Detection of AR-V7 in the peripheral blood appears to be a marker of resistance to both enzalutamide and abiraterone treatment in men who have metastatic castration-resistant prostate cancer, according to a report published online Sept. 3 in the New England Journal of Medicine.
In a blinded prospective study involving 62 patients, researchers explored whether the presence of AR-V7 (androgen-receptor splice variant 7 messenger RNA) in circulating tumor cells would predict resistance to enzalutamide and abiraterone, two new agents that act on different molecular pathways to inhibit androgen-receptor signaling. If their findings are confirmed in larger studies, "it is possible that AR-V7 could be used as a biomarker to predict resistance ... and to facilitate treatment selection," reported Dr. Emmanuel S. Antonarakis of Johns Hopkins University, Baltimore, and his associates.
However, it is important to note that these results do not demonstrate a causal role for AR-V7 in mediating resistance to enzalutamide or abiraterone. It is possible that AR-V7 is simply a marker of more advanced disease or a higher disease burden, the investigators added.
The two drugs "represent important advances in the management of castration-resistant prostate cancer." But a substantial proportion of patients don’t benefit from them, "and a clearer understanding of the mechanisms underlying resistance to these drugs would facilitate selection of alternative therapies for such patients," Dr. Antonarakis and his associates said.
In this study, men with metastatic castration-resistant prostate cancer who were about to begin standard treatment with enzalutamide (31 patients) or abiraterone (31 patients) provided peripheral blood samples for analysis of circulating tumor cells at baseline.
After a median follow-up of approximately 5 months, the prostate-specific antigen (PSA) response in the enzalutamide group was 0% among men who were AR-V7 positive, compared with 53% among men who were AR-V7 negative. In the abiraterone group, the PSA response was 0% among men who were AR-V7 positive, compared with 68% among men who were AR-V7 negative. Not one of the AR-V7-positive patients showed any appreciable clinical benefit from these drugs, the investigators reported (New Engl. J. Med. 2014 Sept. 3 [doi: 10.1056/NEJMoa1315815]).
In addition, progression-free survival was shorter among AR-V7-positive men than among men who had no detectable AR-V7, whether that endpoint was measured by PSA level, radiography, or clinical signs and symptoms.
This study was supported by the Prostate Cancer Foundation, the Department of Defense Prostate Cancer Research Program, and the National Institutes of Health. Dr. Antonarakis reported receiving personal fees from Sanofi, Dendreon, and Janssen Biotech, and his associates reported ties to numerous industry sources.