Imlunestrant-based regimens provide clinically meaningful improvements in progression-free survival (PFS), as well as overall survival (OS), in endocrine-pretreated patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC), results of the phase III EMBER-3 trial have shown.
Adding abemaciclib to imlunestrant also enhances the survival benefit to patients regardless of ESR1m status, resulting in one of the longest PFS durations seen in phase III randomized studies in the endocrine therapy (ET)-pretreated setting.
“Importantly, the observed delay in chemotherapy initiation reinforces the value of dual inhibition with an oral selective ER degraders (SERD) and a CDK4/6 inhibitor, delivered in an all-oral regimen with a favourable safety profile,” the investigators said.
Overall, 874 patients with ER-positive, HER2-negative ABC previously treated with aromatase inhibitors with or without cyclin-dependent kinase 4 and 6 inhibitors were randomized to receive imlunestrant (n=331), standard of care (SOC; n=330), or imlunestrant plus abemaciclib (n=213). Median follow-up was 28.5 months. [Ann Oncol 2026;37:532-543]
The median OS was 34.5 months for imlunestrant and 23.1 months for SOC in patients with ESR1m (hazard ratio [HR], 0.60, 95 percent confidence interval [CI], 0.43‒0.86; p=0.0043, boundary for significant not reached). Regardless of ESR1m, median OS was not reached with imlunestrant plus abemaciclib vs 34.4 months with imlunestrant alone (HR, 0.82, 95 percent CI, 0.59‒1.16; p=0.2622).
Likewise, PFS showed sustained benefit in all patients regardless of ESR1m, with a median of 10.9 months for imlunestrant plus abemaciclib and 5.5 months for imlunestrant monotherapy (HR, 0.59, 95 percent CI, 0.47‒0.74; p<0.0001).
All other exploratory endpoints (ie, time to chemotherapy [TTC], chemotherapy-free survival [CFS], and time to second disease progression [PFS2]) also favoured imlunestrant-based regimens, with a safety profile consistent with previous reports.
“These findings position imlunestrant, both as monotherapy and in combination with abemaciclib, as a promising, chemotherapy-free, all-oral treatment option for patients with limited alternatives,” the investigators said.
Delayed progression
Consistent improvements in exploratory endpoints and the sustained improvement in PFS potentially explained the positive OS results. These findings also show how imlunestrant delays disease progression through the subsequent line of therapy and postpones the need for chemotherapy.
“Given the historically poor outcomes of endocrine monotherapy following CDK4/6 inhibitor-containing therapy, these observations are important and emphasize the clinical benefits of imlunestrant in this population,” the investigators said. [J Clin Oncol 2023;41:4004-4013; J Clin Oncol 2025;43:2084-2093; J Clin Oncol 2022;40:3246-3256]
“This delay in chemotherapy initiation is … relevant in the ABC setting, where initiation of chemotherapy often negatively impacts quality of life,” they added. [Clin Med Insights Oncol 2015;9:137-147]
Safety
The longer follow-up of EMBER-3 did not reveal any new safety signals with imlunestrant, and the profile of both the combination and the monotherapy remained similar with previous findings, according to the investigators.
“Notably, lower frequencies of bradycardia, dyslipidaemia, and photopsia were observed [compared] with other new SERDs,” they said. [J Clin Oncol 2024;42:1193-1201; N Engl J Med 2025;393:569-580; Ann Oncol 2024;35:707-717]
Unsurprisingly, the combination therapy had the highest incidence of treatment-related grade ≥3 adverse events relative to monotherapy and SOC (43 percent vs 5 percent and 2 percent), leading to treatment cessation in 5 percent, 2 percent, and 0 percent, respectively.