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A significant improvement in progression-free survival has been reported with the oral selective estrogen receptor degrader elacestrant vs standard of care treatments for patients with estrogen receptor–positive, HER2-negative breast cancer.
A significant improvement in progression-free survival (PFS) has been reported with the oral selective estrogen receptor degrader (SERD) elacestrant vs standard of care (SOC) treatments for patients with estrogen receptor (ER)–positive, HER2-negative breast cancer. Data from the phase 3 EMERALD trial (NCT03778931), published in the Journal of Clinical Oncology, also demonstrated a marked benefit among patients with an ESR1 mutation.
PFS was evaluated by blind independent central review (BICR) at a median follow-up of 15.5 months. The risk of progression was reduced by 30% with elacestrant vs SOC (HR, 0.70; 95% CI, 0.55-0.88; P = .0018). In a landmark analysis investigators reported the 6-month PFS rate with elacestrant (n = 239) was 34.5% (95% CI, 27.2%-41.5%) vs 20.4% (95% CI, 14.1%-26.7%) with SOC (n = 238). The 12-month PFS rates were 22.3% (95% CI, 15.2%-29.4%) vs 9.4% (95% CI, 4.0%-14.8%), respectively.
At baseline 228 patients had detectable ESR1 mutations; 115 were randomly assigned to the elacestrant arm and 113 to the SOC arm. The hazard ratio was 0.55 (95% CI, 0.39-0.77; P = .0005) favoring the elacestrant. The 6-month PFS rate was 40.8% (95% CI, 30.1%-51.4%) with the oral SERD vs 19.1% (95% CI, 10.5%-27.8%) with SOC. The 12-month PFS rates were 26.8% (95% CI, 16.2%-37.4%) vs 8.2% (95% CI, 1.3%-15.1%), respectively.
“These data represent a long-awaited opportunity to potentially offer second- or third-line, including heavily pretreated patients with breast cancer a new effective option and further advance toward precision medicine in the ER-positive/HER2-negative subtype,” the study authors wrote of the findings.
The EMERALD trial evaluated elacestrant at 400 mg daily vs investigator’s choice SOC of fulvestrant, anastrozole, letrozole, or exemestanse monotherapy. All patients enrolled were required to have prior treatment with a CDK4/6 inhibitor. Baseline patient characteristics were well-balanced in the overall population. The median age was 63 years (range, 24-89) in the elacestrant arm and 64 years (range, 32-83) in the SOC arm. A majority of patients had visceral metastases (68.2% and 71%, respectively), prior adjuvant therapy (66.1% vs 59.2%), and had not received chemotherapy in the advanced or metastatic setting (79.9% vs 75.6%).
Prior endocrine therapies for patients in the elacestrant arm included fulvestrant (29.3%), aromatase inhibitor (80.8%), and tamoxifen (7.9%). In the SOC arm 31.5%, 81.8%, and 6.3% of patients received these therapies, respectively.
Patients were stratified by ESR1 mutational status, visceral metastasis, and prior treatment with fulvestrant.
The efficacy of the oral SERD was maintained in a subgroup analysis of patients in the intention-to-treat population treated with elacestrant (n = 239) vs fulvestrant (n = 165). The hazard ratio was 0.68 (95% CI, 0.52-0.90; P = .0049). The 6-month PFS rate was 34.3% (95% CI, 27.2%-41.5%) vs 22.9% (95% CI, 15.15%-30.57%), respectively, with 12-month PFS rates of 22.3% (95% CI, 15.2%-29.4%) vs 10.2% (95% CI, 3.4%-16.9%). The benefit was among patients with ESR1 mutations with a hazard ratio of 0.50 (95% CI, 0.34-0.74; P = .0005). The 6-month PFS rate was 40.8% (95% CI, 30.1%-51.4%) among the 115 patients who received elacestrant vs 20.8% (95% CI 10.68%-30.83%) among the 83 patients who received fulvestrant. The 12-month PFS rates were 26.8% (95% CI, 16.2%-37.4%) vs 8.4% (95% CI, 0.2%-16.6%).
An interim overall survival (OS) analysis was also reported. The hazard ratio in the intention-to-treat population was 0.75 (95% CI, 0.54-1.04) with a P value of .0821 that was nonsignificant. The 6-month OS rate for patients who received elacestrant was 93.0% (95% CI, 89.7%-96.3%) compared with 85.2% (95% CI, 80.5%-90.0%) with SOC. The 12-month OS rates were 79.3% (95% CI, 73.8%-84.7%) vs 73.3% (95% CI, 67.2%-79.4%), respectively.
Among those with ESR1-mutant disease the 6-month and 12-month OS rates for patients randomly assigned to elacestrant were 92.8% (95% CI, 88.0%-97.6%) and 82.6% (95% CI, 75.3%-90.0%), respectively. For patients who received SOC these rates were 84.4% (95% CI, 77.3%-91.4%) and 73.6% (95% CI, 64.8%-82.4%), respectively. The hazard ratio favored elacestrant with a P value investigators deemed nonsignificant (HR, 0.59; 95% CI, 0.36-0.96; P = 0.325). Investigators noted that final OS results will be reported when data are mature.
In a discussion of the data investigators noted that median PFS in the overall population and the ESR1-mutant population may not be sufficient to reflect the clinical benefit of elacestrant due to an initial drop in PFS observed in both arms. “It is important to evaluate efficacy over longer periods of time using the hazard ratio and landmark analyses at 6 and 12 months in [patients with ER-positive/HER2-negative advanced breast cancer],” the study authors wrote. “The [hazard ratios] reflect a 30% relative reduction in progression or death in the overall cohort and a 45% relative reduction in the ESR1-mutant cohort. The landmark analyses at 6 and 12 months demonstrated substantial improvements in PFS at these later time points with elacestrant. We consider these differences to be clinically meaningful in patients with limited treatment options.”
In the safety analysis the investigators noted elacestrant had a manageable toxicity profile, noting that the agent offers an oral alternative to patients over intramuscular fulvestrant injection. In the intention-to-treat population, the most common all-grade adverse effects (AEs) observed with elacestrant included nausea (35.0%), fatigue (19.0%), vomiting (19.0%), decreased appetite (14.8%), and arthralgia (14.3%). The most common grade 3/4 AEs were nausea (2.5%) and back pain (2.5%). In the SOC arm, the most common all-grade AEs were nausea (18.8%), fatigue (18.8%), and arthralgia (16.2%). Two patients experienced grade 3/4 nausea, both cases were attributed to treatment with an aromatase inhibitor, and 2 patients had grade 3/4 fatigue, one attributed to treatment with fulvestrant and one attributed to an aromatase inhibitor.
Discontinuation rates were comparable between treatment arms: 15 patients (6.3%) in the elacestrant arm and 10 patients (4.4%) in the SOC arm. No deaths were attributed to either treatment arm. Investigator reported that events reported in 150 patients the elacestrant arm and 100 patients in the SOC therapy arm were treatment-related events.
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