Abstract P5-09-21: Selective androgen receptor modulators (SARMs): Enobosarm as targeted therapy for the treatment of androgen receptor-positive breast cancer
Authors: Dalton JT , Narayanan R , Steiner MS 
Published: August 2014

Background: The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER)-positive and 40-70% of ER-negative breast cancers expressing AR. Prior studies have shown that women with metastatic breast cancer who have been previously treated with tamoxifen and progress have responded to non-tissue-selective androgens like fluoxymesterone, medroxyprogesterone and danazol, with overall response rates ranging from 20 to 60%. Although these non-tissue-selective androgens have been used to treat breast cancer, the unwanted virilizing side effects, including facial and body hair, enlargement of voice box, acne, and edema, have limited their widespread clinical use. Nonsteroidal, tissue- selective androgen receptor modulators (SARMs) like enobosarm and GTx-027 may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer without the unwanted virilizing side effects or concerns related to their conversion by aromatase to estrogens.

Methods: MDA-MB-231 triple-negative and MCF-7 triple-positive breast cancer cells stably expressing AR (MDA-MB-231-AR and MCF-7-AR, respectively) were used to evaluate the in vitro and in vivo anti-proliferative and gene expression effects of bicalutamide (an AR antagonist), dihydrotestosterone (DHT), enobosarm, and GTx-027. Phase II clinical studies examined the pharmacologic effects (lean body mass and muscle strength), tissue selectivity (skin, endometrium, and hair growth) and safety of enobosarm, a first-in-class SARM, in postmenopausal women.

Results: DHT and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR and MCF-7-AR cells. DHT and the SARMs functioned as AR agonists in transactivation assays in MDA-MB-231 cells, indicating that AR agonists, but not antagonists, elicit anti-proliferative effects in breast cancer. MDA-MB-231-AR and MCF-7-AR cells were implanted subcutaneously in nude mice and were treated orally with vehicle or 30 mg/kg/day GTx-027. GTx-027 reduced the tumor growth significantly with greater than 75% tumor growth inhibition observed in MDA-MB-231-AR tumors and greater than 50% tumor growth inhibition observed in MCF-7-AR tumors, compared to vehicle-treated tumors. GTx-027 also inhibited tumor weights by greater than 50% concurring with the tumor volume observation. GTx-027 inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. Interestingly, GTx-027 and other AR agonists elicited opposite effects on various AR target genes in ER-positive versus ER-negative breast cancer cells, indicating a potential cross talk between AR and ER signaling pathways on the promoter of these genes. Phase II clinical studies showed that enobosarm was generally well tolerated in postmenopausal women. Statistically significant improvements in lean body mass and physical function were observed after 12 weeks of treatment with 3 mg enobosarm, with no significant changes in sebaceous gland volume (biopsy), hair growth, endometrial stripe thickness (transvaginal ultrasound) or bleeding (medroxyprogesterone challenge).

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-21.