New Treatment Options for Hormone-Positive Breast Cancer

For breast cancer, new hormonal treatment options promise meaningful benefits for patients with hormone-positive breast cancer. These emerging treatments were described at the 2022 Miami Breast Cancer Conference.

Among the many classes and drugs currently in clinical development, selective estrogen receptor degraders (SERDs) are the best known to oncologists. Fulvestrant remains the only SERD approved by the FDA (US Food and Drug Administration), but results from the phase 3 EMERALD trial were recently reported for the oral SERD elacestrant. In preclinical models, elacestrant's antitumor activity appears greater than fulvestrant's, and in phase I/II studies, elacestrant appears effective even in patients previously treated with fulvestrant.

A Different Mechanism of Action

Hormonal therapies in breast cancer are examined in 3 classes:

• Aromatase inhibitors reduce circulating estrogen levels by blocking the aromatase enzyme without affecting the estrogen receptor.
• Agents such as tamoxifen, known as selective estrogen receptor modulators, are competitive inhibitors of the estrogen receptor; by binding to the receptor, they prevent estrogen from binding to it.
• On the other hand, SERDs not only bind to the estrogen receptor but also degrade it; they essentially eliminate the target.

Regarding treatment resistance, the development in the estrogen receptor of an ESR1 mutation is well known to oncologists. In patients with progressive disease on estrogen treatment, ESR1 mutation status is important because it may guide treatment selection. An ESR1 mutation indicates that, although the tumor is independent of estrogen, it probably still depends on the estrogen receptor pathway. Drugs that bind directly to the estrogen receptor – SERDs – are likely to be effective for these patients, whereas those that reduce estrogen levels do not appear effective.

When treatment resistance results from independence from both estrogen and the estrogen receptor, single-agent endocrine (hormonal) therapy is unlikely to be effective, and combination treatment will be needed. Studies are evaluating combinations of SERDs with targeted therapies, including inhibitors of cyclin-dependent kinase 4/6, PI3K (such as alpelisib) and AKT inhibitors as targeted treatments in these combinations.

Elacestrant Data

As presented at the 2021 San Antonio Breast Cancer Symposium, elacestrant met the primary endpoint of the EMERALD trial, reducing the rate of death by up to 30% among those with progressive disease and by up to 43% among patients with an ESR1 mutation. The study compared 400 mg of elacestrant daily with the investigators' choice of fulvestrant or an aromatase inhibitor in postmenopausal women with previously treated estrogen receptor-positive, HER2-negative metastatic breast cancer.

Looking at this study's survival curve, there is an initial drop in both arms (approximately 2 months), probably due to widespread endocrine resistance, but the curves then separate in favor of elacestrant. In this setting, median progression-free survival can be misleading. When curves like these are seen, better measures are progression-free survival at 6 and 12 months, or the hazard ratio encompassing the entire study group and follow-up.

• The 6-month progression-free survival rate was 34.3% with elacestrant compared with 20.4% with standard endocrine therapy.
• The 12-month rates were 22.3% and 9.4%, respectively.
• Approximately half the study group harbored an ESR1 mutation. Rates in this subgroup were 40.8% and 19.1% at 6 months, and 26.8% and 8.2% at 12 months, respectively.

Moreover, oral administration of this new SERD appears to be an important advantage because fulvestrant is administered intramuscularly.

The main adverse effect of elacestrant was nausea, and other adverse effects were similar to those seen with standard endocrine therapy.

Other Oral SERDs in Development

Elacestrant has joined four other oral SERDs already in phase 2 or 3 studies as second- and third-line treatments for metastatic breast cancer;

1. Giredestrant (GDC-9545): Phase 2 aceIERA trial (ClinicalTrials.gov identifier NCT04576455)
2. Amcenestrant (SAR439859): Phase 2 AMEERA-3 trial (NCT04059484)
3. Camizestrant (AZD9833): Phase 2 SERENA-2 trial (NCT04214288)
4. Imlunestrant (LY3484356): Phase 2/3 EMBER-3 trial (NCT04975308)

In a March 2022 press release, the sponsor of amecenestrant announced that the AMEERA-3 trial had not met its secondary endpoint and that full results would be presented at the next scientific meeting. Results from the other clinical studies are eagerly awaited.

A Completely Different Hormonal Treatment Candidate

Following closely behind SERDs are even newer endocrine agents, selective estrogen receptor covalent antagonists, which target wild-type cystine (C530) and other mutant estrogen receptors.

One of these, code-named H3B-6545, is a first-in-class selective estrogen receptor covalent antagonist that binds irreversibly to estrogen receptor alpha and forces a novel antagonist conformation without degrading estrogen receptor alpha.

The rationale for this class is that, unlike other nuclear hormone receptors, the estrogen receptor has a unique cystine residue. The drug binds to it and changes the estrogen receptor, thereby blocking its function. It does not actually degrade the estrogen receptor but blocks it.

Other new classes, such as proteolysis-targeting chimeras bind to the estrogen receptor and then target it for degradation. At the 2021 San Antonio Breast Cancer Symposium, early-phase studies reported demonstrated activity of both types of experimental agents in previously treated metastatic HER2-positive breast cancer.

To select suitable patients for these new treatments and determine whether their tumors depend on the estrogen receptor pathway or are independent of it, we need biomarkers. An ESR1 mutation is a starting point – ESR1 provides some indication of estrogen receptor dependence. Additional biomarkers are needed to help optimize the right endocrine treatment strategy for patients with estrogen receptor-positive metastatic breast cancer.