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

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. (Funded by the Prostate Cancer Foundation and others.).

• Authors: 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 Eisenberger, Jun Luo
• Journal: The New England journal of medicine (N Engl J Med) Vol. 371 Issue 11 Pg. 1028-38 (Sep 11 2014) ISSN: 1533-4406 [Electronic] United States
• PMID: 25184630 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Androstenes
• Androstenols
• Benzamides
• Morphinans
• Nitriles
• RNA, Neoplasm
• Receptors, Androgen
• Phenylthiohydantoin
• Mr 1257 MS
• enzalutamide
• abiraterone

Topics

• Androstenes
• Androstenols (therapeutic use)
• Benzamides
• Drug Resistance, Neoplasm (genetics)
• Humans
• Male
• Morphinans (analysis)
• Nitriles
• Phenylthiohydantoin (analogs & derivatives, therapeutic use)
• Prostatic Neoplasms (drug therapy, genetics)
• RNA, Neoplasm (analysis)
• Receptors, Androgen (analysis, genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Analysis