Novel Drug Has Potential to ‘Become New Standard of Care’ in Advanced, ER-Positive Breast Cancer

Data from the phase 3 EMERALD trial (NCT03778931) demonstrated that treatment with elacestrant (RAD1901) was associated with a significant improvement in progression-free survival in previously CDK4/6 inhibitor-treated patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer.

The study results — which were presented during the 2021 San Antonio Breast Cancer Symposium — indicated that elacestrant, a selective estrogen receptor degrader (SERD), led to a 30% reduction in the risk of disease progression or death compared with standard of care in the study population.

“Elacestrant is the first oral SERD that has demonstrated a statistically significant and clinically meaningful improvement in (progression-free survival) versus 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 Dr. Aditya Bardia, director of breast cancer research and medical oncology at Massachusetts General Hospital Cancer Center in Boston, said during 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 Faslodex (fulvestrant), is linked with an average progression-free survival (time during and after treatment when the patient lives without disease progression) of approximately two 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.

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 milligrams daily (239 patients) or investigator’s choice of standard of care with Faslodex, anastrozole, letrozole, or exemestane (238 patients). Enrolled patients must have experienced disease progression or relapse on or after one or two lines of endocrine therapy for advanced disease, one of which was administered in combination with a CDK4/6 inhibitor and had one or fewer lines of chemotherapy for advanced disease.

Patients received treatment until their disease progressed or they withdrew from the study.

Measuring progression-free survival among the overall patient population, as well as in those whose disease harbored ESR1 mutations, served as the main goal of the study. Additionally, the study authors aimed to evaluate the overall survival of the study population.

Data showed that the median progression-free survival was 2.79 months and 1.91 months with elacestrant and standard therapy, respectively.

In a subgroup of patients with ESR1 mutations, elacestrant was linked with a median progression-free survival of 3.78 months compared with 1.87 months with standard therapy, leading to a 45% reduction in the risk of disease progression or death in this patient subgroup.

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

Additional data showed that in all patients, the six-month progression-free survival rate was 34.3% with elacestrant and 20.4% with standard of care. At 12 months, the progression-free survival rate was 22.32% and 9.42%, respectively.

In patients with ESR1-mutant disease, treatment with study drug induced a six-month progression-free survival rate of 40.8% versus 19.1% with standard of care. Moreover, the 12-month progression-free survival rate was also higher in the group that received elacestrant.

At an interim analysis, the median overall survival was not calculated in either treatment group but appears to have favored elacestrant in both patient populations.

“While no statistically significant differences were noted … in (overall survival), 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.

In terms of safety, the most common treatment-emergent side effects of any severity with elacestrant and standard of care included nausea (25.3% vs. 18.8%, respectively), fatigue (19% vs. 18.8%), vomiting (19% vs. 8.3%), decreased appetite (14.8% vs 9.2%) and joint pain (14.3% vs. 16.2%). The more serious and severe treatment-emergent side effects included nausea (2.5% vs 0.9%, respectively), back pain (2.5% vs 0.4%) and increased alanine aminotransferase (2.1% vs 0.4%). There were no treatment-related deaths in either group.

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

She noted that additional studies are currently evaluating elacestrant in combination with targeted therapies, including CDK4/6 and mammalian target of rapamycin inhibitors, in earlier lines of treatment 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 concluded.

Dr. Carlos Arteaga, director of the Simmons Comprehensive Cancer Center and Lisa K. Simmons Distinguished Chair in Comprehensive Oncology at UT Southwestern Medical Center, commented on the significance of 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.

A version of this article was originally published on OncLive as, “Elacestrant Significantly Improves PFS in Advanced ER+ Breast Cancer, Including ESR1-Mutant Subtype.”

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