EMBER-3 (NCT04975308) was a phase 3, randomized, open-label clinical trial that evaluated the effectiveness and safety of imlunestrant, an oral selective estrogen receptor (ER) degrader, in patients with ER-positive, HER2-negative advanced breast cancer. Imlunestrant is a next-generation drug that enters the brain and provides continuous estrogen receptor inhibition, even in cancers with ESR1 mutations.

The trial included men and pre-/post-menopausal women whose cancer had recurred or progressed following treatment with an aromatase inhibitor used alone or in combination with a CDK4/6 inhibitor. Patients were randomly assigned in a 1:1:1 fashion to receive either imlunestrant, standard endocrine therapy (fulvestrant or exemestane), or imlunestrant plus abemaciclib. The primary endpoint was investigator-assessed progression-free survival (PFS) for imlunestrant versus standard of care (SOC) in all and ESR1-mutated patients as well as imlunestrant plus abemaciclib versus imlunestrant alone in all patients.

The trial randomized 874 patients (imlunestrant, n=331; SOC, n=330; imlunestrant plus abemaciclib, n=213). In patients with ESR1 mutations, compared with SOC, imlunestrant statistically significantly increased PFS, resulting in a median PFS of 5.5 months compared with 3.8 months with standard treatment (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.46-0.82; P<.01). However, imlunestrant did not significantly improve PFS in the overall trial population. The combination of imlunestrant and abemaciclib showed a significant improvement in PFS compared with imlunestrant alone in all patients, with a median PFS of 9.4 months versus 5.5 months (n=426; HR 0.57; 95% CI 0.44-0.73; P<.001). This benefit was seen regardless of ESR1 mutation status, PI3K pathway mutation status, or prior CDK4/6 inhibitor treatment. The objective response rate for all patients was 12% for imlunestrant, 8% for standard therapy, and 27% for the combination of imlunestrant and abemaciclib. Overall survival data for all comparisons were not yet mature at the time of analysis; however, trends favored imlunestrant over standard-of-care in patients with ESR1 mutations and in the overall population.

Imlunestrant demonstrated a favorable safety profile, both alone and when combined with abemaciclib. The most common treatment emergent adverse events (TEAEs) associated with imlunestrant were typically mild and included fatigue, diarrhea, and nausea. Importantly, bradycardia, photopsia, and dyslipidemia were infrequent or absent with imlunestrant. The combination of imlunestrant and abemaciclib demonstrated high rates of all-grade TEAEs, yet lower rates of grade ≥3 TEAEs, in terms of diarrhea (86%/8%), nausea (49%/2%), and neutropenia (48%/20%). Discontinuation rates due to adverse events were low for imlunestrant (4%) alone and in combination with abemaciclib (6%).

In conclusion, EMBER-3 demonstrated that imlunestrant significantly improves PFS in patients with ER-positive, HER2-negative advanced breast cancer and ESR1 mutations. Additionally, the combination of imlunestrant and abemaciclib improves PFS regardless of ESR1 mutation status. Imlunestrant has a favorable safety profile and represents a promising all-oral treatment option for patients with advanced breast cancer who have progressed on prior endocrine therapy.