Abstract OT3-2-01: A phase 2 randomized, double-blind, placebo-controlled multicenter trial evaluating the efficacy and safety of enzalutamide in combination with exemestane in estrogen or progesterone receptor-positive and HER2 non-amplified advanced breast cancer
Authors: Yardley DA , Awada A , Cortes J , Burris HA , Peterson A , Bhattacharya S , Gianni L , Miller K , Winer E 
Published: August 2014

Abstract
Background
Androgen receptor (AR) is expressed in 75% of patients (pts) with ER/PgR+ breast cancer (BC). In some studies, AR expression has been associated with lack of response to endocrine therapies, and forced overexpression in ER+ cell lines can lead to hormone-resistance. Androgens can stimulate in vitro and in vivo growth of ER+/AR+ cells lines which can be blocked by enzalutamide (ENZA), a potent inhibitor of AR. Furthermore, ENZA can block in vitro and in vivo estradiol-mediated growth in MCF7 cells. Treatment with aromatase inhibitors (AIs) increases androgen levels, which in turn could stimulate growth of AR+ ER+ tumors.
Trial design
This phase 2 trial will evaluate ENZA 160mg/day vs placebo in 240 pts with advanced BC treated concurrently with exemestane (EXE). AR expression will be assessed centrally. Two cohorts will each enroll 120 patients (pts) who have received no (Cohort 1: C1) or one (Cohort 2: C2) prior hormone treatment for advanced BC. Randomization is stratified 1:1 by prior hormone (Y/N: C1 only), prior AI (Y/N), and hormone resistance (disease recurrence within 24 mo of initiating hormone treatment in the adjuvant setting [C1]; and, disease progression within 24 wks of initiating hormone treatment in the advanced setting [C2]). The primary endpoint is progression-free survival (PFS) in C1, C2 and the subgroups with AR+ disease. Upon disease progression, eligible pts may choose to receive open-label ENZA in addition to continuing EXE. This trial will be enrolling at time of presentation.
Eligibility criteria
Women with advanced ER+ or PgR+ and HER2-non-amplified (HER2-) BC; 0-1 prior chemotherapy regimens for advanced disease; ECOG performance status ≤1 with measurable or bone-only nonmeasurable disease. Advanced BC is defined as metastatic or locally advanced disease not amenable to curative surgery or radiotherapy. ER/PgR+ disease is defined as ≥1% tumor cell staining by IHC; HER2- disease is defined as 0 or 1+ IHC staining or FISH HER2 negative. Pts with current or previously treated brain metastases or history of seizure are excluded. Prior therapy (&gt;28 days) with EXE for advanced disease is not permitted.
Study endpoints
The primary objective is PFS by cohort and in subgroups with AR+ disease. Secondary endpoints include clinical benefit rate (complete/partial response or stable disease at ≥24 weeks); best objective response per RECIST 1.1, duration and time to response, and safety and tolerability of ENZA.
Statistical methods
Efficacy analyses will be conducted on all randomized pts. Primary analyses for each cohort will be identical and performed separately depending on data maturity for PFS. Primary analysis will use a minimum of 90 PFS events per cohort. The 95% confidence interval (CI) of the PFS hazard ratio (HR) will be reported. For all secondary endpoints, unadjusted P-values will be used to make inferences as appropriate. For a target HR of PFS = 0.67 for each cohort, at least 55 PFS observed events in the AR+ subset (60% of study population) provides an 85% CI that the HR will exclude 1.
Contact information
amy.peterson@medivation.com.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-01.