Enobosarm May Represent a Safe, New Hormone Treatment Approach for AR+, ER+ Metastatic Breast Cancer

The novel oral selective androgen receptor (AR)–activating agent, enobosarm, has been shown to have clinical activity and improved safety over other historical approaches that have been used in patients with AR-positive, estrogen receptor (ER)–positive metastatic breast cancer, making it an appealing option for this population, according to Hannah M. Linden, MD.

Results from the phase 2 G200802 trial (NCT02463032) showed that in patients who received enobosarm at a dose of 9 mg achieved a clinical benefit rate (CBR) of 32% (95% CI, 19.5%-46.7%). In a cohort of patients who received 18 mg of the agent, the agent induced a CBR of 29% (95% CI, 17.1%-43.1%).

Additionally, patients who had over 40% AR staining experienced an overall response rate (ORR) of 50% and a CBR of 79%; 21% of patients developed progressive disease. Those with an AR staining of less than 40% experienced an ORR of 0% and a CBR of 18%. Eighty-two percent of patients in this group developed progressive disease.

“This is an interesting and useful pathway, and one that is extremely appealing to women,” Linden said. “I spend a lot of time dealing with frustrations regarding AEs [experienced with] ER blockade and estradiol depletion. These are very real AEs for patients; having an alternative option that does not [come with] those [toxicities] will be really exciting and appealing for [patients].”

In an interview with OncLive^® during the 2021 ASCO Annual Meeting, Linden, a physician at Seattle Cancer Care Alliance; a professor in the Division of Medical Oncology at the University of Washington School of Medicine; and a professor of the Clinical Research Division at Fred Hutchinson Cancer Research Center, discussed the potential for enobosarm in patients with metastatic breast cancer, data from a phase 2 trial examining its use, and next steps for the agent in the paradigm.

OncLive^®: How might AR-targeted agents serve to overcome mechanisms of resistance in patients with AR-positive, ER-positive metastatic breast cancer?

Linden: The AR has been a known target in breast cancer for a long time. More senior members of the practicing community know that we have given testosterone or androgen blockers effectively [in the past]. [The AR] is just another hormonal pathway that seems to be most relevant for [our patients with] ER-positive [disease].

[We have seen a lot of hype for this strategy in patients with] triple-negative, AR-positive [disease]; it is compelling that we might have a target for this group when we did not previously think that we did. Endocrine therapy is the oldest [approach] we have [in our arsenal], and various endocrine agents are effective. What is exciting is that we may be able to leverage that pathway in a way that makes [treatment] very tolerable for our patients.

What was the design of the phase 2 clinical trial examining enobosarm?

The phase 2 trial looked at a couple of different doses to get some experience with [the approach in] patients who were heavily pretreated. Some patients do not need much in terms of treatment; they may not even need a molecularly targeted agent in addition to endocrine therapy. Some patients are just good responders. That group is the one that we are really looking at in this study; [we want] to offer [these patients] an alternative endocrine approach. Endocrine therapy is generally well tolerated but has been known [to cause] issues for patients in the form of menopausal symptoms, bone density loss, and arthralgias.

[Enobosarm] is a different endocrine agent that does not have any of those adverse effects [AEs], nor any of the other unfortunate toxicities that high-dose estrogen or progestins have had. [The agent also] does not have the [same] AEs [that have been observed with] androgen agonists. This is a nice balance of avoiding the estrogen-deprivation AEs and providing some favorable androgenic effects, such as an improvement in lean body mass.

What are the key takeaways from this trial?

It has been known that AR is co-expressed in many ER-positive tumors, but really drilling down on the numbers is important. We know what it means when [a patient is] highly ER positive vs weakly positive. We know what it means when the progesterone receptor is highly expressed or is not. In this [trial, we asked,] what does the level of AR expression mean? Not surprisingly, it means [a patient is] going to achieve a better response to this treatment because it is an AR-directed therapy.

How do you see this agent potentially fitting into the treatment landscape?

The landscape is really complicated right now with so many different options available. [Enobosarm may] be used as a single agent. I also believe that the agent will be used in concert with some of the molecularly targeted agents, such as CDK4/6 inhibitors.

None of us really know what to do after progression on a CDK4/6 inhibitor. Should [the patient] go on to receive oral chemotherapy? Should you turn to single-agent hormonal therapy? Should you give the same, or a different, CDK4/6 inhibitor with your next agent? [Enobosarm] will be thrown in the mix as a way to think about what you could partner with. [The agent] will be a refreshing partner because [it has] fewer AEs, but it also [targets] a different pathway.

Where will future research efforts be focused?

The drug is going to be tested in a phase 3 study to try to get FDA approval for its use in [patients with] metastatic breast cancer. Also, [the agent] will [probably] be tested in synergy with CDK4/6 inhibitors, which really have changed the way we treat this disease and have improved response rate, time to progression, and survival.

Is there anything you would like to add?

Having a treatment that does not cause those AEs and can make [a patient] feel good, feel stronger, and have a little more energy is extremely appealing. Fatigue is a huge symptom for patients living with cancer. [Enobosarm] is an extremely appealing drug because patients just want [to have better] quality of life. We cannot just prolong the quantity of life; we need to also prolong quality of life.

Reference

1. Palmieri C, Linden HM, Birrell S, et al. Efficacy of enobosarm, a selective androgen receptor (AR) targeting agent, correlates with the degree of AR positivity in advanced AR+/estrogen receptor (ER)+ breast cancer in an international phase 2 clinical study. J Clin Oncol. 2021;39(suppl 15):1020. doi:10.1200/JCO.2021.39.15_suppl.1020