Giredestrant Plus Everolimus Prolongs PFS in ER-Positive, HER2-Negative Advanced Breast Cancer

An all-oral regimen of giredestrant plus everolimus significantly prolonged progression-free survival (PFS) compared with standard endocrine therapy plus everolimus in patients with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer previously treated with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, according to phase 3 results published in NEJM.

Giredestrant, which the journal describes as an ER degrader and full ER antagonist, targets the ER pathway, while everolimus targets the phosphatidylinositol 3-kinase–protein kinase B–mammalian target of rapamycin (PI3K–AKT–mTOR) pathway. The investigators noted that both pathways are implicated in endocrine-therapy resistance.

The open-label evERA Breast Cancer trial randomly assigned 373 patients whose locally advanced or metastatic disease had progressed or recurred after a CDK4/6 inhibitor plus endocrine therapy to oral giredestrant–everolimus (n=183) or standard endocrine therapy (exemestane, fulvestrant, or tamoxifen) plus everolimus (n=190). The primary end point was investigator-assessed PFS, evaluated first in patients with ESR1-mutated tumors and then in the overall population. Among 207 patients with ESR1-mutated tumors, median PFS was 10.0 months with giredestrant–everolimus vs 5.5 months with standard therapy–everolimus (hazard ratio [HR] for disease progression or death, 0.38; 95% CI, 0.27-0.54; P<0.001). In the overall population, median PFS was 8.8 vs 5.5 months, respectively (HR, 0.56; 95% CI, 0.44-0.71; P<0.001).

Adverse events occurred in 98.9% of patients receiving giredestrant–everolimus and 96.8% of those receiving standard therapy–everolimus. The most common were stomatitis (47.3% vs 48.9%), diarrhea (26.9% vs 22.6%), and anemia (23.6% vs 21.0%).

The investigators concluded that the PFS benefit was observed mainly in patients with ESR1-mutated tumors and that the incidence of adverse events was similar between groups. The trial was funded by Genentech, a member of the Roche Group.

Source: Mayer EL, Tolaney SM, Martín M, et al. Giredestrant plus everolimus in advanced breast cancer. N Engl J Med. 2026;395(13):1285-1298. doi:10.1056/NEJMoa2602457