Elacestrant improves outcomes in patients with ER+/HER2- metastatic breast cancer progressing on prior endocrine therapy

Elacestrant is the first oral selective oestrogen receptor degrader to demonstrate a clinical benefit over standard of care endocrine therapy in a phase III clinical trial for postmenopausal patients with ER⁺/HER2^- metastatic breast cancer that progressed on prior endocrine therapy. In the EMERALD study, presented at SABCS 2021, elacestrant significantly improved the progression-free survival compared to standard of care endocrine therapy, both in the overall and ESR1 mutated population.

Endocrine therapy plus a CDK4/6 inhibitor is the mainstay for the management of oestrogen receptor-positive (ER⁺)/HER2-negative (HER2^-) metastatic breast cancer (mBC) as first-line therapy. However, most patients with ER⁺ mBC eventually experience disease progression, including development of ESR1 mutations. In the post-CDK4/6 inhibitor setting, standard single-arm endocrine therapy (such as fulvestrant) is associated with a median progression-free survival (PFS) of approximately two months, highlighting the clinical need for better endocrine therapy for patients with ER⁺/HER2^- mBC. Elacestrant is an oral selective oestrogen receptor degrader (SERD) that blocks ER in a dose-dependent manner and has demonstrated clinical activity in a phase I clinical trial for postmenopausal women with ER⁺/HER2^- mBC.

EMERALD study design

The phase III EMERALD trial enrolled 477 postmenopausal patients with ER⁺/HER2-negative advanced or metastatic breast cancer who received one or two prior lines of endocrine therapy without chemotherapy in the metastatic setting, and who progressed on prior treatment with a CDK4/6 inhibitor. Patients were randomly assigned (1:1) to receive elacestrant (400 mg daily) or standard of care (SOC; investigator’s choice of fulvestrant, anastrozole, letrozole or exemestane). Among the enrolled patients, 228 had tumours with mutated ESR1 (115 in the elacestrant arm and 113 in the SOC arm).

Results

Patients in the elacestrant arm had a median PFS of 2.79 months, as compared to 1.91 months in the SOC arm, translating into a 30% lower risk of disease progression or death (HR[95%CI]: 0.697[0.552-0.880], p=0.0018). The PFS rate at 12 months was 22.3% for patients treated with elacestrant and 9.4% for patients in the SOC arm. Interestingly, elacestrant was also associated with a 45% reduction in the risk of disease progression or death in patients harbouring ESR1 mutations (median PFS 3.78 vs. 1.87 months, HR[95%CI]: 0.546[0.387-0.768], p=0.0005). Moreover, PFS rate at 12 months was in favour of elacestrant (26.8% vs. 8.2%). Subgroup analyses demonstrated that the benefit of elacestrant was consistent among all pre-specified subgroups, including the presence of visceral metastases, the number of prior lines of therapy, pre-treatment with fulvestrant, or geographic region. While no statistically significant differences were noted at the α=0.0001 level in overall survival, an interim analysis demonstrated a clear trend favouring elacestrant in both the intention-to-treat (HR=0.751; p=0.0821) and ESR1 mutated group (HR=0.592, p=0.0325). The final overall survival analysis is expected to take place late 2022 or early 2023.

The most common side effect with elacestrant was nausea (all grade 35.0% compared to 18.8% in the SOC arm). Besides this, there were no major differences in treatment-emergent adverse events between elacestrant and SOC endocrine therapy.

Conclusion

Elacestrant is the first oral SERD that demonstrated a statistically significant and clinically meaningful improvement in PFS compared to SOC endocrine therapy in a randomised global phase III study in patients with ER⁺/HER2^- mBC in the second- and third-line post-CDK4/5 inhibitor setting. Elacestrant was well tolerated with a predictable and manageable safety profile, consistent with other endocrine therapies. Therefore, elacestrant has the potential to become the new standard of care in this patient population.

Reference

Bardia A, et al. Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2-advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial. Presented at SABCS 2021; abstract GS2-02.