Giredestrant plus Everolimus in Advanced Breast Cancer

Why clinicians should know about it

• Picked for Bariatric and Metabolic Surgery (top studies of the week, 4 October 2026): High-quality evidence in a top journal
• Picked for Gastrointestinal and Colorectal Surgery (top studies of the week, 4 October 2026): Breast cancer therapy, outside GI focus
• Picked for Radiation Oncology (top studies of the week, 4 October 2026): Breast cancer endocrine trial, no radiation component
• Picked for Breast and Endocrine Surgery (top studies of the week, 4 October 2026): Randomized trial, high-quality evidence
• Picked for Surgical Oncology (top studies of the week, 4 October 2026): Systemic therapy trial, no surgical arm
• Picked for Dermatology (top studies of the week, 4 October 2026): Not dermatology; focuses on breast cancer therapy
• Picked for Oncology and Radiation Oncology (top studies of the week, 4 October 2026): Phase 3 RCT, PFS benefit in ESR1‑mutated breast cancer
• Picked for Pediatric Surgery (top studies of the week, 4 October 2026): Phase 3 trial of giredestrant plus everolimus in advanced breast
• Picked for Spine Surgery (top studies of the week, 4 October 2026): High-quality evidence in a top journal
• Picked for Plastic and Reconstructive Surgery (top studies of the week, 4 October 2026): High-quality evidence in a top journal

Abstract

BACKGROUND: Giredestrant 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. METHODS: In 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. RESULTS: Overall, 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%). CONCLUSIONS: An 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.).

Abstract as published, via PubMed.