Multinational phase 3 trial of giredestrant plus everolimus in advanced breast cancer

Giredestrant and everolimus target the ER pathway and the PI3K-AKT-mTOR pathway, respectively, pathways that are implicated in endocrine-therapy resistance in breast cancer. The multinational phase 3 evERA Breast Cancer trial evaluated the combination of giredestrant and everolimus in advanced breast cancer. The trial enrolled patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer who had disease progression or recurrence after CDK4/6 inhibitor plus endocrine therapy (ET). Patients were randomized 1:1 to receive giredestrant plus everolimus (n=183) or standard ET (exemestane, fulvestrant, of tamoxifen) plus everolimus (n=190). The primary endpoint was investigator-assessed progression-free survival (PFS), evaluated first among patients with ESR1-mutated tumors and then in the overall trial population. Among 207 patients with ESR1-mutated tumors, the median PFS was 10.0 months with giredestrant-everolimus and 5.5 months with standard ET-everolimus (HR 0.38; p<0.001); in the overall population, the median PFS was 8.8 months with giredestrant-everolimus and 5.5 months with standard ET-everolimus (HR 0.56; p<0.001). Adverse events occurred in 98.8% of patients who received giredestrant-everolimus and in 96.8% of those who received standard ET-everolimus. The authors conclude that the all-oral girestrant-everolimus regimen led to significantly longer PFS than standard ET-everolimus among patients with ER-positive, HER2-negative advanced breast cancer who had receive a CDK4/6 inhibitor previously, mainly in patients with ESR1-mutated tumors. The incidence of adverse events was similar in the two groups (quick take video summary).