Elacestrant Improves PFS Irrespective of ESR1 VAF Level in ER+/HER2-Negative Breast Cancer

Elacestrant (Orserdu) prolonged progression-free survival (PFS) vs standard of care (SOC) therapy with an aromatase inhibitor or fulvestrant (Faslodex) in patients with pretreated, estrogen receptor (ER)–positive, HER2-negative advanced or metastatic breast cancer, regardless of the level of ESR1 variant allele fraction (VAF), according to a post hoc subgroup analysis from the phase 3 EMERALD trial (NCT03778931) presented at the 42nd Annual Miami Breast Cancer Conference.1

Among patients with a high VAF, the median PFS was 9.13 months (95% CI, 2.20-24.25) with elacestrant (n = 35) vs 1.91 months (95% CI, 1.84-3.71) with SOC (n = 44; HR, 0.364; 95% CI, 0.185-0.690). Among patients with a low VAF, the median PFS with elacestrant (n = 42) and SOC (n = 37) was 8.61 months (95% CI, 5.49-10.84) vs 1.87 months (95% CI, 1.87-3.75), respectively (HR, 0.509; 95% CI, 0.259-0.990).

Additionally, the level of VAF did not affect the PFS benefit seen with elacestrant, with median values of 9.13 months in those with high levels vs 8.61 months in those with low levels (HR, 0.84; 95% CI, 0.43-1.67; P =.6).

“In patients with longer prior endocrine therapy and CDK4/6 inhibition, both ESR1 and PIK3CA mutations are known to be drivers of cancer growth, but even at a low VAF, ESR1 mutations become clinically significant, Aditya Bardia, MD, MPH, FASCO, lead study author and professor in the Department of Medicine, Division of Hematology/Oncology at UCLA Health’s Jonsson Comprehensive Cancer Center, and coauthors, wrote in the poster. “In the context of ESR1 and PIK3CA mutations, elacestrant was associated with an improvement in median PFS vs SOC in ER-positive, HER2-negative metastatic breast cancer, regardless of the type of ESR1 mutation variant and the level of VAF.”

Previously, investigators reported a significant improvement in PFS and a manageable safety profile with elacestrant vs SOC endocrine therapy in patients with ER-positive, HER2-negative advanced or metastatic breast cancer who had developed an ESR1 mutation following treatment with endocrine therapy and CDK4/6 inhibition (HR, 0.55; 95% CI, 0.39-0.77; P =.0005).2 Notably,patients who had received prior endocrine therapy and CDK4/6 inhibition for at least 12 months derived even greater benefit with elacestrant (HR, 0.41; 95% CI, 0.26-0.63).3 Moreover, PFS benefit with elacestrant was upheld across ESR1 mutation variants, including D538G, Y537S, and Y537N, which comprise approximately 90% of ESR1-mutated cancers.

Per the trial’s design, patients who had received between 1 and 2 prior lines of endocrine therapy, CDK4/6 inhibition, and no more than 1 line of chemotherapy were randomly assigned to receive oral elacestrant or SOC. The present analysis was performed to better understand how the level of VAF affects clinical benefit with elacestrant.1 As such, investigators evaluated ESR1 in the plasma of patients with endocrine-sensitive tumors, which was defined as those whose prior exposure to endocrine therapy and CDK4/6 inhibition lasted at least 12 months.

Median VAF was 1.2% (95% CI, 0.04%-56.1%). High and low VAF were defined as at least 1.2% and less than 1.2%, respectively, to be consistent with published literature.

Baseline characteristics from the elacestrant arm (n = 78) indicated that the median age was 65.5 years (range, 40-89). All patients were female and were predominantly White (75.6%) with an ECOG performance status of 0 (53.9%). Most patients had fewer than 3 metastatic sites (53.8%), although represented sites include the bone (85.9%), liver and/or the lung (71.8%), or visceral presentations (74.4%). ESR1 mutation variants were D583G (61.5%) and Y537S/N (62.8%). Most patients had a low (53.8%) vs high (44.9%) VAF. Among patients with PIK3CA mutations (34.6%), represented variants were H1047X (12.8%) and E542X/E545X (15.4%).

Additional results from the analysis indicated that the type of ESR1 variant had no effect on PFS benefit with elacestrant. Among patients with the D538G variant, the median PFS was 9.03 months (95% CI, 3.65-16.89) with elacestrant (n = 48) vs 1.87 months (95% CI, 1.87-3.29) with SOC (n = 49; HR, 0.381; 95% CI, 0.212-0.665). Among patients with the Y537S/N variants, the median PFS with elacestrant and SOC was 9.03 months (95% CI, 4.14-10.84) vs 1.87 months (95% CI, 1.81-3.71), respectively (HR, 0.253; 95% CI, 0.132-0.470).

Further findings revealed that PFS benefit with elacestrant was sustained even in the presence of a coaltered PIK3CA-mutated tumor. In this population, the median PFS was 5.45 months (95% CI, 2.14-10.84) with elacestrant (n = 27) vs 1.94 months (95% CI, 1.84-3.94) with SOC (n = 35; HR, 0.423; 95% CI, 0.176-0.941). Notably, 89% of patients in the elacestrant arm and 80% of those in the SOC arm had an ESR1 VAF that was lower than the PIK3CA VAF.

“In patients with ER-positive, HER2-negative metastatic breast cancer who received a longer duration of prior endocrine therapy and CDK4/6 inhibition and with tumors harboring coexisting ESR1 and PIK3CA mutations, elacestrant can be used before PI3K/AKT inhibition, chemotherapy, or antibody-drug conjugate–based regimens,” the authors concluded.

References

1. Bardia A, Cortés J, Clement-Bidard F, et al. Elacestrant vs SOC in ER+, HER2- advanced or metastatic breast cancer (mBC) with ESR1-mutated tumors: ESR1 allelic frequencies and clinical activity from the phase 3 EMERALD trial. Presented at: 42nd Annual Miami Breast Cancer Conference. March 6-9, 2025; Miami, Florida. Poster 27.
2. 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. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338
3. Bardia A, Cortés J, Clement-Bidard F, et al. Elacestrant in ER+, HER2- metastatic breast cancer 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;30(19):4299-4309. doi:10.1158/1078-0432.CCR-24-1073