Where to Apply This Therapy

One must think about the potential of this approach to treatment in a variety of places in the breast cancer care continuum and determine where its use might have the most impact, noted Dr Ellis. For example, it could perhaps be used in the prevention setting at the start of an evolving breast cancer that is estrogen-driven. Once the diagnosis is made, an androgen receptor agonist could be mixed with an ER antagonist. This approach also might be used in the adjuvant setting in which patients with ER-positive breast cancer are predominantly treated with estrogen-lowering drugs to prevent relapse but are subject to treatment side effects, he explained. Targeting the androgen receptor may have a role in this setting, particularly in tumors that have evolved to be fully resistant to standard endocrine drugs, according to Dr Ellis.

“The place I would like to see a focus on is in the secondary prevention setting, but the problem there is that it takes very large studies to prove benefit,” said Dr Ellis. “In this setting, patients are getting aromatase inhibitors and watching their bones melt and sexual function disappear. Perhaps a pilot study to look at parameters such as quality of life should be done in which patients are randomly allocated to enobosarm plus an aromatase inhibitor or an aromatase inhibitor alone.”


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If there are secondary health benefits to enobosarm, randomized trials may be in order. Even if the study findings show no difference in the relapse rate, enobosarm might be shown to be safe and promote bone health, Dr Ellis conjectured.

Ongoing Trials

Dr Hickey agreed that the next step in this research is clinical trials. “The good thing is that we don’t have to start from ground zero on clinical trials because there are a lot of these kinds of drugs out there that never made it to a trial for lack of a clear rationale for a trial,” she explained.

One recent phase 2 trial looked at the use of enobosarm for ER-positive breast cancer in postmenopausal women whose disease had progressed on 1 previous form of endocrine therapy.2 The drug showed significant clinical activity, with 32% of patients meeting the primary endpoint of clinical benefit at 24 weeks with the 9-mg dose and 29% with the 18-mg dose. Additionally, a significant percentage of patients reported improvement in quality-of-life measurements, including mobility, anxiety/depression, and pain discomfort.

More recently, the FDA has approved a phase 3 registration trial designed to evaluate the efficacy and safety of enobosarm compared with either exemestane or tamoxifen for metastatic ER-positive, HER2-negative breast cancer in patients who have failed a nonsteroidal aromatase inhibitor, fulvestrant, and a CDK 4/6 inhibitor.3

“A lot of women take tamoxifen then an aromatase inhibitor or an aromatase inhibitor plus a CDK 4/6 inhibitor. If they progress, there are no more tools in the toolbox,” Dr Hickey said. “We are really hoping to see a surge in interest in exploring this pathway for breast cancer as well as possibly in other diseases.”

References

  1. Hickey TE, Selth LA, Chia KM, et al. The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer. Nature Medicine. 2021;27:310-320. doi:10.1038/s41591-020-01168-7
  2. Palmieri C, Linden H, Birrell S, et al. Efficacy and safety of enobosarm, a selective androgen receptor modulator, to target AR in women with advanced ER+/AR+ breast cancer – final results from an international phase 2 randomized study. Presented at: San Antonio Breast Cancer Symposium; December 8-11, 2020. PD8-10.
  3. Veru. Veru announces nature medicine publication demonstrating that enobosarm, an androgen receptor targeted agent, inhibits hormone receptor positive metastatic breast cancer that has become resistant to estrogen receptor targeted endocrine and CDK4/6 inhibitor [news release]. January 19, 2021. Accessed March 5, 2021.