Dosing, Safety, and Pharmacokinetics of Combination Therapy With Darolutamide, Androgen Deprivation Therapy, and Docetaxel for Metastatic Hormone-Sensitive Prostate Cancer in the ARASENS Study

INTRODUCTION: Darolutamide is a highly potent androgen receptor inhibitor, that is structurally different by design. Darolutamide is approved for treatment of metastatic hormone-sensitive prostate cancer in combination with or without docetaxel. We present dosing, safety, and pharmacokinetic analyses of potential drug-drug interactions in patients in the ARASENS study. PATIENTS AND METHODS: ARASENS was an international, randomized, double-blind, phase 3 study in which patients were randomized 1:1 to receive darolutamide 600 mg or placebo in combination with androgen deprivation therapy (ADT) plus docetaxel. RESULTS: In the 1302 treated patients, median treatment duration was longer with darolutamide versus placebo (41.0 vs. 16.7 months), and most patients completed 6 cycles of docetaxel (darolutamide 87.6%; placebo 85.5%). Treatment-emergent adverse events (TEAEs) led to docetaxel dose reduction in 19.9% and 19.5% and discontinuation in 8.0% and 10.3% of darolutamide and placebo recipients, respectively. The most common TEAE leading to docetaxel dose reduction was decreased neutrophil count (darolutamide 5.4%; placebo 6.0%). Granulocyte colony-stimulating factor use was similar in both groups (darolutamide 42.4%; placebo 44.6%) and was mostly administered after the first dose of docetaxel (41.9%; 44.3%). Docetaxel plasma concentration profiles with and without darolutamide were generally overlapping, indicating that darolutamide had no clinically relevant effect on docetaxel pharmacokinetics. Darolutamide exposure was 10% lower with docetaxel than without docetaxel, which is not considered clinically relevant. CONCLUSION: Darolutamide can be administered with docetaxel and ADT without clinically relevant drug-drug interactions between darolutamide and docetaxel. Known docetaxel TEAEs were the most common reason for docetaxel dose modification. TRIAL REGISTRATION NUMBER: NCT02799602 (ARASENS).