6106 - Assessing the clinical relevance of drug–drug interactions (DDI) with darolutamide (DARO)

Background

DARO is an androgen receptor antagonist with a distinct molecular structure, which has demonstrated prolonged metastasis-free survival vs placebo (PBO) in the phase 3 ARAMIS study in non-metastatic castration-resistant prostate cancer patients. These typically older patients often receive multiple comedications. We assessed DDIs with DARO both in vitro and in clinical trial development.

Methods

The effects of induction and inhibition of transporters and CYP enzymes on DARO, and the effect of DARO on other comedications were studied in vitro and in several phase 1 trials using rifampicin (CYP3A4, P-gp inducer), itraconazole (ICZ; CYP3A4, P-gp inhibitor), rosuvastatin (BCRP, OATP1B1, OATP1B3 and OAT3 substrate), midazolam (CYP3A4 substrate) and dabigatran etexilate (P-gp substrate). The impact of comedication on DARO was investigated in a population pharmacokinetic (popPK) and covariate analysis of a subset of ARAMIS patients. The adverse event (AE) profile for comedication use between PBO and DARO was also analysed.

Results

Concomitant rifampicin led to a 3.5-fold decrease in DARO area under the curve (AUC) vs DARO alone. ICZ resulted in 1.8-fold increase in DARO AUC vs DARO alone. No significant effect of comedications that are CYP or P-gp inhibitors was identified in the popPK analysis; proton pump inhibitors did not significantly affect the PK of DARO. Effects of DARO on CYP inhibition in vitro were negligible and coadministration of midazolam or dabigatran showed no clinically relevant effects. Rosuvastatin AUC increased by 5.2-fold with DARO vs rosuvastatin alone, attributed mainly to BCRP inhibition. The incidence of AEs in ARAMIS was low; comedication use (98.7% in DARO, 98.0% in PBO arms) and AE profile were similar between study arms.

Conclusions

DDIs with DARO and P-gp or CYP enzyme substrates, e.g. antithrombotics, calcium channel blockers or proton pump inhibitors, are not expected. Strong CYP3A4 inducers, e.g. rifampicin and carbamazepine, showed some interaction with DARO. Effects of CYP3A4 or P-gp inhibitors on DARO were not considered clinically relevant. DARO may increase the exposure of concomitant BCRP substrates, e.g. statins, although a safety and AE analysis from ARAMIS did not indicate any relevant impact of DARO.

Clinical trial identification

NCT03237416, NCT03048110, NCT02671097, NCT02200614.

Editorial acknowledgement

Medical writing support: Lucy Smithers, PhD, and editorial support: Beth King, both of Scion Medica, London, supported by Bayer according to Good Publication Practice guidelines.

Legal entity responsible for the study

Bayer.

Funding

Bayer and Orion Corporation.

Disclosure

C.R. Zurth: Full / Part-time employment: Bayer. K. Fizazi: Honoraria (self), Advisory / Consultancy: Merck, Sharp & Dohme; Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Astellas; Advisory / Consultancy: Orion; Advisory / Consultancy: CureVac; Advisory / Consultancy: Clovis. R. Fricke: Full / Part-time employment: Bayer. H. Gieschen: Full / Part-time employment: Bayer. K. Graudenz: Full / Part-time employment: Bayer. M. Koskinen: Full / Part-time employment: Orion Corporation. B.A. Ploeger: Full / Part-time employment: Bayer. O. Prien: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bayer. M.R. Smith: Advisory / Consultancy: Bayer; Advisory / Consultancy: Amgen; Advisory / Consultancy: Astellas; Advisory / Consultancy: Clovis; Advisory / Consultancy: Gilead; Honoraria (self): Hinova; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer. T. Tammela: Honoraria (self), Research grant / Funding (institution): Bayer; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (institution): Lidds AB; Advisory / Consultancy, Research grant / Funding (institution): Astellas. N.D. Shore: Advisory / Consultancy, Research grant / Funding (self): Ferring; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Research grant / Funding (self): Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Dendreon; Advisory / Consultancy, Research grant / Funding (self): Tolmar; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Astellas.