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

BackgroundDarolutamide, 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.ObjectiveOur 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 MethodsComorbidities 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.ResultsMost 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.ConclusionsThese 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 materialThe online version of this article (10.1007/s11523-019-00674-0) contains supplementary material, which is available to authorized users.

Efficacy and safety of darolutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a sub-group analysis of the phase III ARAMIS trial

“…The low blood-brain barrier penetration of darolutamide, as observed in rodent models and supported by a neuroimaging study in humans [28,29], may be associated with a low risk of CNS adverse effects. In addition, patient quality of life was maintained with darolutamide treatment [26,30], and the risk of clinically relevant drug-drug interactions between darolutamide and comedications used in men with nmCRPC was low [31]. Phase I/II studies of mCRPC also support the tolerability of darolutamide and its low risk of TEAEs [32][33][34] and no differences were observed in safety and pharmacokinetics in Japanese patients relative to Western patients in a small cohort (n = 9) [35].…”

<p>Darolutamide: An Evidenced-Based Review of Its Efficacy and Safety in the Treatment of Prostate Cancer</p>

“…41 While enzalutamide and apalutamide strongly induce CYP3A4, darolutamide has shown no clinically relevant inhibition of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4. 56,57 This distinction may explain the lack of significant differences in toxicity between darolutamide and placebo in ARAMIS. 41…”

Next-generation androgen receptor inhibitors in non-metastatic castration-resistant prostate cancer

“…Another important consideration when selecting an AR-targeting therapy in this population with frequent co-medications is the potential drug–drug interaction (DDI) that could lead to a lower efficacy of treatment for comorbidities, or an increased risk of their adverse events. Darolutamide has shown a favourable DDI profile, 48 whereas other AR inhibitors have large numbers of potential DDIs. 49 Whether sequential use of several AR antagonists may prove beneficial to the patient (e.g.…”