798O - AR-V7 splice variant and resistance to enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC): Overall su...

Date 29 September 2014
Event ESMO 2014
Session Genitourinary tumours, prostate 2
Topics Anti-Cancer Agents & Biologic Therapy
Prostate Cancer
Translational Research
Presenter Emmanuel Antonarakis
Citation Annals of Oncology (2014) 25 (5): 1-41. 10.1093/annonc/mdu438
Authors E.S. Antonarakis1, C. Lu2, H. Wang3, B. Luber3, M. Nakazawa2, J. Roeser2, Y. Chen2, H.L. Fedor4, T.L. Lotan4, Q. Zheng4, A.M. De Marzo4, J.T. Isaacs3, W.B. Isaacs2, R. Nadal3, C.J. Paller3, S.R. Denmeade3, M. Carducci3, M.A. Eisenberger3, J. Luo2
  • 1Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 21287 - Baltimore/US
  • 2Urology, Johns Hopkins University School of Medicine, Baltimore/US
  • 3Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore/US
  • 4Pathology, Johns Hopkins University School of Medicine, Baltimore/US

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 < 0.001). In a multivariable model stratified by treatment type, AR-V7 detection remained independently predictive of OS (HR 5.0, 95% CI 1.3–19.8, P = 0.021).

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.