Genetic Variant May Predict Resistance to Prostate Cancer Drugs

Detection of a certain messenger RNA variant called AR-V7 in circulating tumor cells (CTCs) in men with advanced prostate cancer may be associated with resistance to enzalutamide and abiraterone, according to a new study.

“This conceptually simple model is biologically plausible, because the protein encoded by AR-V7 lacks the ligand-binding domain of the androgen receptor (the direct target of enzalutamide and the indirect target of abiraterone) while remaining constitutively active as a transcription factor in a ligand-independent manner,” the investigators wrote in The New England Journal of Medicine (2014;371:1028-1038).

A team led by Emmanuel S. Antonarakis, MD, of Johns Hopkins University in Baltimore, noted that a proportion of men do not benefit from enzalutamide and abiraterone and that a clearer understanding of the mechanisms underlying resistance to these medications would facilitate selection of alternative therapies, such as chemotherapies, for these men.

Dr. Antonarakis and his collaborators studied 31 enzalutamide-treated and 31 abiraterone-treated patients. Of these, 39% and 19%, respectively, had detectable AR-V7 in CTCs. Among men receiving enzalutamide, AR-V7-positive patients had significantly lower PSA response rates than AR-V7-negative patients (0% vs. 53%) as well as significantly shorter PSA progression-free survival (median 1.4 months vs. 6.0 months), and significantly shorter clinical or radiographic progression-free survival (median 2.1 months vs. 6.1 months); and overall survival (median 5.5 months vs. not reached).

Among men treated with abiraterone, AR-V7–positive patients had significantly lower PSA response rates than AR-V7–negative patients (0% vs. 68%) and shorter PSA progression-free survival (median 1.3 months vs. not reached). They also had significant shorter clinical or radiographic progression-free survival (median 2.3 months vs. not reached.

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