Correlating whole blood AR-V7 and AR-V9 with therapy response to AR-targeted therapies in metastatic castrate-resistant prostate cancer (mCRPC).

Background: The expression of androgen receptor splice variants (AR-V) in mCRPC patients has widely been regarded as a predictive biomarker for non-response to AR-targeted therapies. However, recent data from our group and others has questioned this association. We report new data from our whole blood assay, correlating baseline and end-of-treatment (EOT) AR-V7 and AR-V9 expression with clinical outcomes in mCRPC patients treated with abiraterone or enzalutamide. Method(s): We have previously developed a whole-blood, quantitative polymerase chain reaction assay for detecting circulating AR-V7 and AR-V9. The assay was applied to samples prospectively collected from 48 mCRPC patients immediately prior to commencing abiraterone or enzalutamide, and where available, at treatment cessation. Patients positive for either AR-V7 or AR-V9 were defined as AR-V-positive, and AR-Vnegative if neither variant was detected. All AR-V-positive samples underwent confirmatory DNA sequencing to confirm variant expression. AR-V expression was correlated with PSA response rate (chi-square test) and PSA progression-free survival (PSA-PFS) (logrank test). Result(s): The median follow-up was 10.6 mo. Twelve out of 48 patients (25%) were AR-V-positive, with no samples positive for both variants at baseline. Similar response rates were observed in AR-V-positive (7/12) and AR-V-negative (23/36) patients (50% vs. 64%, p = 0.7). PSA-PFS did not differ significantly between groups (8.1 mo vs. not reached, p = 0.5). EOT samples were available in nine patients, with four exhibiting AR-V-positivity. Of these, two (50%) patients were AR-V-positive at baseline, and two (50%) patients converted from AR-V-negative to AR-V-positive at treatment cessation (PSA-PFS 3.4 and 2.6 mo respectively). One of the conversion patients transitioned from V7-/V9- to V7+/V9+. Neither AR-V7 nor AR-V9 were detected in any of 13 normal male controls. Conclusion(s): With extended follow-up, whole blood expression of AR-V7 an