ARV7 and ARFL mRNA in blood to predict androgen receptor inhibitors and docetaxel response in castration-resistant prostate cancer patients.

Abstract

207 Background: The constitutively active androgen receptor (AR) variant 7 ( ARV7) has been associated with AR inhibitors (ARI) resistance, while its role predicting taxanes response remains controversial. We investigated the association between ARV7 and AR full length ( ARFL) expression pre-docetaxel treatment and changes pre- post-treatment in blood with docetaxel activity in metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: ARV7 and ARFL mRNAs were tested by quantitative reverse-transcription PCR in peripheral blood mononuclear cells (PBMC) from mCRPC patients. Measurements were performed before docetaxel treatment and in a subset of patients also post-treatment. A cohort of patients treated with ARI was also included as a control. Results: We included 105 patients: 50 with treated with docetaxel and 55 with ARI. In 28 patients ARV7 and ARFL were evaluated pre and post-docetaxel. High ARV7 correlated with longer PSA-PFS (HR 0.42; 95%CI 0.18-0.99; P= 0.049), radiologic (RX)-PFS (HR 0.32; 95%CI 0.14-0.72; P= 0.006), and overall survival (OS) (HR 0.41; 95%CI 0.18-0.91; P= 0.028) to docetaxel. When relativizing to ARFL we observed that high ARV7/ ARFL ratio also correlated with a better PSA-PFS (HR 0.38; 95%CI 0.17-0.85; P= 0.0179) and RX-PFS (HR 0.43; 95%CI 0.2-0.91; P= 0.0273) to docetaxel. High ARV7 and ARV7/ ARFL were correlated with lower prostatic-specific antigen (PSA) progression-free survival (PFS) to ARI therapy (HR 2.18; 95%CI 1.03-4.6; P= 0.043 and HR 3.84; 95%CI 1.54-9.4; P= 0.004, respectively). ARV7/ ARFL and treatment- ARV7/ARFL interaction were independently associated with better PSA-PFS to docetaxel treatment and lower PSA-PFS to ARI. The increase of ARV7 mRNA levels after docetaxel treatment was indicative of longer OS (HR 0.07; 95%CI 0.008-0.57; P= 0.013). Conclusions: High ARV7 expression and ARV7/ ARFL ratio evaluated in PBMC pre-docetaxel are associated with better clinical outcome in mCRPC patients and lower ARI benefit. The increase of ARV7 levels after docetaxel exposure was also indicative of better outcome.