castration-resistant prostate cancer. A systematic review and meta-analysis. Int J Mol Sci. 2020;21(23):9054. doi:10.3390/ijms21239054

Yadav MP, Ballal S, Sahoo RK, Dwivedi SN, Bal C. Radioligand therapy with 177Lu-PSMA for metastatic castration-resistant prostate cancer: a systematic review and meta-analysis. AJR Am J Roentgenol. 2019;213(2):275-285. doi:10.2214/AJR.18.20845

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