Scientific Poster Session III - Encore

Encore Presentations
  Monday, November 13, 2023
  01:00 PM–02:30 PM

Abstract

Background:

In ARASENS (NCT02799602), DARO in combination with ADT and DOC significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI 0.57–0.80; P<0.001) vs placebo (PBO) + ADT + DOC in patients with mHSPC. Incidences of treatment-emergent adverse events (TEAEs) were similar between treatment groups. We report dosing, safety, and PK of coadministration of DARO and DOC with ADT.

Methods:

Patients with mHSPC were randomized 1:1 to DARO 600 mg twice daily or PBO, plus ADT and DOC (75 mg/m² q21d 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 (PopPK) 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:

Of 1306 randomized patients, 1305 were included in the full analysis set (DARO, n=651; PBO, n=654). The median treatment duration was longer with DARO vs PBO (41.0 vs 16.7 months) and more DARO-treated patients (45.9% vs 19.1%) were still receiving treatment at primary analysis cutoff (Oct 25, 2021). Almost all patients completed 6 cycles of DOC in both groups (DARO, 87.6%; PBO, 85.5%). The proportion of patients requiring DOC dose modification (interrupted/delayed or reduced) was similar between groups (DARO, 60.0%; PBO, 62.9%). TEAEs led to discontinuation/reduction of DOC in 8.0%/19.9% of DARO patients and 10.3%/19.5% of PBO patients. PopPK analysis indicated that DOC PK in ARASENS was generally consistent with that in the literature. A slight numeric increase in DOC exposure was observed in the DARO + DOC + ADT 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 (AUC_0-tlast within an 8-hour sampling interval, 2.10 vs 1.99 µg·h/mL) vs PBO + DOC + ADT. This small numeric increase is likely not clinically relevant given the variability in DOC exposure (coefficient of variation, 23%–54%). PK meta-analysis of ARASENS and ARAMIS, which considered patients’ intrinsic characteristics as covariates (eg, age, body weight, region), indicated a 10% lower AUC_0-12ss of DARO in patients receiving DOC vs those not receiving DOC, which is not considered clinically relevant.

Conclusions:

The combination of DARO + DOC + ADT increases overall survival with 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 PK of DARO or DOC.

Presenting Author

Jane McCullough PharmD
Northwestern Memorial Hospital

Authors

Rui Li MSc
Bayer HealthCare Pharmaceuticals Inc.

Natasha Littleton MSc
Bayer Ltd

Maha Hussain MD
Northwestern University, Feinberg School of Medicine

E. David Crawford MD
UC San Diego School of Medicine

Karim Fizazi MD, PhD
Institut Gustave Roussy, University of Paris-Saclay

Bertrand Tombal MD, PhD
Division of Urology, IREC, Cliniques Universitaires Saint Luc, UCLouvain

Yuan Wang PharmD
Bayer HealthCare Pharmaceuticals Inc.

Weijiang Zhang PhD
Bayer HealthCare Pharmaceuticals Inc.

Arash Rezazadeh Kalebasty MD
University of California

Fred Saad MD, FRCSC
University of Montreal Hospital Center

Matthew R. Smith MD, PhD
Massachusetts General Hospital Cancer Center

Cora N. Sternberg MD
Englander Institute for Precision Medicine, Weill Cornell Department of Medicine, Meyer Cancer Center, New York-Presbyterian Hos