Patient Selection May be Key for Leveraging Elacestrant in ER+/HER2- Breast Cancer

Elacestrant demonstrated improved progression-free survival (PFS) vs standard-of-care (SOC) endocrine therapy in patients with estrogen receptor (ER)–positive, HER2-negative, metastatic breast cancer who had progressed on prior CDK4/6 inhibitors, but the agent may have the most clinical impact in those with ESR1 mutations and chemotherapy-naïve disease, according to Francois-Clement Bidard, MD, PhD.

Primary findings from the phase 3 EMERALD trial (NCT03778931) showed a 12-month PFS rate of 22.3% (95% CI, 15.2%-29.4%) in patients treated with the oral selective estrogen receptor degrader (SERD) vs 9.4% (95% CI, 4.0%-14.8%) in those treated with SOC endocrine therapy. Additionally, a significant benefit was observed in patients with ESR1 mutations with the agent. In this subgroup, the 12-month PFS rate reported in the elacestrant arm was 26.8% (95% CI, 16.2%-37.4%) vs 8.2% (95% CI, 1.3%-15.1%) in the SOC arm.¹

Findings from a subgroup analysis presented during the 2022 ASCO Annual Meeting further demonstrated improved PFS in all patients with ESR1 mutations who had not received prior chemotherapy.² In this population, the 12-month PFS rate was 31.48% (95% CI, 19.34%-43.61%) with elacestrant vs 12.36% (95% CI, 2.39%-22.32%) with SOC.

In June 2022, a new drug application was submitted to the FDA seeking the approval of elacestrant in the treatment of patients with ER-positive, HER2-negative, advanced or metastatic breast cancer based on data from EMERALD.³

“If we want to translate the EMERALD results into practice, we need to select patients,” Bidard said. “One way to do this is to select those without any prior chemotherapy, as reported at ASCO, or to select patients based on the presence of ESR1 mutations, as suggested by the subgroup analysis.”

Bidard, a professor of medicine in the Department of Medical Oncology and co-coordinator of breast cancer research at Institut Curie & UVSQ/Université Paris-Saclay, elaborated on the rationale of, and findings from, the EMERALD study in an interview with OncLive^®. In the interview, he highlighted the benefits of elacestrant in chemotherapy-naïve patients and in those with ESR1 mutations, explained the results of a subgroup analysis done in patients without prior chemotherapy, and voiced his hopes for the future regarding other oral SERDs in development.

OncLive^®: Could you provide some background information about elacestrant? What makes it unique from other options available or under evaluation for patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer?

Bidard: Elacestrant is the first in class of new agents, oral SERDs, which are agents that target the ER. [The aim of elacestrant is to] increase the effect of endocrine therapy over classic, older compounds such as aromatase inhibitors and fulvestrant [Faslodex], which was the first SERD, but which is given intramuscularly.

Elacestrant has the advantage of oral [administration]. It is given at a dose of 400 mg once a day, and daily intake is much easier for patients. The EMERALD trial asked whether elacestrant could prove more effective than SOC endocrine therapy in the context of patients with ER-positive, HER2-negative metastatic breast cancer who progressed on prior CDK4/6 inhibitors.

What data had been seen with elacestrant prior to the EMERALD study?

Prior to [EMERALD], we mostly had phase 1 data from an expansion cohort, which showed that elacestrant was well tolerated. Also, in a nonrandomized manner, we observed that some patients could [achieve a] long PFS when receiving elacestrant as a single agent, despite having received many prior treatments. [For these reasons, we thought] elacestrant would be an effective drug in the context of endocrine-sensitive, metastatic breast cancer.

What were the key objectives of the phase 3 trial?

The primary objective of EMERALD was to compare PFS between the 2 study arms. [In 1 arm, patients] received elacestrant, and in the other arm, patients received SOC endocrine therapy. Although the primary objective was PFS in the general population, the coprimary end point was to investigate the efficacy of elacestrant in the subgroup of patients with ESR1 mutations detected prior to the start of treatment.

Could you expand on the study design and the patient population that was enrolled?

EMERALD was a phase 3 randomized trial with 2 different arms, including patients who received SOC endocrine therapy [in the form of] an aromatase inhibitor or fulvestrant. In the experimental arm, all patients received elacestrant as a single agent at a dose of 400 mg per day.

To be included in the trial, patients needed to have ER-positive, HER2-negative metastatic breast cancer and must have progressed on prior CDK4/6 inhibitors. One line of prior chemotherapy was allowed. [A total of 22.2% of patients] had received prior CDK4/6 inhibitors and 1 prior line of chemotherapy.

What were the key efficacy findings from this trial, which have now been published in the Journal of Clinical Oncology?

Elacestrant was shown to be better than single-agent endocrine therapy when given as a second-line treatment after progression on CDK4/6 inhibitors. This trial demonstrated a hazard ratio for PFS of 0.70 in favor of elacestrant in the general study population. In the subgroup with ESR1 mutations, the benefit was even higher, with a hazard ratio of 0.55, which clearly showed the superiority of elacestrant over single-agent endocrine therapy.

What did the findings from the subgroup analysis of the EMERALD trial, which were presented during the 2022 ASCO Annual Meeting, show about elacestrant in patients who had not received prior chemotherapy?

At ASCO, Virginia G. Kaklamani, [MD, of the University of Texas Health Sciences Center], presented the results of a subgroup analysis of EMERALD that reported the outcome of patients who were randomized in [the trial] but had not received prior chemotherapy; these patients are the pure second-line population.

The median PFS in the experimental arm was much better—especially in patients with ESR1 mutations. In patients with ESR1 mutations [who had] no prior lines of chemotherapy, single-agent elacestrant was able to achieve a median PFS of 5.32 months whereas SOC endocrine therapy led to a [median] PFS of 1.91 months. [These findings show] a huge difference in favor of using elacestrant as a single agent after progression on CDK4/6 inhibitors and in the context of ESR1 mutations.

What are the next steps for this research with elacestrant?

The next step for elacestrant as a compound is to be combined with other agents such as CDK4/6 inhibitors, PIK3CA inhibitors, and mTOR inhibitors. These compounds are key in the current management of [patients with] ER-positive, HER2-negative metastatic breast cancer. Elacestrant as a single agent is superior to single-agent endocrine therapy, but we know that combinations are even better. The company that is developing elacestrant may also be planning to move it to the early stages of breast cancer in patients with nonmetastatic breast cancer.

What is the significance of these data on the treatment paradigm for patients with metastatic, HR-positive, HER2-negative breast cancer?

Elacestrant is better than current endocrine agents, which is good news for all the oral SERDs that are being developed; [these data] show that it is possible for a new agent to be superior to older agents. Additionally, the PFS achieved in EMERALD is limited; it is short in the general population. [Other methods should also] be explored to stratify patients and understand which patients could be safely treated with single-agent elacestrant.

References

1. Bidard, FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: results from the randomized phase III EMERALD trial. J Clin Oncol. Published online May 18, 2022. doi:10.1200/JCO.22.00338
2. Kaklamani V, Bardia A, Aftimos P, et al. Subgroup analysis of patients with no prior chemotherapy in EMERALD: a phase 3 trial evaluating elacestrant, an oral selective estrogen receptor degrader (SERD), versus investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC). J Clin Oncol. 2022;40(suppl 16):1100. doi:10.1200/JCO.2022.40.16_suppl.1100
3. Menarini Group and Radius Health submit new drug application to the US FDA for elacestrant. News release. The Menarini Group and Radius Health, Inc. June 22, 2022. Accessed July 13, 2022. https://bit.ly/3bplt3F