clinical topic updates

Prostate-Specific Membrane Antigen–Positive Metastatic Castration-Resistant Prostate Cancer

by Robert Dreicer, MD, MS, MACP, FASCO

Overview

The US Food and Drug Administration (FDA) recently approved a targeted radioligand therapy for use in previously treated patients with prostate-specific membrane antigen (PSMA)–positive metastatic castration-resistant prostate cancer (mCRPC). Our featured expert explores the new disease construct and its implications in urologic oncology.

Expert Commentary

Robert Dreicer, MD, MS, MACP, FASCO

Section Head, Medical Oncology
Deputy Director, University of Virginia Comprehensive Cancer Center
Associate Director for Clinical Research
Co-Director, Paul Mellon Urologic Cancer Institute
Professor of Medicine and Urology
University of Virginia School of Medicine
Charlottesville, VA

“The biology of PSMA has been actively interrogated for decades; however, it is only in the last several years that we have been able to translate the biology into meaningful diagnostic and therapeutic tools. I do think that we are seeing the needle move with the recent FDA approvals of PSMA PET/computed tomography imaging and lutetium Lu 177 vipivotide tetraxetan.”

Robert Dreicer, MD, MS, MACP, FASCO

With the recent FDA approval of lutetium Lu 177 vipivotide tetraxetan, PSMA-positive disease has emerged as a new construct in urologic oncology. I think that it will take some time to work through some of the nuances of PSMA-positive mCRPC. The biology of PSMA has been actively interrogated for decades; however, it is only in the last several years that we have been able to translate the biology into meaningful diagnostic and therapeutic tools. I do think that we are seeing the needle move with the recent FDA approvals of PSMA positron emission tomography (PET)/computed tomography imaging and lutetitum Lu 177 vipivotide tetraxetan.

Whereas, historically, studies relied on the immunohistochemical staining of tumor specimens to identify PSMA-positive disease, we now have gallium-68 (68Ga) PSMA-11 PET and 18F-DCFPyL PSMA PET, both of which were FDA approved within the last 2 years. Clinicians have begun to adopt PSMA PET imaging to evaluate biochemical failure and to stage patients with high-risk, clinically localized disease. Most recently, 68Ga PSMA-11 PET was approved as a companion diagnostic to detect PSMA-positive lesions in selecting patients for lutetitum Lu 177 vipivotide tetraxetan therapy. 

At present, the use of PSMA-targeted lutetitum Lu 177 vipivotide tetraxetan is guided based on its FDA label, with patients having manifested disease progression following at least 1 next-generation androgen receptor inhibitor and taxane-based chemotherapy. There are a number of other prospective studies that are ongoing and are exploring this agent’s use earlier in the disease course. These studies may provide information to help us sort out the optimal clinical setting in which to use PSMA-targeted lutetitum Lu 177 vipivotide tetraxetan.  

As a clinician who focuses on urologic cancers and sees a lot of prostate cancer, if you asked me for whom I would consider this therapy and in which scenario I thought this therapy might be used optimally, I would describe a patient who has received androgen deprivation therapy intensification with, say, abiraterone, in the hormone-sensitive metastatic state, is relatively asymptomatic but has overt mCRPC, and has a positive PSMA PET scan. I do not have any reason to believe that there is anything particularly significant about having received a taxane before lutetitum Lu 177 vipivotide tetraxetan, except that that is how the study was done. As noted above, there are a range of studies underway that are looking at lutetitum Lu 177 vipivotide tetraxetan in earlier disease settings, including in hormone-sensitive disease and in nonmetastatic CRPC, and results of these and other studies will hopefully inform clinical practice. 

We do not yet know the optimal sequence for many of our newer therapies. For example, radium-223 was approved by the FDA, allowing patients who are either docetaxel treated or naive to receive therapy. The ALSYMPCA trial was designed such that people should have been treated with docetaxel unless they were not candidates, or the patients refused. Some clinicians use radium-223 following docetaxel. In my practice, I prefer to use this agent in relatively asymptomatic patients following progression on an androgen receptor inhibitor but prior to docetaxel.

References

Bravaccini S, Puccetti M, Bocchini M, et al. PSMA expression: a potential ally for the pathologist in prostate cancer diagnosis. Sci Rep. 2018;8(1):4254. doi:10.1038/s41598-018-22594-1

Ferraro DA, Rüschoff JH, Muehlematter UJ, et al. Immunohistochemical PSMA expression patterns of primary prostate cancer tissue are associated with the detection rate of biochemical recurrence with 68Ga-PSMA-11-PET. Theranostics. 2020;10(14):6082-6094. doi:10.7150/thno.44584

Parker C, Nilsson S, Heinrich D, et al; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223. doi:10.1056/NEJMoa1213755

Privé BM, Peters SMB, Muselaers CHJ, et al. Lutetium-177-PSMA-617 in low-volume hormone-sensitive metastatic prostate cancer: a prospective pilot study. Clin Cancer Res. 2021;27(13):3595-3601. doi:10.1158/1078-0432.CCR-20-4298

Sartor O, de Bono J, Chi KN, et al; VISION Investigators. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322

Wu J, Han D, Shi S, et al. A novel fully human antibody targeting extracellular domain of PSMA inhibits tumor growth in prostate cancer. Mol Cancer Ther. 2019;18(7):1289-1301. doi:10.1158/1535-7163.MCT-18-1078


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