Clinical and Biomarker Subgroup Analysis From the Phase 3 evERA Trial: Giredestrant Plus Everolimus in ER-Positive/HER2-Negative Advanced Breast Cancer After CDK4/6 Inhibitor Treatment

The first-line standard of care (SOC) for patients with estrogen receptor (ER)-positive/HER2-negative advanced breast cancer combines CDK4/6 inhibitors with endocrine therapy (ET). However, effective treatment options following improvement on CDK4/6 inhibitors remain limited. Giredestrant targets the ER pathway and everolimus inhibits the PI3K/AKT/mTOR pathway; both are implicated in resistance mechanisms in the post–CDK4/6 inhibitor setting. The phase 3 evERA breast cancer trial (NCT05306340) is the first to demonstrate a statistically significant and clinically meaningful improvement in investigator-assessed progression-free survival (INV-PFS) with the all-oral combination of giredestrant plus everolimus compared with SOC ET plus everolimus in patients with ER-positive/HER2-negative advanced breast cancer after CDK4/6 inhibitor treatment plus ET. This benefit was observed in both patients with detectable ESR1 mutations and the intent-to-treat (ITT) population. The safety profile of giredestrant plus everolimus was manageable, with no unexpected findings. This article reports results from the prespecified exploratory subgroup analyses.

Patients with ER-positive/HER2-negative advanced breast cancer who experienced disease progression after treatment with a CDK4/6 inhibitor plus ET in the advanced setting, or who relapsed during or after treatment with a CDK4/6 inhibitor plus ET in the adjuvant setting, were randomized 1:1 to receive 30 mg oral giredestrant plus 10 mg everolimus or SOC ET (exemestane, fulvestrant, or tamoxifen) plus everolimus until disease progression or unacceptable toxicity. Baseline circulating tumor DNA testing was used to determine mutation status. Co-primary endpoints included INV-PFS in patients with an ESR1 mutation and in the ITT population, assessed per RECIST v1.1. Subgroup analyses evaluated INV-PFS.

A total of 373 patients were randomized (giredestrant plus everolimus, 183; SOC ET plus everolimus, 190), with 55% (n=207) having an ESR1 mutation, 31% (n=115) harboring PIK3CA mutations, and 37% (n=137) exhibiting alterations in PI3K pathway genes (PIK3CA/AKT1/PTEN). Seventeen percent of patients (n=64) had both ESR1 mutations and PIK3CA mutations, while 20% (n=76) had both ESR1 mutations and PIK3CA/AKT1/PTEN alterations. Nearly all patients (98%) had received prior CDK4/6 inhibitors in the metastatic setting. Giredestrant plus everolimus demonstrated an INV-PFS benefit compared with SOC ET plus everolimus in the ESR1 mutation and ITT populations, regardless of PIK3CA or PIK3CA/AKT1/PTEN alterations. In the ESR1 mutation population, the median INV-PFS was 9.99 months in the giredestrant plus everolimus arm and 5.45 months in the SOC ET plus everolimus arm (hazard ratio, 0.38; 95% CI, 0.27-0.54; P<.001). In the ITT population, the median INV-PFS was 8.77 months in the giredestrant plus everolimus arm and 5.49 months in the SOC ET plus everolimus arm (hazard ratio, 0.56; 95% CI, 0.44-0.71; P<.001). There were 31 adverse events (AEs) that led to treatment discontinuation in the giredestrant plus everolimus arm and 22 AEs that led to treatment discontinuation in the SOC ET plus everolimus arm. In the population that had PIK3CA/AKT1/PTEN alterations detected, the median PFS in the giredestrant plus everolimus arm was 10.15 months compared with 5.55 months in the SOC ET plus everolimus arm (hazard ratio, 0.45; 95% CI, 0.27-0.76). The INV-PFS benefit was consistent across subgroups defined by the duration of previous CDK4/6 inhibitor therapy (<12 months, 12-<24 months, or ≥24 months).

The combination of giredestrant plus everolimus provided clinically meaningful improvements in INV-PFS compared with SOC ET plus everolimus, irrespective of genomic alterations (PIK3CA or PIK3CA/AKT1/PTEN) and other key subgroups, including ESR1 mutation status. These findings support the use of giredestrant plus everolimus as an effective, all-oral treatment option for patients with ER-positive/HER2-negative advanced breast cancer following progression on CDK4/6 inhibitor therapy.

Source: Rugo HS, Tolaney SM, Jhaveri KL, et al. Clinical and biomarker subgroup analysis of evERA breast cancer: a phase III trial of giredestrant plus everolimus in patients with estrogen receptor-positive, HER2-negative advanced breast cancer previously treated with a CDK4/6 inhibitor. Presented at: San Antonio Breast Cancer Symposium 2025. December 12, 2025; San Antonio, TX. Presentation GS3-09.