[HTML][HTML] AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer

ES Antonarakis, C Lu, H Wang, B Luber… - … England Journal of …, 2014 - Mass Medical Soc
ES Antonarakis, C Lu, H Wang, B Luber, M Nakazawa, JC Roeser, Y Chen, TA Mohammad
New England Journal of Medicine, 2014Mass Medical Soc
Background The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-
binding domain, which is the target of enzalutamide and abiraterone, but remains
constitutively active as a transcription factor. We hypothesized that detection of androgen-
receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with
advanced prostate cancer would be associated with resistance to enzalutamide and
abiraterone. Methods We used a quantitative reverse-transcriptase–polymerase-chain …
Background
The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone.
Methods
We used a quantitative reverse-transcriptase–polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression–free survival), clinical or radiographic progression–free survival, and overall survival.
Results
A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of whom 39% and 19%, respectively, had detectable AR-V7 in circulating tumor cells. Among men receiving enzalutamide, AR-V7–positive patients had lower PSA response rates than AR-V7–negative patients (0% vs. 53%, P=0.004) and shorter PSA progression–free survival (median, 1.4 months vs. 6.0 months; P<0.001), clinical or radiographic progression–free survival (median, 2.1 months vs. 6.1 months; P<0.001), and overall survival (median, 5.5 months vs. not reached; P=0.002). Similarly, among men receiving abiraterone, AR-V7–positive patients had lower PSA response rates than AR-V7–negative patients (0% vs. 68%, P=0.004) and shorter PSA progression–free survival (median, 1.3 months vs. not reached; P<0.001), clinical or radiographic progression–free survival (median, 2.3 months vs. not reached; P<0.001), and overall survival (median, 10.6 months vs. not reached, P=0.006). The association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length androgen receptor messenger RNA.
Conclusions
Detection of AR-V7 in circulating tumor cells from patients with castration-resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone. These findings require large-scale prospective validation. (Funded by the Prostate Cancer Foundation and others.)
The New England Journal Of Medicine