Abstract 2910: Androgen receptor splice variant-7 predicts resistance to enzalutamide in patients with castration-resistant prostate cancer

Abstract

Abstract Background: Androgen receptor splice variant-7 (AR-V7) is a truncated form of the androgen receptor (AR) protein which lacks the ligand-binding domain, the target of enzalutamide, but remains constitutively active as a transcription factor. Following from preclinical studies implicating AR-V7 as a mechanism of resistance to novel AR-directed therapies, we hypothesized that the presence of AR-V7 in circulating tumor cells (CTCs) from men with advanced prostate cancer would be associated with primary resistance to enzalutamide. Methods: We used quantitative reverse-transcription polymerase-chain-reaction (qRT-PCR) analysis to interrogate CTCs for the presence or absence of AR-V7 from prospectively enrolled patients with metastatic castration-resistant prostate cancer initiating treatment with enzalutamide. We examined associations between AR-V7 status and PSA response rates (the primary clinical endpoint of the study), PSA-progression-free-survival (PSA-PFS), and clinical/radiographic-progression-free-survival (PFS). Multivariable Cox regressions were performed to determine the independent effect of AR-V7 status on clinical outcomes to enzalutamide treatment. A prespecified sample size of 30 patients would yield 85% power to detect a difference in PSA response rates from 10% (in AR-V7-positive men) to 60% (in AR-V7-negative men), using a two-sided α=0.10. Results: Thirty-one (31) enzalutamide-treated patients were enrolled in the study, of which 38.7% (12/31) had detectable AR-V7 mRNA from CTCs. Compared to AR-V7-negative patients, AR-V7-positive men had worse PSA response rates (0% [0/12] vs 52.6% [10/19], P=0.004); in fact, no patient with detectable AR-V7 achieved a PSA response. Furthermore, AR-V7-positive patients had shorter PSA-PFS (median: 1.4 vs 5.9 months, HR 7.4, 95%CI 2.7-20.6, log-rank P<0.001), and shorter PFS (median: 2.1 vs 6.1 months, HR 8.5, 95%CI 2.8-25.4, log-rank P<0.001) than AR-V7-negative patients. In multivariable Cox regression analysis, presence of AR-V7 (HR 3.5, 95%CI 1.2-10.5, P=0.027), baseline PSA level (HR 1.01, 95%CI 1.00-1.01, P=0.042), and prior abiraterone treatment (HR 5.4, 95%CI 1.1-26.5, P=0.039) were all independently predictive of PSA-PFS. Similarly, presence of AR-V7 (HR 3.7, 95%CI 1.2-11.9, P=0.026) and prior abiraterone use (HR 8.7, 95%CI 1.0-75.6, P=0.049) were both independently predictive of PFS in multivariable analysis. Conclusions: Detection of AR-V7 mRNA in circulating tumor cells from patients with metastatic castration-resistant prostate cancer may be associated with primary resistance to enzalutamide. If confirmed by other investigators in larger-scale prospective studies, this could be used as a biomarker to predict enzalutamide resistance (and to direct AR-V7-positive patients away from further AR-targeting therapies). Citation Format: Emmanuel S. Antonarakis, Changxue Lu, Hao Wang, Brandon Luber, Mary Nakazawa, Jeffrey C. Roeser, Yan Chen, Helen L. Fedor, Tamara L. Lotan, Angelo M. De Marzo, John T. Isaacs, William B. Isaacs, Rosa Nadal, Channing J. Paller, Samuel R. Denmeade, Michael A. Carducci, Mario A. Eisenberger, Jun Luo. Androgen receptor splice variant-7 predicts resistance to enzalutamide in patients with castration-resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2910. doi:10.1158/1538-7445.AM2014-2910