AR-V7 in Circulating Tumor Cells Associated With Resistance to Enzalutamide and Abiraterone in Prostate Cancer
The androgen receptor isoform encoded by splice variant 7 is constitutively active as a transcription factor, despite lacking the ligand-binding domain that is the target of enzalutamide (Xtandi) and abiraterone (Zytiga). In a study reported in The New England Journal of Medicine, Antonarakis et al found that the presence of androgen receptor splice variant 7 mRNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer was associated with resistance to enzalutamide and abiraterone. AR-V7–positive patients had dramatically reduced prostate-specific antigen (PSA) response rates, progression-free survival, and overall survival.
Study Details
The study involved quantitative reverse transcriptase polymerase chain reaction measurement of AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were starting treatment with enzalutamide (n = 31) or abiraterone (n = 31) at Johns Hopkins University. Patients had to be naive to assigned treatment, but could have received the alternative agent.
AR-V7 was detected in circulating tumor cells in 12 of the enzalutamide patients (39%), including 11 of 20 patients who had previously received abiraterone and 1 of 11 who had not, and in 6 of the abiraterone patients (19%), including 2 of 4 who had previously received enzalutamide and 4 of 27 who had not.
Outcomes
Median follow-up was 5.4 months in the enzalutamide group and 4.6 months in the abiraterone group. Among men receiving enzalutamide, AR-V7–positive patients had a lower rate of PSA response (≥ 50% reduction maintained for ≥ 4 weeks; 0% vs 53%, P = .004) and significantly reduced median PSA progression-free survival (1.4 vs 6.0 months, P < .001), median clinical or radiographic progression-free survival (2.1 vs 6.1 months, P < .001), and median overall survival (5.5 months vs not reached, hazard ratio [HR] = 6.9, P = .002).
Among men receiving abiraterone, AR-V7–positive patients had a lower PSA response rate (0% vs 68%, P = .004) and reduced median PSA progression-free survival (1.3 months vs not reached, P < .001), clinical or radiographic progression-free survival (2.3 months vs not reached, P < .001), and overall survival (10.6 months vs not reached, HR = 12.7, P = .006).
Adjustment for Full-Length Receptor mRNA
Among all 18 patients with detectable AR-V7, the median ratio of AR-V7 to full-length androgen receptor mRNA was 21.0%, with detection of AR-V7 being associated with increased expression of full-length receptor mRNA (P < .001).
In analysis adjusting for expression of full-length receptor mRNA, AR-V7 remained significantly predictive of PSA response in both the enzalutamide group (P < .001) and the abiraterone group (P = .02).
In multivariate analyses adjusting for expression of full-length androgen receptor mRNA and prior abiraterone use, the detection of AR-V7 remained independently predictive of shorter PSA progression-free survival (HR = 3.1, P = .046) and marginally predictive of shorter clinical or radiographic progression-free survival (HR = 3.0, P = 0.06). In multivariate analyses adjusting for expression of full-length androgen receptor mRNA and prior enzalutamide use, detection of AR-V7 was the only independent predictor of both reduced PSA progression-free survival (HR = 15.7, P = .007) and reduced clinical or radiographic progression-free survival (HR = 7.6, P = .05).
Change in AR-V7 Status
Of 58 patients with at least one follow-up sample, change in AR-V7 status occurred in 6 (4 receiving enzalutamide and 2 abiraterone), all from negative to positive. In these six patients, PSA response rate was 17%, median PSA progression-free survival was 3.0 months, and median clinical or radiographic progression-free survival was 3.2 months.
The investigators concluded: “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.”
Emmanuel S. Antonarakis, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, is the corresponding author for The New England Journal of Medicine article.
The study was funded by the Prostate Cancer Foundation, Department of Defense Prostate Cancer Research, Johns Hopkins Prostate Cancer Specialized Program of Research Excellence, and National Institutes of Health. For full disclosures of the study authors, visit www.nejm.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
