Association of androgen receptor (AR) gene status in plasma DNA with outcome on enzalutamide in chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): Exploratory results from the PREMIERE trial—On behalf of SOGUG.

Abstract

5016 Background: Building on previous discoveries studying AR status in plasma (Carreira S, Sci Transl Med 2014, Romanel A, Sci Transl Med 2015) and following a road-map for biomarker development, we aimed to clinically qualify AR status in chemotherapy-naïve mCRPC using an optimized multiplex droplet digital PCR (ddPCR) assay (Condeduca et al.;ASCO2017;Abstract#). Methods: Between February and November 2015, 98 asymptomatic or oligo-symptomatic chemotherapy-naïve mCRPC patients were recruited in 16 Spanish hospitals. Tissue and blood samples were required at study entry. Although initially designed to study the predictive value of TMPRSS2-ETS, data emerging after the trial was initiated led the group to prioritize alternative predefined exploratory biomarkers, including plasma ARand CTC characterization (Grande E. ESMO 2016 & Font A. et al; ASCO2017; Abstract #). Outcome measures included PSA-progression-free survival (sPFS), radiographic progression-free survival (rPFS) and overall survival (OS). Cox regression was used for survival analyses and Fisher’s exact test for PSA response. Results: Ninety-four patients had plasma DNA available for analysis. At baseline, AR gain was present in 11 pts (12%) and CTCs in 35 (37%). AR gain in CTC-positive and negative patients was 20% and 7%, respectively. At first interim analysis and with a median follow-up of 10.6 months, detection of AR gain was associated with worse sPFS (median, 3.60 versus 15.5 m, HR, 4.33; 95% CI 1.94-9.68; P < 0.001), rPFS (median, 3.90 m versus not reached HR, 8.06; 95% CI, 3.26-19.93; P < 0.001) and OS (medians not reached, HR, 11.08; 95% CI, 2.16-56.95; P = 0.004). These results were independently associated in multivariate analysis including cfDNA and CTCs for all described endpoints. AR gain patients were less likely to have a ≥50% decline in PSA (OR, 4.93; 95% CI, 1.30-18.75; P = 0.025). Conclusions: Detection of AR gain in plasma using a robust multiplex ddPCR method predicts an adverse outcome in chemotherapy-naïve mCRPC. Further prospective randomized studies are warranted. Clinical trial information: NCT02288936.