TY - JOUR
TI - Enzalutamide in Combination with Abiraterone Acetate in Bone Metastatic Castration-resistant Prostate Cancer Patients
AU - Efstathiou, E.
AU - Titus, M.
AU - Wen, S.
AU - Troncoso, P.
AU - Hoang, A.
AU - Corn, P.
AU - Prokhorova, I.
AU - Araujo, J.
AU - Dmuchowski, C.
AU - Melhem-Bertrandt, A.
AU - Patil, S.
AU - Logothetis, C.J.
JO - European urology oncology
PY - 2020
VL - 3
TODO - 1
SP - 119-127
PB - NLM (Medline)
SN - null
TODO - 10.1016/j.euo.2019.01.008
TODO - abiraterone acetate;  antineoplastic agent;  enzalutamide;  phenylthiohydantoin, adult;  aged;  bone tumor;  castration resistant prostate cancer;  human;  male;  middle aged;  pathology;  very elderly, Abiraterone Acetate;  Adult;  Aged;  Aged, 80 and over;  Antineoplastic Combined Chemotherapy Protocols;  Bone Neoplasms;  Humans;  Male;  Middle Aged;  Phenylthiohydantoin;  Prostatic Neoplasms, Castration-Resistant
TODO - BACKGROUND: It is hypothesised that cotargeting the androgen receptor (AR) and paracrine androgen biosynthesis with enzalutamide and abiraterone acetate in metastatic castration-resistant prostate cancer (mCRPC) will dissipate adaptive feedback loops observed with either agent alone. OBJECTIVE: To assess the safety, efficacy, androgen signalling/metabolome, and drug-drug interactions (DDIs) of enzalutamide with abiraterone acetate in progressive bone mCRPC (bmCRPC). DESIGN, SETTING, AND PARTICIPANTS: This open-label, single-centre interventional study was conducted in bmCRPC patients. INTERVENTION: Enzalutamide 160mg and abiraterone acetate 1000mg once daily; prednisone 5mg twice daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adverse events (AEs), prostate-specific antigen (PSA) response, progression-free survival (PFS), tumour biomarker/metabolite expression, and Cmin plasma concentrations were evaluated. RESULTS AND LIMITATIONS: Sixty patients were enrolled. Common AEs independent of grade/causality included fatigue (72%), hyperglycaemia (67%), alkaline phosphatase (ALP) elevation (53%), and hot flush (43%). Grade 3 AEs included hypertension (17%), alanine aminotransferase elevation (12%), ALP elevation (5%), and arthralgia (5%). No treatment-related grade 4 AEs or deaths were reported. Median treatment-discontinuation time was 312d (95% confidence interval [CI] 196.0-483.0). Maximal PSA decline ≥50% and ≥90% occurred in 46 (77%) and 29 (48%) patients, respectively. Median PFS was 251d (95% CI 147-337). At week 9, median tumour microenvironment androgens, precursors, and nuclear AR expression decreased (p<0.001). The baseline tumour AR C/N terminal ratio of ≥80% was associated with treatment benefit. At enzalutamide steady state, abiraterone acetate Cmin was ∼23% lower (range 14.05-200.5ng/ml) than when given alone. CONCLUSIONS: Enzalutamide combined with abiraterone acetate has a manageable safety profile, without a meaningful DDI. Both agents are pharmacodynamically active with no feedback. Efficacy findings do not support significant benefit of combined treatment for unselected bmCRPC. PATIENT SUMMARY: This is the first study combining enzalutamide plus abiraterone in bone metastatic castration-resistant prostate cancer. Results show that this combination is safe. Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
ER -