Improved PFS Outcomes With Elacestrant Correlate With CDK4/6 Duration in ER+/HER2– Metastatic Breast Cancer

Virginia Kaklamani, MD

Longer duration of CDK4/6 inhibitor prior to treatment with elacestrant correlated with progression-free survival (PFS) improvements in patients with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer vs standard-of-care options. The analysis of the phase 3 EMERALD study (NCT03778931) were presented at the 2022 San Antonio Breast Cancer Symposium.

Of note, improvements in PFS were pronounced in patients with ESR1-mutant disease who received the oral selective estrogen receptor degrader (SERD) elacestrant vs SOC endocrine therapy.¹

Results showed that patients who received elacestrant at least 12 months of CDK4/6 inhibition (n = 150) had a median PFS of 3.78 months vs 1.91 months for those who received standard-of-care (SOC) hormonal therapy (n = 160; HR, 0.613; 95% CI, 0.453-0.828). The 6-, 12-, and 18-month PFS rates were 41.56%, 25.64%, and 19.34% with elacestrant vs 21.72%, 7.38%, and 3.69% with SOC.¹

Following at least 12 months of CDK4/6 inhibitor treatment patients with ESR1-mutant tumors had a median PFS was 8.61 months with elacestrant (n = 78) vs 1.91 months with SOC (n = 81) for a 59% reduction in the risk of progression or death (HR, 0.410; 95% CI, 0.262-0.634). The 6-, 12-, and 18-month PFS rates were 55.81%, 35.81%, and 28.49% with elacestrant vs 22.66%, 8.39%, and 0% with SOC. ¹

“Most of the benefit is in the ESR1-mutated tumors,” Virginia Kaklamani, MD, professor of medicine in the Division of Hematology/Oncology at The University of Texas Health San Antonio and leader of the Breast Cancer Program at UT Health San Antonio MD Anderson Cancer Center said in a presentation of this data. “ESR1 mutation status will be important.”

The updated EMERALD analysis assessed PFS outcomes after at least 6, 12, and 18 months of CDK4/6 inhibition. EMERALD trial postmenopausal women and men from 17 different countries with advanced or metastatic ER-positive, HER-negative breast cancer. Patients were randomly assigned to receive 400 mg of elacestrant daily or SOC endocrine therapy of either fulvestrant (Faslodex), anastrozole (Arimidex), letrozole (Femara), or exemestane (Aromasin).

The elacestrant arm had 239 patients, 115 of whom had an ESR1-mutant tumor and the SOC arm had 239 patients, 113 of whom had an ESR1 -mutant tumor. The median age was 63 years (range, 24-89). In terms of prior therapy, 46% of patients in the elacestrant arm received 2 prior lines of therapy and 40.6% of patients in the SOC arm. Prior treatment with fulvestrant was reported in 29.3% and 31.4% of patients in the elacestrant and SOC arms, respectively, with prior chemotherapy reported among 20.1% and 24.7% of patients.¹

For patients who had at least 6 months of prior CDK4/6 inhibition (87.5% of the population), the median PFS for those in the elacestrant arm (n = 202) was 2.79 months vs 1.91 months in the SOC arm (n = 205; HR, 0.688; 95% CI, 0.535-0.884). The PFS rates at 6, 12, and 18 months for those who received elacestrant vs SOC were 34.40% vs 19.88%, 21.0% vs 6.42%, and 16.24% vs 3.21%, respectively.

In the ESR1-mutant cohort, the median PFS for those who received CDK4/6 inhibition for at least 6 months was 4.14 months vs 1.87 months among patients who received elacestrant (n = 103) and SOC (n = 102), respectively (HR, 0.517; 95% CI, 0.361-0.738). The PFS rates for patients who received elacestrant vs SOC at 6, 12, and 18 months were 42.43% vs 19.15%, 26.02% vs 6.45%, and 20.70% vs 0%, respectively.¹

Among patients who received CDK4/6 inhibition for at least 18 months in the overall cohort, the HR for disease progression or death for elacestrant vs SOC was 0.703 (95% CI, 0.482-1.019). The median PFS was 5.45 vs 3.29 months, respectively. The PFS rates at 6, 12, and 18 months were 44.72% vs 25.15%, 26.70% vs 8.23%, and 21.03% vs 4.11%, for elacestrant vs SOC, respectively.

Fifty percent of patients with ESR1-mutant tumors received CDK4/6 inhibition for at least 18 months. The median PFS was 8.61 months vs 2.10 months for those who received elacestrant (n = 55) vs SOC (n = 56; HR, 0.466; 95% CI, 0.270-0.791). The PFS rates at 6, 12, and 18 months were 58.57% vs 27.06%, 35.79% vs 7.73%, and 30.68% vs 0%, for elacestrant vs SOC, respectively.¹

An analysis of patients who received less than 6 months of CDK4/6 inhibition showed that those with ESR1-mutant disease has similar outcomes with elacestrant (n = 9) vs those who received SOC (n = 8; HR, 1.565; 95% CI, 0.424-5.769). The median PFS in both arms was 1.89 months. In the general population, the median PFS with elacestrant (n = 29) was 3.55 months vs 1.87 months with elacestrant (n = 29; HR, 0.709; 95% CI, 0.347-1.405).¹

Observed adverse effects (AEs) were consistent with previously reported findings from the EMERALD trial.² The most common grade 1/2 AE was nausea, with grade 3 nausea reported in 6 and 2 patients in the elacestrant and SOC arms, respectively. Three patients discontinued elacestrant due to nausea. No grade 4 treatment-emergent AEs were reported. Treatment discontinuation was reported among 3.4% of patients receiving elacestrant vs 0.9% of patients receiving SOC. No deaths were reported due to treatment in either arm.¹

Antiemetic use was reported among 8% of patients receiving elacestrant and among 10.3% of patients in the SOC arm who received an aromatase inhibitor and 1.3% of patients who received fulvestrant. Investigators noted that there was no incidence of bradycardia.¹

Kaklamani said these data show that elacestrant can become an important oral endocrine monotherapy agent in the second- and third-line setting. “If you look at the outcomes, not just in this trial but of others in patients whose CDK4/6 [inhibitor therapy] is less than 6 months, it gives you the idea that there are resistant tumors [and patients] need to move on to either chemotherapy or potentially combination endocrine therapy, but those treatments are toxic to our patients. Hopefully, [with this trial] we’ll have options for those patients,” she concluded.

References

1. Bardia A, Bidard FC, Neven P, et al. EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: updated results by duration of prior CDK4/6i in metastatic setting. Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.
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