Prospective comparison of AR-V7 transcripts from whole blood and circulating tumor cells in castration-resistant prostate cancer patients undergoing treatment with androgen-receptor signaling inhibitors: The PEARL trial.

Abstract

253 Background: Androgen receptor splice variant 7 (AR-V7) messenger RNA (mRNA) from whole blood (WB) was reported to predict treatment resistance to androgen-receptor signaling inhibitors (ARSI) in metastatic castration-resistant prostate cancer (mCRPC). This prospective study aimed to validate AR-V7 mRNA from WB in comparison to AR-V7 mRNA from circulating tumor cells (CTCs) for prediction of treatment resistance to ARSI in mCRPC. Methods: PEARL is a prospective biomarker study of mCRPC patients starting ARSI treatment with abiraterone or enzalutamide (NCT03601143). Pretreatment blood samples were analyzed using droplet digital PCR for AR-V7 mRNA quantification in WB and Adnatest for quantitative PCR AR-V7 mRNA detection in CTCs. The primary objective was to validate the predictive ability of AR-V7 status in WB compared to CTCs for treatment response defined by PSA decline ≥50%. Secondary endpoints included PSA progression-free survival (PSA-PFS), clinical progression-free survival (PFS), and overall survival (OS). Results: Overall, 111 blood samples from 107 mCRPC patients were included. Test failure rates were 0% (0/111) for WB-based testing and 19% (21/111) for CTC-based testing. High AR-V7 expression in WB was detectable in 10% (11/111), while AR-V7 in CTCs was detectable in 31% (28/90). AR-V7 detection from WB-tests was significantly associated with treatment response (p=0.02), whereas CTC-based test results were not (p=0.06). In multivariable logistic regression models adjusting for key clinical covariates, AR-V7 status in WB remained an independent predictor of non-response with an odds ratio of 6.1 (95%CI 1.1-67.3; p=0.04) while CTC-based AR-V7 test results was not significantly associated (OR 1.7 95%CI 0.6-4.9; p=0.3). Among cases with positive AR-V7 status, only 1 (10%) achieved PSA decline ≥50% for the WB test vs. 8 (31%) for the CTC-based test. Regarding secondary endpoints, high AR-V7 in WB was significantly associated with shorter PSA-PFS (3.3 vs. 8.5mo, p<0.001), shorter cPFS (3.4 vs. 8.4mo, p<0.001) and shorter OS (12.2 vs. 23.8mo, p<0.001). AR-V7 detection in CTCs was also significantly associated with shorter PSA-PFS (4.8 vs. 8.9mo, p=0.008), shorter cPFS (4.8 vs. 7.5mo, p=0.03) and shorter OS (12.5 vs. 31.4mo, p<0.001). Conclusions: AR-V7 RNA level testing in WB was prospectively validated to predict poor treatment outcome in mCRPC cases undergoing treatment with abiraterone or enzalutamide. Compared to the CTC-based test, the WB-test showed a better test procedure success rate, lower AR-V7 detection rate, but better stratification of treatment resistance. Clinical trial information: NCT03601143 .