Elacestrant Secures a Place for ER+, HER2–, ESR1-Mutated Advanced/Metastatic Breast Cancer

The FDA approval of elacestrant (Orserdu) expands options for postmenopausal patients with estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy.¹

Data from the phase 3 EMERALD trial (NCT03778931) supported the regulatory decision. Elacestrant elicited a median progression-free survival (PFS) of 3.8 months (95% CI, 2.2-7.3) in patients with ESR1 mutations (n=115) compared with 1.9 months (95% CI, 1.9-2.1) in patients who received investigator’s choice of fulvestrant or an aromatase inhibitor (n=113; HR, 0.55; 95% CI, 0.39-0.77; P=.0005). Overall survival was not statistically significant with elacestrant (HR, 0.90; 95% CI, 0.63-1.30).²

“[Elacestrant] is a new drug…that will fill an unmet need for many patients,” François-Clément Bidard, MD, PhD, said. “From a drug development perspective, it is a first-in-class oral selective estrogen receptor degrader [SERD]. We know with this first approval that this drug can make it to patients, and that’s a very significant signal that we can increase the efficacy of endocrine therapy.”

The Guardant360 CDx assay was used to assess ESR1 missense mutations in the ligand binding domain of circulating tumor DNA. The assay was also approved as a companion diagnostic device to identify patients who are eligible to receive elacestrant.¹

In an interview with OncologyLive^®, Bidard, a professor of medicine at the Institut Curie and Université Paris-Saclay, head of translational research group for circulating cancer biomarkers, and cocoordinator of Breast Cancer Research at the Institut Curie in France, discussed how elacestrant fits into the treatment paradigm of patients with ESR1 mutations.

What were some of the key efficacy findings from the EMERALD trial?

EMERALD had almost 500 patients who were randomly assigned between [standard of care] SOC and elacestrant. All patients had to be pretreated with CDK4/6 inhibitors and most patients had received either 2 lines of endocrine therapy in the metastatic stage or 1 line of chemotherapy. Interestingly, there were 2 subgroups of patients [and 1 cohort was for those] who had an ESR1 mutation.

The FDA approval is only for the patients with ESR1 mutations, [and these] were detected [in approximately] about half of the patient population. In the ESR1-mutated specific population, we observed a 45% reduction in the risk of [disease] progression or death during the trial. The 6-month PFS rate was [approximately] 40% with elacestrant vs 20% with SOC. The proportion of patients who were progression free at 1 year was approximately 26%, whereas only 8% of patients treated with SOC were still progression free at 1 year. These landmark analyses are telling you that endocrine therapy can work in a subset of patients.

How does prior treatment with CDK4/6 inhibitors influence the efficacy of this agent?

Recent subgroup analysis has shown that the benefit of elacestrant is influenced by PFS in the first line, namely [by] the duration of CDK4/6 inhibitor treatment.³ Patients [with ESR1 mutations] who received 6 months or more of CDK4/6 in the first line had a median PFS with elacestrant of [approximately] 4.1 months [and] patients treated with SOC had a median PFS of 1.8 months.

If you focus on the subgroup of patients who received CDK4/6 inhibitors for at least 1 year [it is notable that] these patients had a median PFS of 8.6 months with elacestrant vs 1.9 months with SOC when they had an ESR1 mutation detected prior to treatment. [These data] show it is very important to understand that in patients who received more than 1 year of [treatment with] CDK4/6 inhibitors, the median PFS with elacestrant is very acceptable for an oral drug and is very likely to be widely adopted by clinicians all over the world.

What adverse effects were seen with elacestrant?

It is very well tolerated. The main toxicities were nausea and vomiting but it was low grade for most patients. There was also some fatigue that was noted, as well as a decreased appetite but most of these toxicities was low grade. Overall, [based on] my experience and the data we have, we can consider this quite safe and easy to propose to patients.

How does this approval fill an unmet need in this specific patient population?

[One] can see 2 different strategic options. First, you can find patients who had more than 1 year exposure to CDK4/6 inhibitors in the first line and if they have an ESR1 mutation [and] remember the median PFS with elacestrant, as a single agent in the second- or third-line setting. This kind of PFS is very satisfactory in the second line, given the easy [to manage] toxicity profile of the drug, so in that setting, I would consider it as a very reasonable option.

The other way to use elacestrant could be later in the disease because we know that patients treated with multiple lines of therapies, are willing to have a break from the hospital, and we don’t have many oral drugs that could be given. At 1 point or another, pending the detection of an ESR1 mutation, most if not all [patients with] ESR1-mutant [disease] will probably receive elacestrant in the years to come.

What further research directions for elacestrant are on the horizon?

EMERALD is the first step of development for elacestrant since it has shown its efficacy as a single agent. [In] the future, [we could] use [it in] combination with new agents that we know can increase the efficacy of endocrine therapy, such as CDK4/6 inhibitors.

Editor’s Note: Dr. Bidard has received research support from Pfizer, Prolynx, Menarini Silicon Biosystems, Merck KGaA, Rain Oncology, Roche, and Seagen; is a consultant for Astra-Zeneca, Caris, Daiichi-Sankyo, Exact Sciences, GE Healthcare, Gilead, GSK, Inatherys, Lilly, Menarini/Stemline, Novartis, Rain Oncology, Sanofi, and Seagen; is a speaker for Astra-Zeneca, Daiichi-Sankyo, Lilly, Menarini/Stemline, Pfizer, Rain Oncology, Sanofi, and Seagen; and is on the congresses for Astra-Zeneca, Pfizer, and Novartis.

References

1. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed February 13, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
2. Orserdu. Prescribing information. Stemline Therapeutics Inc; 2023. Accessed February 13, 2023. https://www.accessdata.fda.gov/
3. Bardia A, Bidard FC, Neven P, et al. EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: updated results by duration of prior CDK4/6i in metastatic setting. Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.