Advanced breast cancer involves disease that is either metastatic (or is growing outside the breast and lymph nodes) or has locally recurred and cannot be surgically removed. Many patients with advanced breast cancer live for years if their disease is effectively treated. Breast cancer types are frequently characterized by the presence of hormone receptors in the cells (such as estrogen or progesterone receptors) that act to drive tumor growth and make excellent targets to inhibit as a treatment strategy. Androgen receptors are also frequently found on breast cancer tumor cells, and for decades, medical practice had included the use of steroidal androgens to treat patients with advanced breast cancer, resulting in favorable response rates (regression in the tumor size) of up to 25 percent. The use of androgens fell out of favor in the 1970s, largely due to the more favorable side effect profile of the active anti-estrogen drugs, initially tamoxifen. The last 30-plus years of hormonal clinical research have focused on research and treatments geared towards blocking the effects of estrogen in estrogen receptor positive (ER+) breast cancer (BC), utilizing anti-estrogen therapy with the Selective Estrogen Receptor Modulator (SERM) class of drugs (tamoxifen, raloxifene, and toremifene) or steroidal and non-steroidal aromatase inhibitors (exemestane, letrozole, and anastrazole).
The current clinical landscape is now shifting again toward improved targeting of the androgen receptor (AR) because of new and improved drug candidates. Steroidal androgens used historically had side effects that included masculinization (facial and body hair growth; deepening of voice), edema, aggression and acne, which limited widespread use. The emergence and optimization of non-steroidal androgen receptor agonists have reinvigorated the search for hormonal therapies targeting the androgen receptor. Some of the effects associated with this class of drugs (NON-steroidal androgen modulators) result in less masculinization, and in many cases may be beneficial due to healthy bone and muscle growth.
Multiple approaches to targeting the androgen receptor are currently being evaluated, including traditional androgen agonists and, more recently, androgen blockade.
We are developing enobosarm (GTx-024, Ostarine®) for women with two different subtypes of breast cancer:
- ER+/AR+ breast cancer – tumors with measurable level of estrogen and androgen receptors
- AR+ TNBC – tumors with measureable level of androgen receptors (AR positive) but unmeasurable levels of estrogen, progesterone and HER2 receptors, referred to as triple negative breast cancer
Based on historical clinical data and preclinical evidence with Selective Androgen Receptor Modulators (SARMs), GTx believes that a safe, non-steroidal SARM is a rational therapeutic approach targeting the AR in ER+ breast cancer patients who have demonstrated previous hormonal responsiveness, and in TNBC patients who have currently no treatment options beyond chemotherapy. In both of these patient groups, there is a significant unmet need for additional, less toxic, therapy.