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.
To assess the safety, efficacy, androgen signalling/metabolome, and drug-drug interactions (DDIs) of enzalutamide with abiraterone acetate in progressive bone mCRPC (bmCRPC).
This open-label, single-centre interventional study was conducted in bmCRPC patients.
Enzalutamide 160mg and abiraterone acetate 1000mg once daily; prednisone 5mg twice daily.
Adverse events (AEs), prostate-specific antigen (PSA) response, progression-free survival (PFS), tumour biomarker/metabolite expression, and Cmin plasma concentrations were evaluated.
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.
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.
This is the first study combining enzalutamide plus abiraterone in bone metastatic castration-resistant prostate cancer. Results show that this combination is safe.
European urology oncology. 2019 Apr 19 [Epub ahead of print]
Eleni Efstathiou, Mark Titus, Sijin Wen, Patricia Troncoso, Anh Hoang, Paul Corn, Ina Prokhorova, John Araujo, Carl Dmuchowski, Amal Melhem-Bertrandt, Shiva Patil, Christopher J Logothetis
Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA; Department of Clinical Therapeutics, University of Athens, Athens, Greece. Electronic address: ., Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA., Department of Biostatistics, West Virginia University, Morgantown, WV, USA., Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Astellas Pharma, Inc., Northbrook, IL, USA.