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

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. Electronic supplementary material The online version of this article (10.1007/s11523-019-00674-0) contains supplementary material, which is available to authorized users.
Plain Language Summary Background Darolutamide is a medicine used to treat men with prostate cancer that has not spread to other parts of the body (nonmetastatic). Often, these patients are taking other medicines for common age-related illnesses. Taking more than one medicine at the same time increases the chances of what is known as drug–drug interactions. Drug–drug interactions can decrease how well the medicines work or may sometimes increase side effects. Study Aim To test for possible drug–drug interactions in men with prostate cancer who take darolutamide alongside other medicines. Study Participants Men with nonmetastatic prostate cancer who were being treated with a medicine that lowers testosterone, a chemical in the body that causes prostate cancer tumors to grow. Participants took two darolutamide 300 mg tablets, or an inactive placebo, twice a day. What Did the Researchers Measure? The researchers documented the number of medicines taken by each participant and the number of other medical conditions that they had. Tests were done to find out whether other medicines affected the way that darolutamide works in the body and whether patients taking darolutamide alongside other medicines experienced more side effects. Results As would be expected, based on the typical age of patients with prostate cancer, more than 90% of participants in this study used medicines other than darolutamide to manage common age-related illnesses or medical conditions. Taking medicines alongside darolutamide did not impact how darolutamide worked in the body and did not increase the number of side effects experienced by patients. Darolutamide is known to interact with rosuvastatin, a cholesterol-lowering drug. However, in this study, there was no overall increase in side effects among darolutamide-treated patients who took this type of drug compared with in those who did not. Conclusion In this study of patients with nonmetastatic prostate cancer, limited drug–drug interactions were seen when taking darolutamide alongside other medicines given to these patients to manage age-related medical conditions. Electronic supplementary material The online version of this article (10.1007/s11523-019-00674-0) contains supplementary material, which is available to authorized users.