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Drug-drug interaction (DDI) of darolutamide with cytochrome P450 (CYP) and P-glycoprotein (P-gp) substrates: Results from clinical and in vitro studies.

297 Background: Maintaining quality of survival, by delaying disease progression and minimizing therapy burden, is critical for patients and has been evaluated in the pivotal phase III ARAMIS study in patients with non-metastatic castration-resistant prostate cancer. Due to comorbidity, elderly men often receive multiple comedications, including CYP and P-gp substrates, eg, simvastatin and digoxin. Enzalutamide and apalutamide, approved androgen receptor (AR) inhibitors, are strong CYP3A4 inducers and thus have potential for CYP-mediated DDIs. The effect of darolutamide, a structurally unique AR antagonist, on CYP activity ( in vitro and in vivo) and P-gp activity ( in vivo) was assessed. Methods: Inhibition of CYP isoforms by Daro was investigated in human liver microsomes using standard substrates. In addition, CYP and P-gp activity during darolutamide treatment was studied in a phase I trial of 15 healthy men who received 75 mg dabigatran etexilate (DABE, P-gp substrate) + 1 mg midazolam (MDZ, CYP3A4 substrate) once followed by 600 mg darolutamide (two 300 mg tablets) twice daily (BID) given with food for 9 days. On day 9, darolutamide was concomitantly administered with a single dose of 75 mg DABE + 1 mg MDZ. Results: Based on in vitro data, no clinically relevant inhibition of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 by darolutamide is expected. In 13 evaluable subjects in the phase I study, concomitant darolutamide reduced MDZ Cmax by ~32% and AUC by ~29% vs MDZ alone. Concomitant darolutamide reduced non-conjugated dabigatran Cmax by 16% and AUC by 9% vs DABE alone. The observed treatment-emergent adverse events were consistent with the known safety profile of darolutamide. No new safety risks were revealed by co-administration of darolutamide and DABE or MDZ. Safety data for patients in ARAMIS who received darolutamide, including those with concomitant CYP or P-gp substrates, will be presented. Conclusions: Darolutamide showed only weak effects or none on P-gp, CYP3A4, or any other relevant CYP enzyme. Thus, darolutamide is not expected to cause any clinically relevant DDI with CYP or P-gp substrates, minimizing complications of polypharmacy. Clinical trial information: NCT03237416.