Novel hormonal therapies for breast cancer could provide additional therapeutic options for patients with hormone receptor–positive breast cancer. The emerging landscape for these new agents was described at the 2022 Miami Breast Cancer Conference, sponsored by PER, by Aditya Bardia, MD, MPH, Director of Breast Cancer Research and Attending Physician at Massachusetts General Hospital, and Associate Professor at Harvard Medical School.1
Among numerous classes and drugs now in clinical development, the selective estrogen receptor degraders (SERDs) are most familiar to clinicians. Although fulvestrant remains the single SERD approved by the U.S. Food and Drug Administration, the phase III EMERALD trial results have recently been reported for the oral SERD elacestrant. In preclinical models, the antitumor activity of elacestrant was higher than that of fulvestrant, and in phase I/II trials, elacestrant was active even in patients previously treated with fulvestrant, he said.
Different Mechanisms of Action
There are three broad categories of endocrine therapies. Aromatase inhibitors block the aromatase enzyme, lowering circulating levels of estrogen but not impacting the estrogen receptor. Selective estrogen receptor modulators, such as tamoxifen, are “competitive” inhibitors of the estrogen receptor: by binding to the receptor, they prevent estrogen from binding to it. SERDs, on the other hand, not only bind to the estrogen receptor, but also degrade it; they basically remove the target.
In patients with disease progression on endocrine therapy, ESR1 mutation status is important because it can guide treatment selection.— Aditya Bardia, MD, MPH
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In terms of resistance to therapy, clinicians are most familiar with the ESR1 mutation that develops in the estrogen receptor. In patients with disease progression on endocrine therapy, ESR1 mutation status is important because it can guide treatment selection. Its presence suggests that although the tumor is estrogen independent, it is likely still dependent on the estrogen receptor pathway. For these patients, drugs that bind to the estrogen receptor directly—SERDs—are likely to be effective, but those lowering ligand (estrogen) levels—aromatase inhibitors—may not, he said.
When resistance is due to both estrogen independence and estrogen receptor independence, single-agent endocrine therapy is unlikely to be effective, and combination therapy will be needed. Studies are evaluating SERDs in combination with targeted therapies, including inhibitors of cyclin-dependent kinases 4/6, PI3K, and AKT.
Data on Elacestrant
At the 2021 San Antonio Breast Cancer Symposium, Dr. Bardia reported that the EMERALD trial met its primary endpoint, with elacestrant reducing the risk of death and disease progression by 30% among all patients and by 43% among patients with ESR1 mutations.2 The study compared elacestrant at 400 mg daily with the investigator’s choice of fulvestrant or an aromatase inhibitor in pretreated postmenopausal patients with estrogen receptor–positive HER2-negative metastatic breast cancer.
Commenting on the “complex” findings, Dr. Bardia said: “Looking at the survival curves, you see an initial drop in both arms [at approximately 2 months], likely due to broad endocrine resistance, and then you see a separation of the curves. In this setting, median progression-free survival can be misleading. Better metrics, when you see curves like this, are progression-free survival at 6 months and 12 months, or the hazard ratio (HR), which captures the whole study population and follow-up.”
The 6-month progression-free survival rate was 34.3% with elacestrant vs 20.4% with standard endocrine therapy (HR = 0.697; 95% confidence interval [CI] = 0.552–0.880). The 12-month rate was 22.3% vs 9.4%, respectively (HR = 0.546; 95% CI = 0.387–0.768).
Approximately half the study population harbored ESR1 mutations. In that subset, the 6-month progression-free survival rate was 40.8% vs 19.1%, respectively; the 12-month rate was 26.8% vs 8.2% (HR = 0.546; 95% CI = 0.387–0.768).
Since many patients received fulvestrant (rather than an aromatase inhibitor), the investigators were interested to see how the oral SERD measured up against intramuscular fulvestrant. These findings were similar to the study’s overall findings, both for the entire population (HR = 0.684; P = .0049) and for patients with ESR1 mutations (HR = 0.504; P = .0005).
