A phase 1 open-label study evaluating the safety, tolerability, and pharmacokinetics of enzalutamide alone or combined with an aromatase inhibitor i...
|Date||08 May 2014|
|Session||Welcome reception and Poster Walk|
|Topics|| Anti-Cancer Agents & Biologic Therapy
|Citation||Annals of Oncology (2014) 25 (suppl_1): i4-i4. 10.1093/annonc/mdu064|
T.A. Traina1, D.A. Yardley2, M.R. Patel3, L.S. Schwartzberg4, A. Elias5, A. Gucalp1, M.E. Blaney6, J. Gibbons6, C.A. Hudis1, P. LoRusso7
Enzalutamide (ENZA) is a potent novel oral inhibitor of the androgen receptor (AR) which is expressed in a majority of breast cancers (BC). ENZA demonstrated preclinical activity in all BC subtypes that express the AR and thus could be effective in AR+ BC. This is the first trial of ENZA in women with advanced BC (aBC).
Stage 1 (S1) of this Phase 1 study in patients (pts) with aBC evaluated single agent ENZA at daily doses of either 80 or 160 mg; blood was collected for PK analysis and dose-limiting toxicities (DLTs) were recorded through Day 35. Stage 2 (S2) evaluated daily ENZA (160 mg) added to patients receiving either anastrozole 1 mg (ANA) or exemestane 25 mg (EXE). In S2, blood for PK and hormones was collected pre (D1) and post (D29) ENZA treatment. Tumor assessments were performed approximately every 3 months in both stages.
S1 (n = 15) confirmed 160 mg of ENZA as the daily dose in women with aBC. A single DLT (adrenal insufficiency) occurred at the 80 mg dose. As of 8 Oct 2013, 20 pts were enrolled to ANA and 16 to EXE. Median age, ECOG, and prior therapies for aBC were 57, 1, and 5 in S1, and the values were 59, 0, and 4 in S2, respectively. In S1, common (>15%) treatment-related adverse events (TAEs) of any grade included: AST elevation, nausea, and nasal congestion, and in S2: fatigue, anorexia, nausea, hot flush, and vomiting. Grade ≥3 AEs in ≥2 pts were anemia (n = 2) in S1 and fatigue (n = 2) in S2. The geometric mean ratio (GMR) of D29:D1 AUC for ANA was 0.12 (90% CI: 0.07, 0.20) and for EXE was 0.60 (90% CI: 0.40, 0.81). Preliminary hormone data showed increased estradiol on D29 over D1 in 7 of 14 pts in ANA vs. 1 of 12 in EXE.
The PK and tolerability of single-agent ENZA in women is similar to that reported in men. ENZA reduced exposure to ANA by 88% and to EXE by 40%. Estradiol remained low in combination with EXE but possibly not with ANA. EXE with or without ENZA is being evaluated in a randomized Phase 2 study.
T.A. Traina: Advisory board membership for Genentech, Eisai and Prostrakan. Received honoraria from Genentech, Celgene, Merck, Eisai and Prostrakan. Received research funding from Medivation, AstraZeneca, Eisai, Ziopharm, Janssen, Genentech and Novartis.
D.A. Yardley: Consultancy and advisory board membership for Medivation
. M.R. Patel: Honoraria for speakers bureau for Medivation
. M.E. Blaney: Employee of Medivation
. J. Gibbons: Employee of Medivation
. P. LoRusso: Research grant form Astellas. Consultancy for Astellas.
All other authors have declared no conflicts of interest.