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).