Elacestrant was found to result in a statistically significant and clinically meaningful improvement in progression-free survival over standard-of-care treatment in patients with estrogen receptor–positive, HER2-negative metastatic breast cancer who previously received CDK4/6 inhibitors.
Elacestrant (RAD-1901) was found to result in a statistically significant and clinically meaningful improvement in progression-free survival (PFS) over standard-of-care treatment in patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer who previously received CDK4/6 inhibitors, according to data presented during the 39th Annual Miami Breast Cancer Conference.1
Results come from the phase 3 EMERALD study (NCT03778931) which examined the safety and efficacy of the oral selective estrogen receptor degrader versus the standard of care (SOC) for the treatment of patients with ER-positive, HER2-negative metastatic breast cancer in the second-/third-line, post-CDK4/6 inhibitor setting.2
While endocrine therapy plus CDK4/6i is the main first-line therapy used to manage patients with ER-positive, HER2-negative metastatic breast cancer, most of these patients eventually experience disease progression due to therapeutic resistance, including the development of ESR1 mutations.
The use of sequential endocrine therapy before chemotherapy is recommended in treatment guidelines when there is an absence of visceral crisis or until all endocrine therapy options have run out. Standard single-agent endocrine therapies including fulvestrant (Faslodex) are associated with poor median PFS at 2 months in second-/third-line setting post-CDK 4/6i, making the clinical need for better endocrine therapy for these patients very apparent.
Thus, the multicenter, randomized, open-label trial, EMERALD, was created. The study enrolled 466 participants consisting of both men and postmenopausal women with advanced or metastatic ER+/HER2- breast cancer. These subjects must have progressed or relapsed on or after 1 or 2 lines of endocrine therapy for advanced disease, had an ECOG score of 0 or 1, and had visceral metastasis which included lung, liver, brain, pleural and peritoneal involvement.
Subjects within the first arm received elacestrant orally at 400 mg a day while those in arm 2 received the investigators choice of one of the SOC drugs including fulvestrant, anastrozole, letrozole (Femara), or exemestane (Aromasin). Fulvestrant was administered at 500 mg intramuscularly (IM) into the buttocks as two 5 mL injections on C1D1, C1D15 and C2D1 and day 1 of every subsequent 28-day cycle, anastrozole at 1 mg a day on a continuous dosing schedule, Letrozole at 2.5 mg a day on a continuous dosing schedule, or exemestane at 25 mg a day on a continuous dosing schedule.
Primary outcomes consisted of PFS in all patients as well as in ESR1-mutated subjects with a time frame from the date of randomization until disease progression or death up to 12 months after. The secondary outcome was overall survival (OS).
The study was designed with ≥ 90% power to evaluate a PFS hazard ratio (HR) of 0.667 in all patients and ≥80% power for a PFS HR of 0.610 in the ESR1-mutant subset. The OS analysis at the final PFS analysis allocated a 2-sided alpha level of 0.0001.
Findings revealed there to be a 30% reduction in the risk of progression or death within the patients administered elacestrant compared to those who received the SOC (HR, 0.697; 95% CI: 0.552-0.880; P = .0018). A 45% reduction in the risk of progression or death with elacestrant compared to the SOC in patients with ESR1 mutations (HR, 0.546; 95% CI: 0.387-0.768; P = .0005).
In the overall population, there was an extended median PFS by 2.79 months in the elacestrant arm versus 1.91 months in the SOC arm. In the ESR1 mutation population, an extended median PFS was reported by 3.78 months for those administered elacestrant versus 1.87 months for SOC.
Additionally, higher PFS rates were observed at 6 months (34.3% versus 20.4%) and 12 months (22.3% vs 9.4%) with elacestrant versus the SOC, endocrine therapy group. Results of elacestrant versus fulvestrant were also found to be consistent. Ultimately, both primary end points of the trial were met and found to be statistically significant in favor of the elacestrant arm.
No statistically significant differences were reported in regard to OS, but an evident trend which favored elacestrant over SOC was shown in both groups. A final OS analysis with updated data is expected to come out between late 2022 and early 2023.
In regard to safety, elacestrant was shown to be well tolerated and have an encouraging safety profile. Treatment-related adverse events (TRAEs) led to discontinuation in both elacestrant and SOC arms (3.4% and 0.9%). Of the 237 patients in the elacestrant arm, grade 3 and higher TRAEs were reported in 7.2% compared to 3.1% for the SOC (n = 229).
Some grade 3/4 and higher treatment-emergent adverse events (TEAEs) for elacestrant included back pain (2.5%), nausea (2.5%), fatigue (0.8%), vomiting (0.8%), decreased appetite (0.8%), and arthralgia (0.8%).
Comparatively, the SOC arm reported TEAEs grade 3/4 and higher to be nausea (0.9%), fatigue (0.9%), decreased appetite (0.4%), and back pain (0.4%). Other TEAEs reported include diarrhea (0.9%) and aspartate aminotransferase increased (0.9%).
Elacestrant is shown to have the potential to become a new treatment option in the studied patient population. Other elacestrant combinations in earlier lines and with other targeted therapies, including CDK4/6 and mTOR inhibitors, are ongoing/planned for patients with ER+/HER2- breast cancer.