Giredestrant Combo Cuts Progression Risk by 44% in Advanced Breast Cancer

Patients with ER-positive, HER2-negative advanced breast cancer lived longer without their cancer worsening when treated with giredestrant plus Afinitor (everolimus) compared with standard endocrine therapy plus Afinitor, according to findings from the phase 3 evERA Breast Cancer trial published in The New England Journal of Medicine.

The benefit was greatest among patients whose tumors had ESR1 mutations. In this group, treatment with giredestrant plus Afinitor reduced the risk of disease progression or death by 62% compared with standard endocrine therapy plus Afinitor. Across all patients in the trial, the risk was reduced by 44%.

“Despite advancements with CDK4/6 inhibitor treatment in the first-line setting, many people with advanced breast cancer will eventually experience disease progression as their tumors become resistant to endocrine therapy,” Dr. Erica L. Mayer, a medical oncologist at Dana-Farber Cancer Institute, said in a news release.

What did the evERA Breast Cancer trial find?

Among patients with ESR1-mutated tumors, median progression-free survival (PFS), or the length of time patients lived without their cancer worsening, was 10 months with giredestrant plus Afinitor compared with 5.5 months with standard endocrine therapy plus Afinitor.

In the overall study population, median PFS was 8.8 months with the giredestrant combination and 5.5 months with standard therapy.

The difference was smaller among patients whose tumors did not have a detectable ESR1 mutation. In an exploratory analysis, median PFS was 5.7 months with giredestrant plus Afinitor and 5.5 months with standard therapy.

Researchers noted that the overall findings should be viewed in the context of the trial design because a larger proportion of enrolled patients had ESR1-mutated tumors.

Tumor responses were also more common with the giredestrant combination.

Among patients with ESR1-mutated tumors whose cancer could be measured on scans, 26.6% experienced a confirmed response with giredestrant plus Afinitor compared with 13.8% with standard therapy. Those responses lasted a median of 14.9 months and 7.3 months, respectively.

Across all patients with measurable disease, confirmed response rates were 23.8% with the giredestrant combination and 11.7% with standard therapy.

Overall survival data were not mature at the time of the analysis, meaning there had not yet been enough deaths to determine whether the treatment helps patients live longer. Longer follow-up is needed.

How was the evERA Breast Cancer trial designed?

The trial included 373 patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer whose disease had progressed or returned after treatment with a CDK4/6 inhibitor and endocrine therapy.

Patients were randomly assigned to receive giredestrant plus Afinitor or standard endocrine therapy plus Afinitor. Standard endocrine therapy included exemestane, fulvestrant or tamoxifen.

Both giredestrant and Afinitor are taken by mouth. Mayer noted that the combination could provide an all-oral treatment option for patients who need another line of therapy after their cancer progresses.

CDK4/6 inhibitors combined with endocrine therapy are commonly used as an initial treatment for ER-positive, HER2-negative advanced breast cancer. However, endocrine-based treatments may become less effective as the disease develops resistance.

One way this resistance can develop is through ESR1 mutations, which can allow the estrogen receptor to remain active even when estrogen levels are suppressed. These mutations may develop in about 40% of patients whose cancer progresses after treatment with a CDK4/6 inhibitor and endocrine therapy.

Giredestrant is an oral selective estrogen receptor degrader (SERD), a type of treatment designed to block and break down the estrogen receptor. Afinitor targets the mTOR pathway, another pathway involved in resistance to endocrine therapy.

What side effects occurred with giredestrant plus Afinitor?

Nearly all patients in both treatment groups experienced at least one side effect.

Side effects occurred in 98.9% of patients who received giredestrant plus Afinitor and 96.8% of those who received standard endocrine therapy plus Afinitor.

The most common side effects with the giredestrant combination were mouth sores, reported in 47.3% of patients; diarrhea, reported in 26.9%; and anemia, or low red blood cell counts, reported in 23.6%.

Serious side effects occurred in 29.1% of patients treated with giredestrant plus Afinitor compared with 23.1% of patients who received standard therapy plus Afinitor.

The researchers noted that the overall results should be interpreted in the context of the trial design, which enrolled a larger proportion of patients with ESR1-mutated tumors.

References

1. Mayer EL, et al. "Giredestrant plus Everolimus in Advanced Breast Cancer." The New England Journal of Medicine. Published Oct. 1, 2026.
2. News release. "Genentech's Giredestrant Combination Significantly Improved Progression-Free Survival in ER-Positive Advanced Breast Cancer in Phase III evERA Data Published in The New England Journal of Medicine." Genentech. Posted: Sept. 30, 2026.

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