Giredestrant plus Everolimus in Advanced Breast Cancer

BackgroundGiredestrant and everolimus target the estrogen receptor (ER) pathway and the phosphatidylinositol 3-kinase (PI3K)–protein kinase B (AKT)–mammalian target of rapamycin (mTOR) pathway, respectively, which are implicated in endocrine-therapy resistance. MethodsIn this phase 3, open-label, randomized trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)–negative locally advanced or metastatic breast cancer who had disease progression or recurrence after receipt of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor plus endocrine therapy. Patients were assigned, in a 1:1 ratio, to receive giredestrant plus everolimus (each given orally) or standard endocrine therapy (i.e., exemestane, fulvestrant, or tamoxifen) plus everolimus. The primary end point was investigator-assessed progression-free survival, evaluated first among patients with ESR1-mutated tumors and then in the overall trial population. Research Summary Giredestrant plus Everolimus in Advanced Breast Cancer ResultsOverall, 373 patients underwent randomization, with 183 assigned to the giredestrant–everolimus group and 190 to the standard therapy–everolimus group. Among 207 patients with ESR1-mutated tumors, the median progression-free survival was 10.0 months with giredestrant–everolimus and 5.5 months with standard therapy–everolimus (hazard ratio for disease progression or death, 0.38; 95% confidence interval [CI], 0.27 to 0.54; P<0.001). In the overall population, the median progression-free survival was 8.8 months with giredestrant–everolimus and 5.5 months with standard therapy–everolimus (hazard ratio, 0.56; 95% CI, 0.44 to 0.71; P<0.001). Adverse events occurred in 98.9% of patients who received giredestrant–everolimus and in 96.8% of those who received standard therapy–everolimus. The most common adverse events were stomatitis (in 47.3% of giredestrant–everolimus recipients and 48.9% of standard therapy–everolimus recipients), diarrhea (in 26.9% and 22.6%, respectively), and anemia (in 23.6% and 21.0%). ConclusionsAn all-oral giredestrant–everolimus regimen led to significantly longer progression-free survival than standard endocrine therapy–everolimus among patients with ER-positive, HER2-negative advanced breast cancer who had received a CDK4/6 inhibitor previously, mainly in patients with ESR1-mutated tumors. The incidence of adverse events was similar in the two groups. (Funded by Genentech; evERA Breast Cancer ClinicalTrials.gov number, NCT05306340.) Quick Take Giredestrant plus Everolimus in Breast Cancer 2m 38s