Patient selection may be key to benefit from Elacestrant in ER+/HER2- breast cancer

Elacestrant demonstrated improved progression-free survival (PFS) compared to standard hormone therapy (SOC) in patients with estrogen receptor (ER) positive, HER2 negative, metastatic breast cancer who had progressed with prior CDK4/6 inhibitors, but the agent may have the most clinical impact in people with CSR1 mutations and chemotherapy naïve disease, according to François-Clément Bidard, MD, PhD.

Key results from the EMERALD Phase 3 trial (NCT03778931) showed a 12-month PFS rate of 22.3% (95% CI, 15.2% to 29.4%) in patients treated with the selective estrogen receptor degrader (SERD) route. oral versus 9.4% (95% CI, 4.0% to 14.8%) in people treated with SOC hormone therapy. In addition, a significant benefit was observed in patients CSR1 mutations with the agent. In this subgroup, the reported 12-month PFS rate in the elacestrant arm was 26.8% (95% CI, 16.2%-37.4%) versus 8.2% (95% CI , 1.3%-15.1%) in the SOC arm.1

Results of a subgroup analysis presented at the 2022 ASCO Annual Meeting further demonstrated improved PFS in all patients with CSR1 mutations that had not received prior chemotherapy.2 In this population, the rate of PFS at 12 months was 31.48% (95% CI, 19.34%-43.61%) with elacestrant versus 12.36% (95% CI, 2, 39%-22.32%) with SOC.

In June 2022, a new drug application has been submitted to the FDA seeking approval of elacestrant for 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 EMERALD results into practice, we need to select patients,” Bidard said. “One way to do this is to select those who have had no previous chemotherapy, as advised by ASCO, or to select patients based on the presence of CSR1 mutations, as suggested by subgroup analysis.

Bidard, professor of medicine in the Department of Medical Oncology and co-coordinator of breast cancer research at Institut Curie & UVSQ/Paris-Saclay University, explained the reasons and results of the EMERALD study in a interview with Live®. In the interview, he highlighted the benefits of elacestrant in chemotherapy naïve patients and in those who have CSR1 mutations, explained the results of a subgroup analysis performed in patients without prior chemotherapy, and expressed his hopes for the future regarding other oral SERDs in development.

Live®: Could you provide general information about elacestrant? What makes it unique compared to other options available or being evaluated for patients with estrogen receptor (ER) positive and HER2 negative advanced breast cancer?

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

Elacestrant has the advantage of the oral route [administration]. It is administered at a dose of 400 mg once a day, and daily intake is much easier for patients. The EMERALD trial asked whether elacestrant might be more effective than SOC hormone therapy in the setting of patients with ER-positive, HER2-negative metastatic breast cancer that progressed with prior CDK4 inhibitors /6.

What data had been observed with elacestrant before the EMERALD study?

Prior to [EMERALD], we mainly had phase 1 data from an expansion cohort, which showed that elacestrant was well tolerated. Also, in a non-randomized way, we observed that some patients could [achieve a] Long PFS when receiving elacestrant monotherapy, despite having received many previous treatments. [For these reasons, we thought] elacestrant would be an effective drug in the context of metastatic endocrino-sensitive breast cancer.

What were the main objectives of the phase 3 trial?

The main objective of EMERALD was to compare PFS between the 2 arms of the study. [In 1 arm, patients] received elacestrant, and in the other arm, patients received SOC hormone therapy. Although the primary objective was PFS in the general population, the primary endpoint was to study the efficacy of elacestrant in the subgroup of patients with CSR1 mutations detected before the start of treatment.

Could you tell us more about the study design and the patient population that was recruited?

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

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

What were the main efficacy results of this trial, which have now been published in the Journal of Clinical Oncology?

Elacestrant has been shown to be more effective than hormone therapy monotherapy when given as 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 CSR1 mutations, the benefit was even greater, with a hazard ratio of 0.55, clearly showing the superiority of elacestrant over hormone therapy as monotherapy.

What do the results of the subgroup analysis from the EMERALD trial, which were presented at 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 outcomes of patients who were randomized to [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 CSR1 mutations. In patients with CSR1 mutations [who had] no prior line of chemotherapy, elacestrant monotherapy was able to achieve a median PFS of 5.32 months whereas SOC hormone therapy led to a [median] PFS of 1.91 months. [These findings show] a huge difference in favor of using elacestrant as monotherapy after progression on CDK4/6 inhibitors and as part of CSR1 mutations.

What are the next steps in 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 essential in the current management of [patients with] ER-positive, HER2-negative metastatic breast cancer. Elacestrant monotherapy is superior to hormone therapy monotherapy, but we know that combinations are even better. The company that develops elacestrant might also consider moving it to early stages of breast cancer in patients with non-metastatic breast cancer.

What does this treatment paradigm data mean for patients with metastatic, HR-positive, HER2-negative breast cancer?

Elacestrant is better than current endocrine agents, which is good news for all oral SERDs in development; [these data] show that it is possible for a new agent to be superior to older agents. Moreover, the PFS obtained 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 elacestrant monotherapy.

References

  1. Bidard, FC, Kaklamani VG, Neven P, et al. Elacestrant (Selective Oral Estrogen Receptor Degrader) Versus Standard Hormone 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 Without Prior Chemotherapy in EMERALD: A Phase 3 Trial Evaluating the Oral Selective Estrogen Receptor Degrader (SERD) Elacestrant Versus Investigator’s Choice of Endocrine Monotherapy for ER+/HER2- advanced/metastatic (mBC) breast cancer. J Clin Oncol. 2022;40(supplement 16):1100. doi:10.1200/JCO.2022.40.16_suppl.1100
  3. Menarini Group and Radius Health submit New Drug Application to US FDA for elacestrant. Press release. The Menarini Group and Radius Health, Inc. June 22, 2022. Accessed July 13, 2022. https://bit.ly/3bplt3F

Martin E. Berry