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Open Access 01-10-2019 | Prostate Cancer | Original Research Article

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

Authors: Neal Shore, Christian Zurth, Robert Fricke, Hille Gieschen, Kristina Graudenz, Mikko Koskinen, Bart Ploeger, Jonathan Moss, Olaf Prien, Gustavo Borghesi, Oana Petrenciuc, Teuvo L. Tammela, Iris Kuss, Frank Verholen, Matthew R. Smith, Karim Fizazi

Published in: Targeted Oncology | Issue 5/2019

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.

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Title: 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
Authors: Neal Shore
Christian Zurth
Robert Fricke
Hille Gieschen
Kristina Graudenz
Mikko Koskinen
Bart Ploeger
Jonathan Moss
Olaf Prien
Gustavo Borghesi
Oana Petrenciuc
Teuvo L. Tammela
Iris Kuss
Frank Verholen
Matthew R. Smith
Karim Fizazi
Publication date: 01-10-2019
Publisher: Springer International Publishing
Keywords: Prostate Cancer
Pharmacokinetics
Statins
Prostate Cancer
Rosuvastatin
Darolutamide
Apalutamide
Enzalutamide
Androgens
Published in: Targeted Oncology / Issue 5/2019
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI: https://doi.org/10.1007/s11523-019-00674-0

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