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FDA scientists published a detailed rationale for the approval of elacestrant (Orserdu), the first oral estrogen receptor (ER) antagonist specifically indicated for breast cancer patients with tumor estrogen receptor 1 (ESR1) mutations.

The agency approved elacestrant in Jan. 2023 for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression after at least one line of endocrine therapy.

"To our knowledge, this is the first approval of an oral estrogen receptor antagonist and the first approval specifically for patients with ESR1 mutations," Mirat Shah, MD, of the FDA's Center for Drug Evaluation and Research in Silver Spring, Maryland, and colleagues wrote in the . "This article summarizes FDA's rationale for determining a favorable benefit-risk assessment for elacestrant for the treatment of ER1, HER2–, ESR1-mutated metastatic breast cancer."

In the following interview, Shah, a medical oncologist and clinical reviewer on the Breast, Gynecologic, and Supportive Oncology team, discussed the on which approval was based, key aspects of the FDA decision, and future research.

Why is targeting tumor ESR1 mutations important in patients with metastatic breast cancer?

Shah: Development of ESR1 mutations is one mechanism by which ER-positive tumors may acquire resistance to endocrine therapies -- particularly aromatase inhibitors. Cancer therapies that are effective following development of tumor resistance to initial endocrine-based therapy may improve long-term outcomes for patients with ER+HER2- advanced or metastatic breast cancer.

Approval of elacestrant was only for the subset of patients in EMERALD with ESR1 mutations. Can you explain the risk-benefit assessment behind this decision?

Shah: When FDA examined the results from the EMERALD trial, we concluded that the benefit-risk profile for elacestrant was favorable only in the patients with detectable tumor ESR1 mutations. In patients with tumor ESR1 mutations, EMERALD showed a statistically significant improvement in progression-free survival (PFS) and a favorable overall survival (OS) trend. Although the PFS improvement was modest in magnitude, it was statistically robust.

Elacestrant was associated with increases in some side effects -- nausea, vomiting, dyslipidemia -- compared with the standard-of-care endocrine therapies, but this was thought to be acceptable because PFS benefit was demonstrated.

Conversely, the magnitude of PFS benefit was less robust in those who did not have detectable ESR1 mutation. Due to the design of the EMERALD trial, the results in the subset of patients without detectable ESR1 mutations were considered exploratory. The observed marginal trend towards PFS improvement in this subset of patients was difficult to interpret due to lack of statistical power, and it was not robust to sensitivity analyses.

Additionally, there was uncertainty in the OS findings due to imbalances in the number of patients who withdrew from the trial in the elacestrant arm compared with the standard-of-care arm. Given the marginal effect in both the PFS and OS findings in the context of increased side effects with elacestrant, FDA did not feel the benefits outweighed the risks for use of elacestrant in patients without tumor ESR1 mutations.

The FDA also approved a companion diagnostic device, the Guardian360 CDx assay. Can you tell us about this device?

Shah: A companion diagnostic (CDx) is a device that provides essential information for the safe and effective use of the associated drug. Elacestrant is approved only for patients with ESR1-mutated ER+HER2- breast cancer, and the Guardant360 CDx is a blood (plasma)-based assay that detects tumor ESR1 mutations in circulating cell-free DNA. When a CDx is required for the safe and effective use of the drug, FDA's goal is to approve the drug and the device contemporaneously, as occurred in this case.

What postmarketing studies of elacestrant will be conducted?

Shah: At the time of approval, FDA may issue postmarketing requirements (PMRs) and postmarketing commitments (PMCs). PMRs are additional trials or studies that drug sponsors are required to do based on federal regulations, and PMCs are additional evaluations that drug sponsors have agreed to do but are not required.

FDA issued a PMR for evaluation of elacestrant in patients with severe hepatic impairment. FDA issued a PMC for evaluation of elacestrant in patients from underrepresented racial and ethnic groups.

Is there anything else about this drug or its approval you want to make sure oncologists understand?

Shah: FDA approved elacestrant for patients with tumor ESR1 mutations based on demonstration of a favorable benefit-risk assessment in this group. While this offers another option for patients, the PFS improvement was modest, and additional safe and effective therapies are still needed for patients with ER+HER2- advanced or metastatic breast cancer.

Read the FDA approval summary special article here.