Abstract OT3-02-02: ENDEAR: A randomized international phase 3 study comparing the efficacy and safety of enzalutamide in combination with paclitaxel chemotherapy or as monotherapy vs placebo with paclitaxel in patients with advanced diagnostic-positive triple-negative breast cancer
Authors: Dent R , Schmid P , Cortes J , Kim S-B , Andre F , Abramson V , Cardoso F , Colleoni M , Morris P , Steinberg J , Tudor IC , Uppal H , Paton VE , Peterson A , Traina TA 
Published: March 2017

Abstract
Background:Enzalutamide (ENZA), a potent androgen receptor (AR) inhibitor, demonstrated clinical activity in patients (pts) with advanced triple-negative breast cancer (aTNBC) (NCT01889238). TNBC with AR-driven biology has been previously confirmed; however, using immunohistochemistry (IHC) to identify this pt subset is suboptimal for AR-directed treatment. A novel binary genomic signature (Dx + or −) that identifies AR-driven disease was developed for its potential to select pts who may benefit from ENZA. Clinical outcomes in a phase 2 trial utilizing a genomic signature (Dx) showed improvement in Dx+ vs Dx− subgroups with ENZA being well tolerated; fatigue was the only grade ≥3 AE with a ≥5% incidence (Table).1
Progression-Free Survival (mo) (Median, 95% CI)Overall Survival (mo) (Median, 95% CI)All0-1 Prior TxAll0-1 Prior TxDx+ (n=56)3.7 (2.4-6.4)7.5 (3.4-14)21.3 (12.9-21.3)NR (14-NR)Dx- (n=62)1.9 (1.6-2.9)1.9 (1.6-3.7)7.5 (4.8-11.2)10 (6.6-NR)Data cutoff date, Sep 15, 2015. NR=not reached; Tx=treatment.
Preclinically, ENZA + paclitaxel (PAC) has been shown in an MBA-MB-453 xenograft model to significantly reduce tumor volume compared to either single agent. Phase 1b dose-finding studies of ENZA + taxane combinations have shown the combination to be generally well tolerated.2,3 The aim of this phase 3 study is to evaluate and compare the clinical benefit and safety of ENZA + PAC or ENZA vs PAC alone in pts with Dx+ aTNBC.
Methods:ENDEAR is an international, double-blind, randomized, placebo-controlled, 3-arm phase 3 study in pts with Dx+ aTNBC who previously received 0-1 prior regimen for advanced disease. A total of 780 pts will be randomized (1:1:1) to 1 of 3 treatment arms: (A) ENZA + PAC; (B) placebo + PAC; (C) ENZA monotherapy followed by PAC at time of disease progression on ENZA monotherapy. Randomization will be stratified by the number of prior systemic therapies in the advanced disease setting (0 vs 1 line), prior taxane use in the neo/adjuvant setting (yes vs no), and geographic region of enrollment. Archival tissue samples are required for diagnostic assessment. Pts must have either measurable or evaluable disease; brain metastases and seizure history are exclusionary. PAC 90 mg/m2 (dose reduction allowed) will be given intravenously weekly for ≥16 weeks; ENZA 160 mg/day or placebo will be given daily until progression or other discontinuation criteria are met (crossover prohibited). The primary endpoint is progression-free survival (PFS) as assessed by an independent review; the key secondary endpoint is overall survival (OS). Assessment of tumor response will be done every 8 weeks. A hierarchical testing plan will control for multiplicity across PFS and OS. A stratified log-rank test will be used to compare the treatment groups: arm A vs B and arm C vs B. The primary analysis will be performed when ≥360 PFS events occur in arms A and B. Recruitment is ongoing.
References:1. Medivation. Data on file.
2. Morris MJ et al. Clin Cancer Res. 2016 Feb 8 [Epub ahead of print].
3. Mahipal A et al. J Clin Oncol. 2015;33:e15250.
Citation Format: Dent R, Schmid P, Cortes J, Kim S-B, Andre F, Abramson V, Cardoso F, Colleoni M, Morris P, Steinberg J, Tudor IC, Uppal H, Paton VE, Peterson A, Traina TA. ENDEAR: A randomized international phase 3 study comparing the efficacy and safety of enzalutamide in combination with paclitaxel chemotherapy or as monotherapy vs placebo with paclitaxel in patients with advanced diagnostic-positive triple-negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-02-02.