Chemotherapy-Free Regimens Seek to Replace Current Standards in Metastatic HR+ Breast Cancer

Sara Tolaney, MD, MPH

Oral selective estrogen receptor degraders (SERDs) and the selective androgen receptor (AR) agonist enobosarm are being evaluated as potential chemotherapy-free treatments for patients with metastatic hormone receptor (HR)–positive, HER2-negative breast cancer who have progressed on CDK4/6 inhibitors, a setting in which the efficacy of standard of care endocrine therapy is insufficient, explained Sara Tolaney, MD, MPH.

“What we’re seeing in metastatic HR-positive breast cancer is that post–CDK4/6 inhibition, the efficacy of endocrine monotherapy is limited. It’s nice to be able to have other options outside of chemotherapy for these patients after progression on a couple lines of endocrine therapy. The third-line setting is where we need more agents that are not chemotherapy to allow for other options. Enobosarm is really trying to develop in that space,” said Tolaney.

In an interview with OncLive®, Tolaney, chief of the Division of Breast Oncology and associate director at the Susan F. Smith Center for Women’s Cancers, senior physician at Dana-Farber Cancer Institute, and an associate professor of medicine at Harvard Medical School, discussed the data with the oral SERD, elacestrant, and the AR agonist, enobosarm, in estrogen receptor (ER)–positive, HER2-negative breast cancer.

OncLive®: We saw exciting data from the phase 3 EMERALD (NCT03778931) study with elacestrant in patients with ER-positive, HER2-negative breast cancer at the 2021 San Antonio Breast Cancer Symposium. What are your thoughts on oral SERDs as a treatment class?

Tolaney: We saw some exciting data with SERDs from the EMERALD study with elacestrant. It is nice to see a robust monotherapy response in a pretreated post–CDK4/6 inhibitor population. That being said, [the data also] show there is still room for growth because the PFS [progression-free survival] that we’re seeing, even though elacestrant performed better than standard of care endocrine therapy, [indicate that] we still need to do better here, and combinations are going to be needed.

How does the nonsteroidal selective AR agonist enobosarm differ from elacestrant?

Enobosarm is a little different because it’s a selective AR modulator, which is an intriguing pathway. We’ve seen some data previously for enobosarm where we saw that there was robust clinical benefit from this agent in pretreated HR-positive breast cancer. What we saw was that the activity was even greater when you looked at patients who had high AR expression. The investigators used an AR expression cutoff of greater than or equal to 40% and that’s where they started seeing their objective responses.

Because of that, they’ve now moved into a phase 3 design, which is comparing enobosarm with standard of care endocrine therapy, in this case, it could be exemestane plus or minus everolimus [Afinitor], or a SERM [selective ER modulator] in patients who previously had an AI [aromatase inhibitor] and fulvestrant [Faslodex], [at least one of which must have been given in combination with] a CDK4/6 inhibitor, so predominantly a third-line, metastatic AR-positive population. [The study] is restricted to patients who have AR expression of greater than or equal to 40% given the previous data we saw from the phase 2 trial. Enobosarm is a nice oral agent, but for a select population of patients with ER-positive disease, and we’ll have to see how it compares with our standard of care.

What is the unmet need that the phase 3 ARTEST trial (NCT04869943) could fulfill?

If you look at the control arm of EMERALD, it’s a little under 2 months for PFS for standard endocrine therapy. We’ve moved to combination therapy with either everolimus or alpelisib [Piqray] in someone who has a PIK3CA mutation. We certainly see that even post–CDK4/6 inhibition, while there’s benefit for these strategies, it’s still not as good as it was in the CDK4/6 inhibitor–naïve population. There is an unmet need there, because otherwise we’re moving toward chemotherapy.