1. Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study.
- Author
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Conteduca V, Wetterskog D, Sharabiani MTA, Grande E, Fernandez-Perez MP, Jayaram A, Salvi S, Castellano D, Romanel A, Lolli C, Casadio V, Gurioli G, Amadori D, Font A, Vazquez-Estevez S, González Del Alba A, Mellado B, Fernandez-Calvo O, Méndez-Vidal MJ, Climent MA, Duran I, Gallardo E, Rodriguez A, Santander C, Sáez MI, Puente J, Gasi Tandefelt D, Wingate A, Dearnaley D, Demichelis F, De Giorgi U, Gonzalez-Billalabeitia E, and Attard G
- Subjects
- Adult, Aged, Aged, 80 and over, Androstenes adverse effects, Antineoplastic Agents, Hormonal adverse effects, Benzamides, Biomarkers, Tumor genetics, Circulating Tumor DNA genetics, DNA Mutational Analysis, Disease Progression, Disease-Free Survival, Europe, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Multiplex Polymerase Chain Reaction, Multivariate Analysis, Mutation, Nitriles, Odds Ratio, Patient Selection, Phenylthiohydantoin adverse effects, Phenylthiohydantoin therapeutic use, Precision Medicine, Predictive Value of Tests, Proportional Hazards Models, Prospective Studies, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant mortality, Receptors, Androgen genetics, Risk Factors, Time Factors, Treatment Outcome, Androstenes therapeutic use, Antineoplastic Agents, Hormonal therapeutic use, Biomarkers, Tumor blood, Circulating Tumor DNA blood, Phenylthiohydantoin analogs & derivatives, Prostatic Neoplasms, Castration-Resistant blood, Prostatic Neoplasms, Castration-Resistant drug therapy, Receptors, Androgen blood
- Abstract
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 < 0.001 and 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, and HR 1.95; 95% CI 1.23-3.11; P = 0.01, respectively) and rate of PSA decline ≥50% [odds ratio (OR), 4.7; 95% CI 1.17-19.17; P = 0.035 and OR, 5.0; 95% CI 1.70-14.91; P = 0.003, respectively]. AR mutations [2105T>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)., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)
- Published
- 2017
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