Presenting Author: Ji Sun, PharmD, PhD, BCNSP, BCOP, University of California San Diego, La Jolla, CA
Co-Authors: Matthew R. Smith, MD, PhD, Massachusetts General Hospital Cancer Center, Boston, MA; Bertrand Tombal, MD, PhD, Division of Urology, IREC, Cliniques Universitaires Saint Luc, UCLouvain, Brussels, Belgium; Maha Hussain, MD, Northwestern University, Feinberg School of Medicine, Chicago, IL; Fred Saad, MD, University of Montreal Hospital Center, Montreal, Quebec, Canada; Karim Fizazi, MD, PhD, Institut Gustave Roussy, University of Paris-Saclay, Villejuif, France; Cora N. Sternberg, MD, Englander Institute for Precision Medicine, Weill Cornell Department of Medicine, Meyer Cancer Center, New York-Presbyterian Hospital, New York, NY; E. David Crawford, MD, UC San Diego School of Medicine, San Diego, CA; Natasha Littleton, Bayer Ltd., Dublin, Ireland; Yuan Wang, Weijiang Zhang, and Rui Li, Bayer HealthCare Pharmaceuticals, Whippany, NJ; Arash Rezazadeh Kalebasty, MD, University of California, Irvine, Orange, CA
BACKGROUND: In the ARASENS study (NCT02799602), darolutamide (DARO) plus androgen-deprivation therapy (ADT) and docetaxel (DOC) significantly reduced the risk for death by 32.5% (hazard ratio, 0.68; 95% confidence interval, 0.57-0.80; P<.001) versus placebo (PBO) plus ADT and DOC in patients with metastatic hormone-sensitive prostate cancer (mHSPC). The incidences of treatment-emergent adverse events (TEAEs) were similar between the treatment groups. We report the dosing, safety, and pharmacokinetics (PK) of the coadministration of DARO plus ADT and DOC.
METHODS: Patients with mHSPC were randomized 1:1 to DARO 600 mg twice daily or PBO, plus ADT and DOC (75 mg/m2 every 21 days for 6 cycles). The effect of DARO on DOC PK was assessed by noncompartmental analysis from the first 25 patients with dense PK data and by population PK for all patients. DARO PK from ARASENS were compared with PK data from ARAMIS (NCT02200614; without DOC) to evaluate the impact of DOC on DARO PK.
RESULTS: The full analysis set included 1305 patients (DARO, n=651; PBO, n=654). The median treatment duration was longer with DARO than with PBO (41 months vs 16.7 months, respectively), and more DARO-treated patients (45.9% vs 19.1%, respectively) were receiving treatment at the data cutoff (October 25, 2021). Most patients completed 6 cycles of DOC (DARO, 87.6%; PBO, 85.5%), and a similar proportion of patients required DOC dose modification (interrupted/delayed or reduced; DARO, 60% vs PBO, 62.9%). TEAEs led to DOC discontinuation or reduction in 8% versus 19.9% and 10.3% versus 19.5% of patients who received DARO and PBO, respectively. Population PK analysis indicated that DOC PK in ARASENS was generally consistent with the existing literature. A slight numeric increase in DOC exposure was observed in the DARO plus ADT and DOC arm, with 15% higher maximum plasma concentration (geometric mean, 1.93 vs 1.68 µg/mL) and 6% higher area under the concentration-time curve (AUC0-tlast within an 8-hour sampling interval, 2.10 vs 1.99 µg·h/mL) versus PBO plus ADT and DOC. This small increase is likely not clinically relevant given the variability in DOC exposure (coefficient of variation, 23%-54%). PK meta-analysis of ARASENS and ARAMIS, including the patients’ intrinsic characteristics as covariates (eg, age, body weight, region), indicated a 10% lower AUC0-12ss of DARO in patients receiving DOC versus not receiving DOC, which is not considered clinically relevant.
CONCLUSION: DARO plus ADT and DOC increases overall survival with a similar overall incidence of TEAEs and no observed drug-drug interactions between DARO and DOC. DARO can be effectively and safely administered with DOC in patients with mHSPC without clinically relevant changes in the PK of either agent.
- Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386:1132