AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer

Emmanuel S. Antonarakis, Changxue Lu, Hao Wang, Brandon Luber, Mary Nakazawa, Jeffrey C. Roeser, Yan Chen, Tabrez A. Mohammad, Yidong Chen, Helen L. Fedor, Tamara L. Lotan, Qizhi Zheng, Angelo M. De Marzo, John T. Isaacs, William B. Isaacs, Rosa Nadal, Channing J. Paller, Samuel R. Denmeade, Michael A. Carducci, Mario A. EisenbergerJun Luo

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1028-1038
Number of pages11
JournalNew England Journal of Medicine
Volume371
Issue number11
DOIs
StatePublished - Sep 11 2014

ASJC Scopus subject areas

  • Medicine(all)

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