Elacestrant Treatment Achieves Significant PFS Improvement in Advanced ER+ Breast Cancer With or Without ESR1 Mutations

Aditya Bardia, MD, MPH

In patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer who previously received CDK4/6 inhibition, elacestrant (RAD1901), a selective estrogen receptor degrader (SERD), achieved a 30% reduction in the risk of disease progression or death compared with standard of care (SOC) in the phase 3 EMERALD trial (NCT03778931).¹

Data presented in a press briefing ahead of the 2021 San Antonio Breast Cancer Symposium showed that the median progression-free survival (PFS) by independent review was 2.79 and 1.91 months with elacestrant and standard therapy, respectively, in the intent-to-treat population (HR, 0.697; 95% CI, 0.552-0.880; P = .0018).

In a subgroup of patients with ESR1 mutations, elacestrant was linked with a median PFS of 3.78 months vs 1.87 months with standard therapy, leading to a 45% reduction in the risk of disease progression or death in this subgroup (HR, 0.546; 95% CI, 0.387-0.768; P = .0005).

“Elacestrant is the first oral SERD that has demonstrated a statistically significant and clinically meaningful improvement in PFS vs standard-of-care endocrine therapy in a randomized global phase 3 study in men and postmenopausal women with ER-positive, HER2-negative metastatic breast cancer in the second-/third-line, post-CDK4/6 inhibitor setting,” lead study author Aditya Bardia, MD, MPH, director of breast cancer research and medical oncology, and attending physician at Massachusetts General Hospital Cancer Center, as well as associate professor at Harvard Medical School, said in a virtual press briefing ahead of the conference.

Endocrine therapy plus a CDK4/6 inhibitor is standard frontline treatment for patients with ER-positive, HER2-negative metastatic breast cancer. However, most patients experience disease progression, which include acquired mutations in ESR1.

Additionally, following CDK4/6 inhibitor, single-agent endocrine therapy, such as fulvestrant (Faslodex), is linked with a median PFS of approximately 2 months, emphasizing the unmet need for this patient population.

Elacestrant is an oral SERD that blocks ER in a dose-dependent manner that has previously shown clinical activity in postmenopausal women with ER-positive, HER2-negative metastatic breast cancer.^2,3

In the phase 3 EMERALD trial, investigators randomized 477 men and postmenopausal women with advanced or metastatic ER-positive, HER2-negative breast cancer to receive elacestrant at 400 mg daily (n = 239) or investigator’s choice of SOC with fulvestrant, anastrozole, letrozole, or exemestane (n = 238). Patients must have progressed or relapsed on or after 1 or 2 lines of endocrine therapy for advanced disease, one of which was given in combination with a CDK4/6 inhibitor, had 1 or fewer lines of chemotherapy for advanced disease, and had an ECOG performance status of 0 or 1.

Treatment was given until progressive disease or withdrawal.

The co-primary end points were PFS in the overall population, and in those with ESR1 mutations. Overall survival (OS) was a secondary end point.

Patients were stratified by ESR1-mutation status, prior fulvestrant, and visceral metastases.

A total 91.6% of patients discontinued elacestrant compared with 93.7% of those who discontinued standard of care. Most patients discontinued due to elacestrant due to disease progression per investigator (84.5%), adverse event (AE; 2.1%), withdrawal of consent (2.5%), or investigator’s decision (2.5%).

Additional data showed that in all patients, the 6-month PFS rate was 34.3% (95% CI, 27.2%-41.5%) with elacestrant and 20.4% (95% CI, 14.1%-20.7%) with SOC. At 12 months, the PFS rate was 22.32% (95% CI, 15.24%-29.40%) and 9.42% (95% CI, 4.02%-14.81%), respectively.

In patients with ESR1-mutant disease, the 6-month PFS rate with elacestrant was 40.8% (95% CI, 30.1%-51.4%) and 19.1% (95% CI, 14.1%-26.7%) with SOC. The 12-month PFS rates were 26.76% (95% CI, 16.17%-37.36%) and 8.2% (95% CI, 1.26%-15.12%), respectively.

The PFS benefit with elacestrant was also observed across most prespecified subgroups, including those who had prior fulvestrant (HR, 0.679; 95% CI, 0.438-1.029) and visceral metastasis (HR, 0.665; 95% CI, 0.607-0.869). However, those of Asian (HR, 1.091; 95% CI, 0.456-2.642) and Other race (HR, 1.075; 95% CI, 0.309-3.580) performed better on standard treatment.

At an interim analysis, the median OS was not calculated in either arm, but favored elacestrant in both the ITT (HR, 0.751; 95% CI, 0.542-1.038; P = .0821) and ESR1-mutant (HR, 0.592; 95% CI, 0.361-0.958; P = .0325) population.

“While no statistically significant differences were noted […] in OS, an evident trend favoring elacestrant was noted in both groups,” Bardia said, adding that the final analysis is expected to take place in late 2022 or early 2023.

Regarding safety, the most common all-grade treatment-emergent AEs (TEAEs) with elacestrant and SOC included nausea (25.3% vs 18.8%, respectively), fatigue (19.0% vs 18.8%), vomiting (19.0% vs 8.3%), decreased appetite (14.8% vs 9.2%), and arthralgia (14.3% vs 16.2%). Grade 3/4 TEAEs included nausea (2.5% vs 0.9%, respectively), back pain (2.5% vs 0.4%), increased alanine aminotransferase (2.1% vs 0.4%). No treatment-related deaths occurred in either arm.

“Elacestrant was well tolerated with a predictable and manageable safety profile consistent with other endocrine therapies,” Bardia explained.

Bardia concluded that elacestrant in combination with targeted therapies, including CDK4/6 and mTOR inhibitors, are being studied in earlier lines of treatment in ongoing trials of patients with ER-positive, HER2-negative breast cancer.

“Clinically, elacestrant has the potential to become the new standard of care in the studied patient population,” Bardia said.

Carlos Arteaga, MD, FAACR, director of the Simmons Comprehensive Cancer Center and Lisa K. Simmons Distinguished Chair in Comprehensive Oncology at UT Southwestern Medical Center, commented on the findings during the press briefing.

“The results clearly suggest that this new SERD may be a new treatment option for patients with breast cancer, not only as a single therapy, but also in combination with other targeted therapies,” Arteaga said.

_References

_{1. Bardia A. Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2-advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-02.}

_{2. Bihani T, Patel HK, Arkt H, et al. Elacestrant (RAD1901), a selective estrogen receptor degrader (SERD), has antitumor activity in multiple er+ breast cancer patient-derived xenograft models. Clin Cancer Res. 2017;23(16):4793-4804. doi:10.1158/1078-0432.CCR-16-2561}

_{3. Bardia A, Kaklamani V, Wilks S, et al. Phase I study of elacestrant (RAD1901), a novel selective estrogen receptor degrader, in ER-Positive, HER2-negative advanced breast cancer.J Clin Oncol. 2021;39(12):1360-1370. doi:10.1200/JCO.20.02272}