The investigational oral selective estrogen receptor degrader (SERD) elacestrant (RAD1901) significantly reduced the risk for death or disease progression and improved progression-free survival (PFS) compared with standard of care (SOC) endocrine therapy in patients with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer who had progressed on previous endocrine and targeted therapies, according to results of the phase 3 EMERALD clinical trial.
The median PFS by independent review was 2.79 months with elacestrant versus 1.91 months with SOC in an intent-to-treat analysis of all study participants (P = .0018).
In a subgroup of patients with ESR1 mutations, treatment with elacestrant resulted in a median PFS of 3.78 months versus 1.87 months with SOC, demonstrating a significant 45% reduction in the risk for disease progression or death (P = .0005).
“Elacestrant is the first oral SERD that has demonstrated a statistically significant and clinically meaningful improvement in PFS versus SOC 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- and third-line, post-CDK4/6 inhibitor setting,” said lead investigator Aditya Bardia, MD, MPH, Attending Physician, Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, and Assistant Professor, Harvard Medical School, Boston, who presented the results at the 2021 San Antonio Breast Cancer Symposium.
Dr Bardia explained that endocrine therapy plus a CDK4/6 inhibitor is standard first-line treatment for ER-positive, HER2-negative metastatic breast cancer. However, many patients experience disease progression, sometimes associated with ESR1-acquired mutations. Treatment with single-agent fulvestrant (Faslodex) after a CDK4/6 inhibitor is associated with a median PFS of approximately 2 months.
“Second- and third-line therapy represent an unmet need for this patient population,” he stated.
Elacestrant, which blocks ER in a dose-dependent manner, has previously shown clinical activity in postmenopausal women with ER-positive, HER2-negative metastatic breast cancer.
Study Details
The EMERALD trial randomized 477 postmenopausal patients with advanced or metastatic ER-positive, HER2-negative breast cancer to elacestrant at 400 mg daily (N = 239) or investigator’s choice of SOC with fulvestrant, anastrozole (Arimidex), letrozole (Femara), or exemestane (Aromasin; N = 238). Patients had to have disease progression or relapse on 1 or 2 lines of endocrine therapy for advanced disease, one of which was given in combination with a CDK4/6 inhibitor; had received ≤1 lines of chemotherapy for advanced disease; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Study treatment was continued until progressive disease or patient withdrawal. Discontinuation rates were similar in both treatment arms; 91.6% in patients treated with elacestrant and 93.7% in those treated with SOC. Most patients discontinued elacestrant due to disease progression (84.5%), adverse events (2.1%), withdrawal of consent (2.5%), or investigator’s decision (2.5%).
The co-primary end points of the study were PFS in the overall population, and in those with ESR1 mutations. Overall survival was a secondary end point. Stratification factors were ESR1-mutation status, previous fulvestrant therapy, and visceral metastases.
Among all patients, the 6-month PFS rates were 34.3% with elacestrant and 20.4% with SOC. The 12-month PFS rates were 22.32% and 9.42%, respectively. In patients with ESR1 mutation–positive disease, the 6-month PFS rates were 40.8% with elacestrant and 19.1% with SOC, and the 12-month PFS rates were 26.76% and 8.19%, respectively.
The PFS benefit with elacestrant was also observed across most prespecified subgroups, including those who had received previous fulvestrant treatment and who had visceral metastasis. Interestingly, SOC was superior to elacestrant in Asians and other racial categories.
The OS data were not yet mature but trended in favor of elacestrant versus SOC in both the overall population and the ESR1 mutation–positive population. Dr Bardia noted that final survival data should be ready in late 2022.
Safety Profile
Elacestrant was well-tolerated with a predictable and manageable safety profile consistent with other endocrine therapies. The most common all-grade treatment-emergent adverse events with elacestrant and SOC included nausea (25.3% vs 18.8%, respectively), fatigue (19.0% vs 18.8%, respectively), vomiting (19.0% vs 8.3%, respectively), decreased appetite (14.8% vs 9.2%, respectively), and arthralgia (14.3% vs 16.2%, respectively). Grade 3/4 treatment-emergent adverse events included nausea (2.5% vs 0.9%, respectively), back pain (2.5% vs 0.4%, respectively), and increased alanine aminotransferase (2.1% vs 0.4%, respectively). No treatment-related deaths were reported in either arm.
Elacestrant in combination with targeted therapies, including CDK4/6 and mTOR inhibitors, is being studied in earlier lines of treatment in ongoing trials of patients with ER-positive, HER2-negative breast cancer.
“Elacestrant has the potential to become the new standard of care in the studied patient population,” Dr Bardia said.