Ar-V7 Splice Variant and Resistance to Enzalutamide and Abiraterone in Men with Metastatic Castration-Resistant Prostate Cancer (Mcrpc): Overall Survival Results

Abstract

ABSTRACT Aim: Androgen receptor splice variant-7 (AR-V7) is a truncated form of the AR that lacks the ligand-binding domain, the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We previously reported (ASCO 2014; abstract 5001) that detection of AR-V7 in circulating tumor cells (CTCs) from men with mCRPC was associated with resistance to enzalutamide and abiraterone: PSA responses and progression-free survival (PFS) were inferior in AR-V7–positive men treated with both agents. Here, we present overall survival (OS) data from this study. Methods: We used qRT-PCR to interrogate CTCs for the presence or absence of AR-V7 from prospectively enrolled patients with mCRPC starting treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status and OS. Multivariable Cox regression analyses were conducted to determine the independent effect of AR-V7 status on OS. We also performed a combined analysis of OS using data from all patients. Results: 31 enzalutamide-treated men and 31 abiraterone-treated men were enrolled, of which 12/31 (38.7%) and 6/31 (19.4%) had detectable AR-V7 in pretreatment CTC samples, respectively. In men receiving enzalutamide [n = 31], AR-V7–positive patients demonstrated inferior OS compared to AR-V7–negative patients (HR 6.9, 95% CI 1.7–28.1, log-rank P = 0.002). Similarly, in men receiving abiraterone [n = 31], AR-V7–positive patients had inferior OS (HR 12.7, 95% CI 1.3–125.3, log-rank P = 0.006). In the combined analysis [n = 62], the negative prognostic impact of AR-V7 was maintained (HR 8.3, 95% CI 2.5–27.4, log-rank P Conclusions: Detection of AR-V7 in CTCs from men with mCRPC is associated with resistance to both enzalutamide and abiraterone, as evidenced by inferior PSA responses, PFS and OS. AR-V7 status may be used as a non-invasive biomarker to predict resistance to AR-targeting agents, facilitate treatment selection, and fuel the development AR N-terminal–domain inhibitors. Disclosure: E.S. Antonarakis is a paid consultant/advisor for Janssen, Sanofi and Dendreon. He receives research funding from Janssen, Johnson & Johnson, Sanofi, Dendreon, Aragon, Exelixis, Millennium, Genentech and Novartis. All other authors have declared no conflicts of interest.