Emmanuel Antonarakis, MBBCh
It may be possible to predict which men with metastatic castration-resistant prostate cancer (mCRPC) will not respond to enzalutamide (Xtandi) by using a simple blood test to detect the presence of AR-V7 in circulating tumor cells (CTCs). In the first reported study using this blood test, men whose CTCs expressed AR-V7 prior to treatment initiation with enzalutamide were unlikely to respond and experienced greater disease progression than men without this marker.
“Enzalutamide has been hailed as a miracle drug for many patients with advanced prostate cancer, but about 20% of men do not benefit from this treatment,” said lead author Emmanuel Antonarakis, MBBCh, assistant professor of Oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. “Our data show that the presence of AR-V7 seems to predict resistance to enzalutamide in virtually all cases. These findings have the potential to save time and money, because oncologists could identify men most unlikely to respond to enzalutamide before they receive it and steer them to other therapies.”
The study, which was presented at the 2014 AACR Annual Meeting, was based on 31 men with mCRPC about to initiate treatment with enzalutamide. Blood samples were obtained from each patient prior to treatment initiation, at the time of the best response to treatment, and again at the time of disease progression. CTCs were isolated from the blood and analyzed for the presence of AR-V7 mRNA using the AdnaTest ProstateCancer Select and Detect kits.
Antonarakis said that several mechanisms of resistance to enzalutamide have been proposed, including splice variants of the androgen receptor gene. “We believe AR-V7 is the most important of these,” he noted.
Antonarakis presented results related to baseline samples prior to treatment initiation. Of the 31 patients, 12 had detectable AR-V7 at baseline. All 12 of these patients had worse responses to therapy compared with those with no detectable AR-V7. Additionally, PSA levels did not drop in the AR-V7–positive patients, whereas a PSA response (ie, PSA levels reduced by >50% from baseline) was observed in 10 of 19 (52.6%) AR-V7–negative patients.
Disease progression was observed sooner in patients with detectable AR-V7. In this group, time to radiographic progression in bones was 2.1 months compared with 6.1 months in patients with no detectable AR-V7. This study is the first step toward establishing the clinical utility of the test, Antonarakis explained. The test has to be certified by CLIA (Clinical Laboratory Improvement Amendments), which is now in process.
Antonarakis and co-investigators are also evaluating whether the test might predict resistance to abiraterone acetate (Zytiga), another AR-targeted therapy.
The study was funded by the Prostate Cancer Foundation.
Antonarakis ES, Lu C, Wang H, et al. Androgen receptor splice variant-7 predicts resistance to enzalutamide in patients with castration-resistant prostate cancer. Presented at: 2014 AACR Annual Meeting; April 5-9, 2014; San Diego, CA. Abstract 2910.