A New Drug for Treatment-Resistant Hormone-Positive Breast Cancer: Elacestrant

CDK4/6 inhibitors and standard hormonal therapies: a new treatment option is emerging for advanced breast cancer that has developed resistance to these therapies.

An experimental oral selective estrogen receptor degrader (SERD), elacestrant, significantly reduced the risk of death and disease progression and improved progression-free survival compared with standard single-agent endocrine therapy when given as second- or third-line treatment to postmenopausal patients with advanced estrogen receptor-positive (HR +) breast cancer. Results of this phase III EMERALD study were presented at the 2021 San Antonio Breast Cancer Symposium by Dr. Aditya Bardia and colleagues.

Metastatic ER-positive breast cancer is typically treated with endocrine therapies such as aromatase inhibitors or fulvestrant; however, in some cases mutations in the ESR1 gene commonly cause resistance to these treatments. Fulvestrant, given by intramuscular injection, is currently the only SERD approved for breast cancer patients.

What is an ESR1 Mutation?

ESR1 is a gene that encodes the estrogen receptor. In metastatic hormone receptor-positive breast cancer, hormonal treatment frequently leads to mutations in the ESR1 gene. ESR1 mutations most often occur in breast cancers that have progressed on aromatase inhibitors.

Dr. Bardia, director of the Breast Cancer Research Program at Massachusetts General Cancer Center and a faculty member at Harvard Medical School, said, "There is an urgent unmet need for alternative SERDs that are effective against hormone-positive metastatic breast cancer, including cancers with ESR1 mutations". 

What is Elacestrant? How Does it Work?

Unlike fulvestrant, elacestrant is an experimental SERD administered orally. Dr. Bardia explained that elacestrant has greater absorption, improved pharmacokinetics and improved ER (estrogen receptor) inhibition compared with fulvestrant. It has also shown greater antitumor activity in mouse models of ER-positive breast cancer. A phase I clinical trial found an acceptable safety profile and meaningful responses in heavily pretreated postmenopausal patients with ER-positive/HER2-negative metastatic breast cancer.

Elacestrant crosses the blood-brain barrier much more readily than fulvestrant, another hormonal treatment in the SERD class, suggesting it may be an appropriate option for breast cancer patients with brain metastases.

Dr. Bardia and colleagues initiated the phase III EMERALD study to understand how elacestrant compares with the current standard of care. It is the first oral SERD investigated in a randomized phase III clinical trial.

Details of the EMERALD Study

The study enrolled postmenopausal patients with ER-positive/HER2-negative metastatic breast cancer who had not received chemotherapy for metastatic disease but whose cancer had progressed after one or two lines of hormonal therapy and a CDK4/6 inhibitor: 477 patients.

Patients were randomly assigned to the experimental or control group to receive either elacestrant or standard treatment (the investigator's choice of fulvestrant or an aromatase inhibitor). Tumors in 228 patients had mutated ESR1: 115 in the experimental arm and 113 in the standard treatment arm.

Results

• Patients in the experimental arm were found to have a 30% lower risk of death or disease progression compared with the standard treatment arm.
• Among patients whose tumors carried ESR1 mutations, those in the experimental arm had a 45% reduction in the risk of death or disease progression.

Subgroup analyses showed improved outcomes with elacestrant regardless of visceral (internal organ) metastases, number of prior treatment lines, pretreatment with fulvestrant or geographical region.  

• At month 12, patients in the experimental arm had a significantly higher progression-free survival rate than patients receiving standard treatment (22.32% versus 9.42%).
• ESR1 -mutated tumors had 12-month progression-free survival rates of 26.76% with elacestrant, compared with 8.19% in patients receiving standard care.

An interim analysis of overall survival showed a trend favoring elacestran, including in patients with ESR1- mutated tumors.

Side Effects

Mild treatment-related side effects (grade 1 or 2) were more common with elacestrant than standard treatment, including nausea (25.3% versus 8.7%), vomiting (11% versus 2.6%) and fatigue (11% versus 7.9%).

Treatment-related side effects of grade 3 or higher occurred in 7.2% of patients in the elacestrant arm and 3.1% in the standard treatment arm. Neither arm had any treatment-related deaths.

Conclusion

Elacestrant is the first oral SERD to demonstrate statistically and clinically meaningful improvement in progression-free survival in patients whose tumors carry an ESR1 mutation as well as other patients with ER-positive/HER2-negative metastatic breast cancer in the second- and third-line settings. It was well tolerated, with manageable and reversible side effects. This drug has the potential to become a new standard of care for these breast cancer patients.

Dr. Bardia noted that future studies will aim to understand elacestrant's effectiveness in earlier treatment lines and in combination with other therapies. A planned phase II trial will examine its effect with abemaciclib, particularly for patients with brain metastases.

One study limitation was that all enrolled patients had previously received a CDK4/6 inhibitor; its effectiveness in patients without prior CDK4/6 inhibitor treatment is therefore unknown.