Abstract PD3-6: A phase 1 open-label, dose-escalation study evaluating the safety, tolerability, and pharmacokinetics of enzalutamide (previously MDV3100) alone or in combination with an aromatase inhibitor in women with advanced breast cancer
Authors: Traina TA , Yardley DA , Patel M , Schwartzberg L , Elias A , Gucalp A , Peterson AC , Hannah A , Gibbons J , Khondker Z , Hudis CA , LoRusso P 
Published: August 2014

Abstract
Background: Enzalutamide (ENZA) is a potent novel oral inhibitor of androgen receptor (AR) signaling. AR expression is observed in ∼70% of breast cancers (BC) and across the 3 major histologic subtypes (ER+, HER2+ and triple negative) [Collins LC et al. Mod Pathol 2011; 24:924-31]. Based on findings in preclinical models of AR+ BC, the potential therapeutic effect of ENZA in AR+ BC is being evaluated. This is the first trial of ENZA in women with advanced BC (aBC).
Methods: This Phase 1 study in patients (pts) with aBC comprised a dose-escalation stage evaluating ENZA 80 mg/d or 160 mg/d (3+3 design) to determine the Phase 2 dose, and a dose-expansion stage evaluating the Phase 2 dose alone (C1) or in combination with the aromatase inhibitors (AI), anastrozole (C2) or exemestane (EXE; C3). Pts on single-agent ENZA must have received ≥2 treatment regimens for aBC. Tumor tissue was collected at screening for central analysis of AR expression. In the dose-escalation stage, single-dose ENZA was given on Day 1 with pharmacokinetic (PK) sampling through Day 8, followed by ENZA daily until discontinuation criteria were met, dose-limiting toxicities (DLTs) were recorded through Day 35. In C2 and C3, pts received ≥14 days of AI before starting ENZA, and AI PK sampling occurred on Days -1 and 29 of ENZA dosing to assess PK interactions. Blood for central assessment of estrogens was collected at Days 1, 29 and with tumor assessments performed at 2 months then ∼every 3 months thereafter.
Results: The dose-escalation stage (n = 15) defined the Phase 2 dose as 160 mg/d. A single DLT (adrenal insufficiency) occurred in a pt at the 80 mg/d dose. This pt had pre-existing history of adrenal insufficiency and a PK interaction with her daily steroids could not be excluded. As of 1 May 2013, the dose-expansion stage has enrolled 3 pts in C1, 10 in C2, and 16 in C3. For pts receiving single-agent ENZA (n = 18) median age/ECOG was 58/1 and median prior therapies for aBC was 5; these values were 55/0 and 3 for combination cohorts (n = 26). Common (&gt;15%) treatment-related adverse events (AEs) in the single-agent ENZA cohorts included nausea and nasal congestion and in C2 and C3 included nausea, fatigue, back pain, decreased appetite, and hot flush. To date, no serious treatment-related AEs have been reported for single-agent ENZA (other than the DLT) or in C2; in C3 back pain, hypercalcemia and nausea were observed. For single-agent ENZA, a preliminary PK analysis indicates that the apparent clearance and volume of distribution are approximately 0.4 L/h and 120 L, respectively, and steady-state trough concentration is approximately 13 μg/mL. ENZA + EXE resulted in ∼50% reduction in exposure to EXE (AUC pre vs post ENZA: 134±65 vs 70±39 ng.h/mL). PK, tolerability, estrogen levels and anti tumor activity in all cohorts will be presented.
Conclusions: The PK and tolerability of single-agent ENZA appear similar in women with aBC vs. data reported in men. As ENZA reduced exposure to EXE, effects on estrogens (i.e., EXE pharmacodynamics) are being assessed and will be reported.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-6.