As an oral medication, elacestrant’s main side effect was nausea. Other side effects were similar to those seen with standard endocrine therapy, he said.
Other Oral SERDs in Development
Elacestrant is joined by four other oral SERDs already in phase II or III trials as second- and third-line treatments of metastatic breast cancer:
- Giredestrant (GDC-9545): Phase II aceIERA trial (ClinicalTrials.gov identifier NCT04576455)
- Amcenestrant (SAR439859): Phase II AMEERA-3 trial (NCT04059484)
- Camizestrant (AZD9833): Phase II SERENA-2 trial (NCT04214288)
- Imlunestrant (LY3484356): Phase II/III EMBER-3 trial (NCT04975308).
In a press release in March 2022, the sponsor of amcenestrant announced that the AMEERA-3 trial did not meet its primary endpoint and full results will be presented at a future scientific meeting. Results from other clinical trials are eagerly awaited.3
Now, for Something Completely Different
On the heels of SERDs come even more novel endocrine agents. Selective estrogen receptor covalent antagonists target a unique cysteine (C530) in wild-type and mutant estrogen receptors not conserved in other nuclear hormone receptors. H3B-6545 is a first-in-class selective estrogen receptor covalent antagonist that binds estrogen receptor alpha irreversibly and enforces a novel antagonist conformation without degrading estrogen receptor alpha, he said.
“The rationale for this class is that, as opposed to other nuclear hormone receptors, the estrogen receptor has a unique cysteine residue. The drug binds to that and changes the estrogen receptor, so its function is blocked. It does not degrade the estrogen receptor per se, but blocks it,” he explained.
Yet another new class, the proteolysis-targeting chimera, binds to the estrogen receptor and then targets it for degradation. Early-phase studies reported at the 2021 San Antonio Breast Cancer Symposium demonstrated activity for both types of experimental agents in previously treated metastatic HER2-positive breast cancer. Both H3B-6545, a selective estrogen receptor covalent antagonist, and ARV-471, a proteolysis-targeting chimera, led to a clinical benefit in about 40% of patients.4,5
“Obviously, we need biomarkers to identify estrogen receptor pathway independence or dependence to select patients for these therapies. The ESR1 mutation is a start—it provides some signal regarding estrogen receptor dependency,” he said. “Additional biomarkers are needed to help optimize the right endocrine therapy strategy for patients with estrogen receptor–positive metastatic breast cancer.”
DISCLOSURE: Dr. Bardia has served as a consultant or advisor to Genentech/Roche, Immunomedics/Gilead, Novartis, Pfizer, Merck, Radius Health/Menarini, Foundation Medicine, Sanofi, AstraZeneca, Daiichi Sankyo, and Eli Lilly; and has received institutional research funding from Genentech/Roche, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Sankyo/AstraZeneca, Eli Lilly, and Natera.
REFERENCES
1. Bardia A: Emerging data on oral selective estrogen receptor degraders and other novel hormonal therapies. 2022 Miami Breast Cancer Conference. Presented March 4, 2022.
2. Bardia A, Neven P, Streich G, et al: Elacestrant, an oral selective estrogen receptor degrader vs investigator’s choice of endocrine monotherapy for ER+/HER2– advanced/metastatic breast cancer following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial. 2021 San Antonio Breast Cancer Symposium. Abstract GS2-02. Presented December 8, 2021.
4. Hamilton EP, Wang JS, Pluard T, et al: H3B-6545, a novel selective estrogen receptor covalent antagonist in estrogen receptor positive, human epidermal growth factor receptor 2 negative advanced breast cancer: A phase II study. 2021 San Antonio Breast Cancer Symposium. Abstract P1-17-10. Presented December 8, 2021.
5. Hamilton E, Vahdat L, Han HS, et al: First-in-human safety and activity of ARV-471, a novel PROTAC estrogen receptor degrader, in ER+/HER2– locally advanced or metastatic breast cancer. 2021 San Antonio Breast Cancer Symposium. Abstract PD13-08. Presented December 10, 2021.
