Evaluation of Clinically Relevant Drug-Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial

Abstract

Background: Darolutamide, an androgen receptor antagonist with a distinct molecular structure, significantly prolonged metastasis-free survival versus placebo in the phase III ARAMIS study in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). In this population, polypharmacy for age-related comorbidities is common and may increase drug-drug interaction (DDI) risks. Preclinical/phase I study data suggest darolutamide has a low DDI potential-other than breast cancer resistance protein/organic anion transporter protein substrates (e.g., statins), no clinically relevant effect on comedications is expected.

Objective: Our objective was to evaluate the effect of commonly administered drugs on the pharmacokinetics of darolutamide and the effect of comedications potentially affected by darolutamide on safety in patients with nmCRPC.

Patients and methods: Comorbidities and comedication use in the 1509 ARAMIS participants treated with darolutamide 600 mg twice daily or placebo were assessed. A population pharmacokinetic analysis evaluated whether comedications affected the pharmacokinetics of darolutamide in a subset of 388 patients. A subgroup analysis of adverse events (AEs) in statin users versus nonusers was conducted.

Results: Most participants (median age 74 years) had at least one comorbidity (98.4% in both arms) and used at least one comedication (98.7% with darolutamide vs. 98.0% with placebo); these were similar across study arms. Despite frequent use of comedications with DDI potential, no significant effects on darolutamide pharmacokinetics were identified. Comedications included lipid-modifying agents (34.5%), β-blockers (29.7%), antithrombotics (42.8%), and systemic antibiotics (26.9%). AE incidence was similar across study arms in statin users and nonusers. Study limitations include the small sample size for sub-analyses.

Conclusions: These analyses suggest the pharmacokinetic profile of darolutamide is not affected by a number of commonly administered drugs in patients with nmCRPC. Although pharmacokinetic data have indicated that darolutamide has the potential to interact with rosuvastatin, used to assess DDI in these studies, this finding did not seem to translate into increased AEs due to statin use in the ARAMIS trial. Clinicaltrials.gov identifier: NCT02200614.

Conflict of interest statement

Dr. Shore reports personal fees from Ferring, Bayer, Amgen, Janssen, Dendreon, Tolmar, Astellas, Pfizer, AstraZeneca, Genentech/Roche, Myovant Sciences, Merck, AstraZeneca, Bristol Meyers Squibb, and Nymox outside the submitted work. Drs. Zurth, Fricke, Gieschen, Graudenz, Ploeger, Prien, Borghesi, Petrenciuc, and Kuss report employment by and stock ownership in Bayer. Dr. Koskinen reports employment by and stock ownership in Orion. Dr. Moss reports personal fees from Akari, AstraZeneca, Bayer, Carrick Therapeutics, Debiopharm, Orphazym, Proveca, Richmond Pharmacology, and the University of Leicester outside the submitted work. Dr. Tammela reports personal fees from Janssen, and grants and personal fees from Bayer, Lidds AB, and Astellas, outside the submitted work. Dr. Verholen reports employment by Bayer. Dr. Smith reports personal fees from Amgen, Astellas, Bayer, Clovis, Gilead, Janssen, Lilly, Novartis, and Pfizer, outside the submitted work. Dr. Fizazi reports personal fees from Amgen, Astellas, AstraZeneca, Bayer, Clovis, Curevac, ESSA, Janssen, Orion Pharma, Roche/Genentech, and Sanofi outside the submitted work.