Abstract OT3-2-08: A phase 2 single-arm study of the clinical activity and safety of enzalutamide in patients with advanced androgen receptor-positive triple-negative breast cancer
Authors: Traina TA , O'Shaughnessy J , Kelly C , Schwartzberg L , Gucalp A , Peterson A , Bhattacharya S , Trudeau M , Hudis CA , Schmid P 
Published: August 2014

Abstract
Background:
Androgen receptor (AR) expression by IHC is observed in 10-30% of patients (pts) with triple-negative breast cancer (TNBC). Molecular profiling of TNBC has identified a subtype, luminal AR, so called as it clusters with luminal A or B on PAM50 profiling. This AR positive (AR+) subtype of TNBC expresses high levels of AR mRNA and is heavily enriched in hormone-regulated pathways, yet lacks expression of estrogen and progesterone receptors. Experiments using AR+ TNBC cell lines have demonstrated enhanced growth, both in vitro and in vivo, in response to androgen stimulation that can be inhibited by enzalutamide (ENZA), a potent inhibitor of AR signaling that lacks the agonist activity observed with bicalutamide. AR+ TNBC may represent a novel clinical subtype of breast cancer, driven by AR signaling and which may respond to ENZA.
Trial design:
ENZA will be administered orally at 160mg daily to pts with AR+ TNBC until disease progression or intolerability. The primary endpoint is clinical benefit rate (CBR), defined as the proportion of pts with complete response (CR), partial response (PR), or stable disease (SD) at ≥16 weeks (wks). A Simon 2-stage design is used to ensure that a minimum threshold for activity is met. If the CBR at 16 wks exceeds 2 in 26 pts, the sample size will increase to enroll 62 evaluable pts. AR testing may be performed locally for eligibility, but central testing is required in all pts. This trial is currently enrolling pts.
Eligibility criteria:
Eligible pts are adult women with advanced AR+ (any nuclear staining by IHC) TNBC. TNBC is determined locally and defined as &lt;1% IHC staining for both ER and PgR and 0 or 1+ IHC staining for Her2 or negative for Her2 amplification in IHC 2+ disease. Advanced is defined as metastatic or locally advanced disease not amenable to curative surgery or radiotherapy. Bone-only non-measurable disease is permitted. Pts must have adequate organ and bone marrow function and ECOG status ≤1. Pts with current or previously treated brain metastases or a history of seizure are excluded, as are pts who received prior AR targeted agents for 28 or more days.
Specific aims:
The primary objective is to determine CBR at ≥16 wks. Secondary objectives include CBR at ≥24 wks, response rates and duration of response, progression-free survival, pharmacokinetics of ENZA, and safety and tolerability. Exploratory endpoints include overall survival and evaluation of the relationship between AR expression and signaling in breast tissue and ENZA activity.
Statistical methods:
Efficacy analyses will be conducted on all enrolled pts with centrally defined AR+ TNBC and at least 1 available post-baseline tumor assessment. Efficacy analyses will use investigator-assessed outcomes according to RECIST 1.1. The null hypothesis (H0), that the true CBR is 8%, will be tested against a 1-sided alternative; if CBR is &lt;3 in 26 pts in Stage 1, enrollment will stop. If CBR exceeds 9 in 62 pts in Stage 2, H0 will be rejected. This design yields a 1-sided type 1 error rate of 5% and 85% power when the true response rate is 20%.
Contact information:
For more information on this trial, please contact Amy Peterson at Medivation (amy.peterson@medivation.com).
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-08.