AR-V7 Splice Variant as Prognostic Marker for Resistance to Enzalutamide or Abiraterone in Men with Metastatic Prostate Cancer
Androgen receptor splice variant-7 (AR-V7) is a truncated form of the androgen receptor that is the molecular target of enzalutamide and of abiraterone. Antonarakis and colleagues previously reported (ASCO 2014: Abstract 5001) that detection of AR-V7 in circulating tumor cells (CTCs) in men with metastatic castrate-resistant prostate cancer (mCRPC) was associated with resistance to enzalutamide and to abiraterone, such that prostate-specific antigen (PSA) responses and progression-free survival (PFS) were inferior in men receiving both agents, when these men had AR-V7–positive CTCs. At ESMO 2014, Antonarakis and colleagues presented the overall survival (OS) data from the same study (Antonarakis E, et al. ESMO 2014: Abstract 798O).
A total of 62 men with mCRPC, 31 treated with enzalutamide and 31 treated with abiraterone were enrolled in the study, of which 39% and 19%, respectively, had detectable AR-V7 in their CTCs. In men receiving enzalutamide, AR-V7–positive patients demonstrated significantly inferior OS compared with AR-V7–patients (hazard ratio [HR], 6.9; 95% confidence interval [CI], 1.7-28.1, log rank; P = .002). Similarly, in men receiving abiraterone, AR-V7–positive patients had inferior OS compared with AR-V7–negative patients with (HR, 12.7; 95% CI, 1.3-125.3, log rank; P = .006).
A combined analysis of all 62 men treated with either enzalutamide or abiraterone, the negative prognostic impact of AR-V7 was maintained (HR, 8.3; 95% CI, 2.5-27.4, log rank; P <.001). In a multivariate model stratified by treatment type, AR-V7 detection remained independently predictive of OS. Thus, detection of AR-V7 in CTCs of men with mCRPC is predictive of resistance to enzalutamide and to abiraterone, in terms of inferior PSA responses, PFS, and OS.
Therefore, AR-V7 may be used as a noninvasive biomarker to facilitate treatment selection for this patient population and may represent a useful molecular biomarker to fuel the development of new androgen receptor inhibitors, especially those that target the N-terminal domain of the receptor molecule.