Dr Mayer on Imlunestrant in HR+/HER2-Negative Advanced Breast Cancer Following Prior Endocrine Therapy

"We already have an oral SERD approved for breast cancer—elacestrant as monotherapy— but maybe we really need to be moving toward combinations with SERDS [and] a targeted partner, and that's where we may see the greatest benefit that can extend to a broader population of patients."

Erica L. Mayer, MD, MPH, director of Breast Cancer Clinical rResearch at Dana-Farber Cancer Institute, and associate professor of medicine at Harvard Medical School, discussed clinical significance of findings from the phase 3 EMBER-3 trial (NCT04975308), which evaluated the oral selective estrogen receptor degrader (SERD) imlunestrant with or without abemaciclib (Verzenio) in patients with hormone receptor–positive, HER2-negative advanced breast cancer who have progressed following prior endocrine therapy.

Mayer explained that EMBER-3 was a 3-arm, randomized trial designed to compare imlunestrant monotherapy and the combination of imlunestrant plus abemaciclib vs physician’s choice of endocrine therapy. All enrolled patients had previously received at least one line of endocrine therapy with an aromatase inhibitor with or without a CDK4/6 inhibitor, either in the advanced setting, or in the adjuvant setting if patients experienced recurrence on or within 12 months of completing treatment.

The primary comparison between imlunestrant and standard endocrine therapy showed a progression-free survival (PFS) benefit in favor of imlunestrant, particularly in patients with detectable ESR1 mutations. The median PFS among patients with ESR1 mutations was 5.5 months (95% CI, 3.9-5.5) for imlunestrant (n = 138) vs 3.8 months (95% CI, 3.7-5.5) for the control arm (n = 118; HR, 0.62; 95% CI, 0.46-0.82; P < .001). In the overall patient population, imlunestrant plus abemaciclib (n = 213) led to a median PFS of 9.4 months (95% CI, 7.5-11.9) vs 5.5 months (95% CI, 3.8-5.6) for standard-of-care endocrine therapy (n = 213; HR, 0.57; 95% CI, 0.44-0.73; P < .001).

Mayer noted that this PFS duration is among the longest reported in the post-endocrine therapy setting, highlighting the potential utility of SERD-based combinations in overcoming resistance.

Updated analyses from EMBER-3 presented at the 2025 ASCO Annual Meeting also showed that patient-reported outcomes were improved in both imlunestrant arms compared with the SOC arm.

Mayer emphasized that although the oral SERD elacestrant (Orserdu) is already FDA approved for patients with ESR1-mutant tumors, the EMBER-3 findings suggest broader applicability of oral SERDs when used in combination with targeted therapies. The data support a potential shift in treatment strategy from SERD monotherapy to combination regimens to extend this class of drugs to a larger portion of patients, she concluded.