A Phase I/Ib Study of Enzalutamide Alone and in Combination with Endocrine Therapies in Women with Advanced Breast Cancer

Abstract

Several lines of evidence support targeting the androgen signaling pathway in breast cancer. Enzalutamide is a potent inhibitor of androgen receptor signaling. Preclinical data in estrogen-expressing breast cancer models demonstrated activity of enzalutamide monotherapy and enhanced activity when combined with various endocrine therapies (ET). Enzalutamide is a strong cytochrome P450 3A4 (CYP3A4) inducer, and ETs are commonly metabolized by CYP3A4. The pharmacokinetic (PK) interactions, safety, and tolerability of enzalutamide monotherapy and in combination with ETs were assessed in this phase I/Ib study. Enzalutamide monotherapy was assessed in dose-escalation and dose-expansion cohorts of patients with advanced breast cancer. Additional cohorts examined effects of enzalutamide on anastrozole, exemestane, and fulvestrant PK in patients with estrogen receptor-positive/progesterone receptor-positive (ER/PgR) breast cancer. Enzalutamide monotherapy ( = 29) or in combination with ETs ( = 70) was generally well tolerated. Enzalutamide PK in women was similar to prior data on PK in men with prostate cancer. Enzalutamide decreased plasma exposure to anastrozole by approximately 90% and exemestane by approximately 50%. Enzalutamide did not significantly affect fulvestrant PK. Exposure of exemestane 50 mg/day given with enzalutamide was similar to exemestane 25 mg/day alone. These results support a 160 mg/day enzalutamide dose in women with breast cancer. Enzalutamide can be given in combination with fulvestrant without dose modifications. Exemestane should be doubled from 25 mg/day to 50 mg/day when given in combination with enzalutamide; this combination is being investigated in a randomized phase II study in patients with ER/PgR breast cancer. .

Development of selective androgen receptor modulators (SARMs)

“…Recent press release from GTx, Inc., which is currently conducting a clinical trial with enobosarm in women with ER-positive breast cancer, indicated that the SARM slowed further growth of cancer (partial response and stable disease) in a subset of patients (101). Although no clinical data have been published on enzalutamide in ER-positive breast cancer, a phase I clinical trial to evaluate safety and bioavailability of enzalutamide in women with ER-positive breast cancer showed that enzalutamide reduced the serum concentration of anastrozole and exemestane by 90% and 50%, respectively, which could impact the efficacy of the aromatase inhibitors (102). However, enzalutamide has shown early promise in triple-negative breast cancer (TNBC).…”

Receptors for Insulin-Like Growth Factor-2 and Androgens as Therapeutic Targets in Triple-Negative Breast Cancer

“…Although it was hypothesized that treatment with enzalutamide would only be effective in the LAR molecular subtype of TNBC, other molecular subtypes including basal-like and mesenchymal-like subtypes were also responsive to antiandrogen interventions [ 5 ], outcomes that are supported by this work. Additionally, clinical trials indicate that enzalutamide, alone or in combination, is well tolerated in women with advanced breast cancer [ 55 , 56 , 57 ].…”

Phase II Study of Dehydroepiandrosterone in Androgen Receptor-Positive Metastatic Breast Cancer

“…Androgens have variable effects in different BC models [3][4][5]: often antiproliferative [6][7][8][9][10][11][12][13], mainly in ER-positive tumors; sometimes pro-proliferative [14-18], mainly in triple-negative and human epidermal growth factor receptor 2 (HER2)-positive/ER-negative tumors. Both ARagonists [19-22] and AR-antagonists are being studied as antitumor agents in BC [23][24][25][26][27]. Dehydroepiandrosterone (DHEA) is a steroid produced mainly by the adrenal cortex and transformed into sex hormones (androgens and estrogens) within peripheral target tissues [28][29][30][31][32][33].…”