Abstract P1-16-05: MDV3100-08: A phase 1 study evaluating the safety and pharmacokinetics of enzalutamide plus fulvestrant in women with advanced hormone receptor-positive breast cancer
Authors: Elias AD , Burris HA , Patel MR , Schwartzberg LS , Richer JK , Kavalerchik E , Stopatschinskaja S , Gibbons J , Markova D , Steinberg JL , Traina TA 
Published: May 2016

Abstract
Background: Fulvestrant (FUL), an estrogen receptor (ER) antagonist, is an effective treatment for patients (pts) with hormone receptor-positive (HR+) breast cancer (BC) whose disease has progressed or recurred during previous anti-estrogen therapy. The androgen receptor (AR), expressed in the majority of HR+ BC, may contribute to resistance to hormonal therapy. Enzalutamide (ENZA) is a potent inhibitor of AR signaling. Preclinical models with ER+/AR+ BC cell lines showed synergistic inhibitory effects for ENZA combined with FUL on tumor cell growth. ENZA is a potent CYP3A4 inducer, and in vitro studies show that CYP3A4 is the only CYP enzyme involved in the oxidative metabolism of FUL. In this phase 1 trial (NCT01597193), we evaluated the potential for ENZA to affect FUL pharmacokinetics (PK), as well as the safety and tolerability of the combination of ENZA with FUL.
Methods: Postmenopausal pts with HR+/AR+ advanced BC were enrolled; any number of prior therapies were permissible. Tumor tissue was analyzed centrally for AR expression; pts who had ?10% tumor cells with nuclear AR staining were eligible. All pts received at least 3 doses of FUL (500 mg intramuscularly on days 1, 15, and 29 and once monthly thereafter) to ensure steady-state concentrations prior to initiating ENZA 160 mg/day orally. The combination of ENZA with FUL was given until disease progression. PK and hormone sampling occurred on day 1 prior to ENZA initiation and on days 29 and 57. All pts were monitored for safety and response to treatment.
Results: As of 01May2015, 11 pts were enrolled; PK data are available for 8 of 11 pts, and 6 pts remain on study. Median age was 59 years; median ECOG performance status was 1. Two pts previously received FUL as a prior therapy for advanced BC; 4 pts received no prior therapy for advanced BC. The median duration of exposure to the combination was 16.6 weeks (range 4.0-42.3); the median duration of exposure to FUL (including at least 3 preloading doses) was 24.4 weeks (range 11.7-67.3). Common (&gt;2 pts) ENZA-related adverse events (AEs) included fatigue (n=6), nausea (n=5), cognitive disorder (n=4) and diarrhea (n=3). Cognitive changes Grade 1/2 were reported in 4 pts based on the cognitive function assessment questionnaire. Two pts reported unrelated serious AEs (erosive gastritis, urinary tract infection, iron deficiency anemia, and dehydration). Four pts had AEs ≥ Grade 3: hypertension, anemia, hyperglycemia, urinary tract infection, asthenia, erosive gastritis, dehydration, and iron deficiency anemia; only asthenia and hypertension were considered treatment-related. Circulating levels of estradiol and estrone were within the expected range. Trough plasma concentrations of FUL (Cmin) were similar for FUL alone and FUL combined with ENZA (Cmin=13.7 ± 2.8 and 12.5 ± 1.8 ng/mL, respectively).
Conclusions: The safety profile for the combination of daily ENZA with FUL appears to be consistent with the published data for ENZA and FUL monotherapies. ENZA with FUL achieves similar plasma exposure to FUL alone, indicating no PK drug interaction.
Citation Format: Elias AD, Burris HA, Patel MR, Schwartzberg LS, Richer JK, Kavalerchik E, Stopatschinskaja S, Gibbons J, Markova D, Steinberg JL, Traina TA. MDV3100-08: A phase 1 study evaluating the safety and pharmacokinetics of enzalutamide plus fulvestrant in women with advanced hormone receptor-positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-16-05.