Abstract
Scientists at the Johns Hopkins Kimmel Cancer Center report that prostate cancer patients whose tumors contain the AR-V7 protein, a shortened form of the androgen receptor, which can be detected in the blood, are less likely to respond to two widely used drugs for metastatic prostate cancer. If large-scale studies validate the findings, the investigators say men with detectable blood levels of AR-V7 should avoid these two drugs and instead take other medicines to treat their disease.
The team's work (“AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer”) is described in the New England Journal of Medicine.
The study evaluated two groups of 31 men with prostate cancer that had spread and whose blood levels of prostate-specific antigen (PSA) were still rising despite low testosterone levels. Investigators gave each man either enzalutamide (Xtandi) or abiraterone (Zytiga) and tracked whether their PSA levels continued to rise, an indication that the drugs were not working.
In the enzalutamide group, none of 12 patients whose blood samples tested positive for AR-V7 responded to the drug, compared with 10 responders among 19 men who had no AR-V7 detected. In the abiraterone group, none of six AR-V7-positive patients responded, compared with 17 responders among 25 patients lacking AR-V7.
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Enzalutamide and abiraterone have been very successful in lengthening the lives of about 80% of patients with metastatic prostate cancer, said Emmanuel Antonarakis, M.D., assistant professor of oncology at Johns Hopkins, but the drugs do not work in the remaining 20% of patients.
“Until now, we haven't been able to predict which patients will not respond to these therapies. If our results are confirmed by other researchers, a blood test could use AR-V7 as a biomarker to predict enzalutamide and abiraterone resistance, and let us direct patients who test positive for AR-V7 toward other types of therapy sooner, saving time and money while avoiding futile therapy,” noted Dr. Antonarakis.
Prostate cancer thrives on androgens, including testosterone. Enzalutamide and abiraterone target androgen receptors and block the receptors' ability to activate prostate cancer cells. AR-V7 lacks a binding spot targeted by enzalutamide and abiraterone. With no binding spot for the two drugs, AR-V7 is free to manipulate prostate cancer cells' genetic material, which makes the cancer cells grow and spread.
“Detection of AR-V7 in circulating tumor cells from patients with castration-resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone,” concluded the investigators in their research article. “These findings require large-scale prospective validation.”