Enzalutamide in Combination with Abiraterone Acetate in Bone Metastatic Castration-resistant Prostate Cancer Patients

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 160 mg and abiraterone acetate 1000 mg once daily; prednisone 5 mg twice daily. Outcome measurements and statistical analysis: Adverse events (AEs), prostate-specific antigen (PSA) response, progression-free survival (PFS), tumour biomarker/metabolite expression, and C-min 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 312 d (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 251 d (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 C-min was similar to 23% lower (range 14.05-200.5 ng/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. (C) 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.