Suchergebnisse

[Background] There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC. ; [Methods] We optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naïve and 98 post-docetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naïve patients treated with enzalutamide (Secondary cohort; PREMIERE trial). ; [Results] In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naïve and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74–9.10; P A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naïve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47–not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94–9.68; P < 0.001), radiographic-PFS (rPFS) (HR 8.06; 95% CI 3.26–19.93; P < 0.001) and OS (HR 11.08; 95% CI 2.16–56.95; P = 0.004). Plasma AR was an independent predictor of outcome on multivariable analyses in both cohorts. ; [Conclusion] Plasma AR status assessment using ddPCR identifies CRPC with worse outcome to enzalutamide or abiraterone. Prospective evaluation of treatment decisions based on plasma AR is now required. ; [Clinical Trial number] NCT02288936 (PREMIERE trial). ; This work was funded by Prostate Cancer UK (PG12-49) and Cancer Research UK (A13239) and was supported by the NIHR Royal Marsden and the Institute of Cancer Research (ICR) Biomedical Research Centre. VC was funded by a European Society of Medical Oncology Translational Clinical Research Fellowship, AJ by an Irish Health Research Board Clinical Research Fellowship and a Medical Research Council Clinical Research Fellowship, DGT by a European Union Marie Curie Intra-European Postdoctoral Fellowship, EG by Instituto de Salud Carlos III and the Spanish Society of Medical Oncology (SEOM)/Chris Foundation (no grant numbers apply) and GA by a Cancer Research UK Advanced Clinician Scientist Fellowship. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The PREMIERE trial was sponsored by Spanish Genito-Urinary oncology Group that received a grant from Astellas to support the conduct of the trial. ; Peer reviewed