TY - JOUR
T1 - Evaluation of Clinically Relevant Drug–Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer
T2 - Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial
AU - Shore, Neal
AU - Zurth, Christian
AU - Fricke, Robert
AU - Gieschen, Hille
AU - Graudenz, Kristina
AU - Koskinen, Mikko
AU - Ploeger, Bart
AU - Moss, Jonathan
AU - Prien, Olaf
AU - Borghesi, Gustavo
AU - Petrenciuc, Oana
AU - Tammela, Teuvo L.
AU - Kuss, Iris
AU - Verholen, Frank
AU - Smith, Matthew R.
AU - Fizazi, Karim
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85073609132&partnerID=8YFLogxK
U2 - 10.1007/s11523-019-00674-0
DO - 10.1007/s11523-019-00674-0
M3 - Article
C2 - 31571095
AN - SCOPUS:85073609132
SN - 1776-2596
VL - 14
SP - 527
EP - 539
JO - Targeted Oncology
JF - Targeted Oncology
IS - 5
ER -