Association of androgen receptor (AR) status in plasma DNA with outcome on enzalutamide (enza) or abiraterone (abi) for castration resistant prostate cancer (CRPC).

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5060 Background: There is an urgent need to identify biomarkers to guide personalized therapy in CRPC. We aimed to clinically qualify the association of AR status in plasma DNA with worse outcome in pre- and post-docetaxel (doc) CRPC. Methods: We used droplet digital (dd)PCR to assess AR copy number (CN) and mutations (mut) (2105T > A (p.L702H) and 2632A > G (p.T878A) status in plasma DNA from 171 patients (pts) treated with abi/enza in biomarker protocols at 2 institutions. The aim to evaluate plasma AR was defined after sample collection but prior to analysis. Results: We first optimised multiplex ddPCR to accurately define AR status and identified an AR CN cutpoint = 2.01 as having the greatest likelihood to split pts into 2 prognostic groups. We confirmed a strong agreement between ddPCR and NGS for quantitating AR CN and mut allelic frequency (Bland-Altman test: mean difference -0.02 95%CI -2.45 to 2.41; mean difference -0.01 95%CI -0.015 to 0.016 respectively). AR CN gain was observed in 10 (14%) pre- and 33 (34%) postdoc pts and associated with a worse OS (HR 3.98 95%CI 1.74-9.10 p < 0.001; HR 3.81 95%CI 2.28-6.37 p < 0.001 respectively), PFS (HR 2.18 95%CI 1.08-4.39 p = 0.03; HR 1.95 95%CI 1.23-3.11 p = 0.01 respectively) and PSA decline ≥50% (OR 4.7 95%CI 1.17-19.17 p = 0.035; OR 5.0 95%CI 1.70-14.91 p = 0.003 respectively). AR mut were observed in 8 (11%) postdoc but no pre-doc abi-treated pts and also associated with worse OS (HR 3.26 95%CI 1.47-not reached p = 0.004). There was no interaction between AR and doc status (p = 0.83 for OS, p = 0.99 for PFS). Multivariate analysis, adjusting for AR CN and mut, previous doc, double stranded DNA concentration, LDH, confirmed AR status was independently associated with OS (HR 3.77 95%CI 2.42-5.88 p < 0.001 and HR 2.76 95%CI 1.26-6.07 p = 0.011 for AR CN and mut respectively) and PFS (HR 1.96 95% CI 1.32-2.93 p = 0.001). Conclusions: Plasma AR status assessment using multiplex ddPCR identifies CRPC with worse outcome to enza/abi in pre/postdoc CRPC. Additional clinical qualification is available from the PREMIERE study (Grande et al;ASCO2017;Abstract#). Prospective evaluation of treatment decisions based on plasma AR is now required.