AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer

TLDR

The AR‑V7 splice variant lacks the ligand‑binding domain targeted by enzalutamide and abiraterone, remains constitutively active, and its clinical relevance requires large‑scale prospective validation. The study aimed to determine whether AR‑V7 mRNA in circulating tumor cells predicts resistance to enzalutamide and abiraterone in advanced prostate cancer. The authors performed qRT‑PCR on circulating tumor cells from 62 metastatic castration‑resistant prostate cancer patients initiating enzalutamide or abiraterone, then correlated AR‑V7 status with PSA response, progression‑free survival, and overall survival. AR‑V7 positivity in circulating tumor cells was linked to markedly lower PSA response rates, shorter PSA progression‑free survival, clinical/radiographic PFS, and overall survival for both enzalutamide and abiraterone, even after adjusting for full‑length AR expression. Funding was provided by the Prostate Cancer Foundation and other organizations.

Abstract

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.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.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.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.).