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.

Article Details

Citation Copy to clipboard

Shore N, Zurth C, Fricke R, Gieschen H, Graudenz K, Koskinen M, Ploeger B, Moss J, Prien O, Borghesi G, Petrenciuc O, Tammela TL, Kuss I, Verholen F, Smith MR, Fizazi K

Target Oncol. 2019 Oct;14(5):527-539. doi: 10.1007/s11523-019-00674-0.

PubMed ID

31571095 [ View in PubMed

]

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%), beta-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.

DrugBank Data that Cites this Article

Drugs

Darolutamide

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Darolutamide	Androgen receptor	Protein	Humans	Yes	Antagonist	Details

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Darolutamide	ATP-binding cassette sub-family G member 2	Protein	Humans	Unknown	Substrate Inhibitor	Details
Darolutamide	P-glycoprotein 1	Protein	Humans	Unknown	Substrate	Details

Drug Interactions

Drugs	Interaction
Integrate drug-drug interactions in your software
Abemaciclib Darolutamide	The serum concentration of Abemaciclib can be increased when it is combined with Darolutamide.
Afatinib Darolutamide	The serum concentration of Afatinib can be increased when it is combined with Darolutamide.
Allopurinol Darolutamide	The serum concentration of Allopurinol can be increased when it is combined with Darolutamide.
Apixaban Darolutamide	The serum concentration of Apixaban can be increased when it is combined with Darolutamide.
Berotralstat Darolutamide	The serum concentration of Berotralstat can be increased when it is combined with Darolutamide.