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Outcomes of Elacestrant in ER+/HER2− MBC With ESR1-Mutated Tumors Based on Prior Duration of Endocrine Therapy Plus CDK4/6 Inhibitor and Clinical Subgroups
TAKE-HOME MESSAGE
- The EMERALD trial was a randomized phase III trial of patients with ER+/HER2− metastatic breast cancer who had progressed on CDK4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) who then received the oral selective ER degrader elacestrant versus standard-of-care ET. Significant improvements in progression-free survival were noted with elacestrant among patients with ESR1 mutations. This study was a biomarker and subgroup analysis of the EMERALD trial. Patients with ESR1-mutated tumors who had previously received CDK4/6i plus ET for at least 12 months derived the greatest progression-free survival benefit from elacestrant. Consistent benefits were noted, regardless of the location of metastasis, the presence of PIK3CA or TP53 mutations, or the type of ESR1 mutation.
- A longer duration of exposure to CDK4/6i plus ET is associated with a greater benefit from elacestrant in patients with ESR1 mutations. A longer duration on CDK4/6i suggests endocrine sensitivity; however, better measures of endocrine sensitivity are needed.
abstract
This abstract is available on the publisher's site.
Access this abstract nowPURPOSE
Elacestrant significantly prolonged progression-free survival (PFS) with manageable safety versus standard-of-care (SOC) endocrine therapy (ET) in patients with ER+, HER2- mBC and tumors harboring ESR1 mutation following ET plus a cyclin-dependent kinase 4/6 inhibitor (ET+CDK4/6i). In patients with ESR1-mutated tumors, we evaluated the efficacy and safety of elacestrant versus SOC based on prior ET+CDK4/6i duration, and in clinical subgroups with prior ET+CDK4/6i ≥12 months.
METHODS
EMERALD, an open-label phase III trial, randomized patients with ER+, HER2- mBC, 1-2 prior lines of ET, mandatory CDK4/6i, and ≤1 chemotherapy to elacestrant (345 mg daily) or SOC (aromatase inhibitor or fulvestrant). PFS was assessed across subgroups in post-hoc exploratory analyses without adjustment for multiple testing.
RESULTS
In patients with ESR1-mutated tumors and prior ET+CDK4/6i ≥12 months, median PFS (mPFS) for elacestrant versus SOC was 8.6 versus 1.9 months (HR, 0.41; 95% CI, 0.26-0.63). In this population, mPFS (in months) for elacestrant versus SOC was 9.1 versus 1.9 (bone metastases), 7.3 versus 1.9 (liver and/or lung metastases), 9.0 versus 1.9 (<3 metastatic sites), 10.8 versus 1.8 (≥3 metastatic sites), 5.5 versus 1.9 (PIK3CA mutation), 8.6 versus 1.9 (TP53 mutation), 9.0 versus 1.9 (HER2-low), 9.0 versus 1.9 (ESR1 D538G-mutated tumors), and 9.0 versus 1.9 (ESR1 Y537S/N-mutated tumors). Subgroup safety was consistent with the overall population.
CONCLUSIONS
Duration of prior ET+CDK4/6i ≥12 months in mBC was associated with a clinically meaningful improvement in PFS for elacestrant compared to SOC and was consistent across all subgroups evaluated in patients with ER+, HER2-, ESR1-mutated tumors.
Additional Info
Disclosure statements are available on the authors' profiles:
Elacestrant in ER+, HER2- MBC with ESR1-mutated tumors: Subgroup Analyses from the Phase III EMERALD Trial by Prior Duration of Endocrine Therapy Plus CDK4/6 Inhibitor and in Clinical Subgroups
Clin. Cancer Res 2024 Aug 01;[EPub Ahead of Print], A Bardia, J Cortes, FC Bidard, P Neven, J Garcia-Saenz, P Aftimos, J O'Shaughnessy, J Lu, G Tonini, S Scartoni, A Paoli, M Binaschi, T Wasserman, V KaklamaniFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Treatment options for patients with HR+ metastatic breast cancer are expanding owing to the increasing pace of drug development in this rapidly evolving field. An improved understanding of the genomic drivers of breast cancer has resulted in the development of several new targeted therapies and novel endocrine therapies.
Elacestrant is the first approved oral selective estrogen receptor degrader, and its approval was based on the EMERALD trial. The EMERALD trial was a randomized multicenter trial that enrolled 478 postmenopausal women and men with ER+, HER2-negative advanced or metastatic breast cancer, of whom 228 patients had ESR1 mutations. Patients were required to have disease progression on one or two prior lines of endocrine therapy, including one line containing CDK4/6 inhibitor therapy. Eligible patients could have received up to one prior line of chemotherapy in the advanced or metastatic setting. Patients were randomized (1:1) to receive elacestrant 345 mg orally once daily (n = 239) or the investigator's choice of endocrine therapy (n = 239), which included fulvestrant (n = 166) or an aromatase inhibitor (n = 73). Randomization was stratified by ESR1 mutation status (detected vs not detected), prior treatment with fulvestrant (yes vs no), and visceral metastasis (yes vs no). ESR1 mutational status was determined by blood circulating tumor DNA using the Guardant360 CDx assay.
In 228 patients (48%) with ESR1 mutations, the median progression-free survival (PFS) duration was 3.8 months (95% CI, 2.2–7.3) in the elacestrant arm and 1.9 months (95% CI, 1.9–2.1) in the fulvestrant/aromatase inhibitor arm (HR, 0.55 [95% CI, 0.39– 0.77]; P = .0005). An exploratory analysis of PFS in 250 patients (52%) without ESR1 mutations showed a hazard ratio of 0.86 (95% CI, 0.63–1.19), indicating that the improvement observed in the intention-to-treat population was primarily owing to the outcomes in the ESR1-mutated population. As such, the approval of elacestrant is limited to patients with ESR1-mutated tumors.
Given the small magnitude of benefit observed, additional post hoc subgroup analyses were performed in an attempt to identify clinical and genomic characteristics that may help inform treatment selection. These analyses, as reported by Bardia and colleagues, demonstrated that prior treatment with endocrine therapy plus CDK4/6 inhibitor for ≥12 months was associated with a clinically meaningful improvement in PFS with elacestrant versus standard of care (8.6 vs 1.9 months; HR, 0.41 [95% CI, 0.26–0.63]). Additionally, elacestrant was associated with prolonged PFS compared with standard of care across relevant subgroups, regardless of metastatic site location or number, coexisting PIK3CA or TP53 mutations, HER2-low expression, or ESR1 mutation variant. It is important to note again that these were unplanned post hoc subgroup analyses; however, the information provided is important, as it is relevant to the decisions that physicians must make routinely in the clinic.
These data can help inform patients who may be appropriate to receive elacestrant monotherapy while we await the results of ongoing studies exploring combination strategies, such as the ELEVATE trial. Certainly, personalized decisions must be made between the physician and patient, considering disease burden, mutational status, prior duration of disease control, and patient preference.