Giredestrant Combo Yields Positive PFS in Subgroups After CDK4/6i in ER+/HER2– Breast Cancer

Results from the phase 3 evERA BC trial (NCT05306340) showed giredestrant (GDC-9545) plus everolimus (Afinitor) improved progression-free survival (PFS) vs endocrine therapy (ET) plus everolimus in patients with estrogen receptor–positive (ER+), HER2-negative advanced breast cancer after receiving prior CDK4/6 inhibitor. These findings were presented at the 2025 San Antonio Breast Cancer Symposium.

In the evERA BC trial, there was consistent benefit to investigator-assessed progression-free survival (PFS) in those with ESR1 mutations and the intent-to-treat (ITT) population irrespective of PIK3CA mutations or PIK3CA/AKT1/PTEN alterations.

“The magnitude of clinical benefit was clinically meaningful and consistent, and was regardless of PIK3CA mutations or alterations in the PIK3CA pathway, duration of prior CDK4/6 inhibitors, including patients who progress within 6 to 12 months, and the choice of prior CDK4/6 inhibitors,” said Hope S. Rugo, MD, division chief of breast medical oncology and a professor of medical oncology and therapeutics research at City of Hope in Duarte, California, in her presentation.

Patients who have previously received CDK4/6 inhibitor and ET in the first line for advanced ER+, HER2-negative breast cancer have limited effective options. Giredestrant is an oral selective estrogen receptor degrader (SERD) which showed favorable efficacy and safety in combination with everolimus in an arm of the phase 1/2 MORPHEUS BC trial (NCT04802759).²

evERA BC Subgroup Outcomes

The evERA BC study is the first head-to-head phase 3 trial of an all-oral regimen including a SERD to show improvement vs a standard-of-care combination in this setting. The median PFS was 8.77 months with giredestrant plus everolimus vs 5.49 months with ET plus everolimus (HR, 0.56; 95% CI, 0.44-0.71; P <.0001). In those with an ESR1 mutation, the median PFS was 9.99 months vs 5.45 months, respectively (HR, 0.38; 95% CI, 0.27–0.54; P < .0001).³

In those with both ESR1 and PIK3CA mutations, the HR favoring giredestrant plus everolimus was 0.38 (95% CI, 0.20–0.69) whereas it was 0.54 (95% CI, 0.36–0.83) for those with PIK3CA mutations in the ITT population.¹ Among patients with ESR1 mutations but no detectable PIK3CA mutation, the HR for giredestrant plus everolimus was 0.47 (95% CI, 0.31–0.70), compared with 0.59 (95% CI, 0.45–0.79) in the ITT population.

For individuals with PIK3CA/AKT1/PTEN alterations, the HR was 0.45 (95% CI, 0.27–0.76) in the ESR1-mutant cohort and 0.54 (95% CI, 0.38–0.77) in the ITT population. In contrast, for those without PIK3CA/AKT1/PTEN alterations, the HR was 0.41 (95% CI, 0.26–0.63) in the ESR1-mutant subgroup and 0.60 (95% CI, 0.44–0.83) in the ITT population.

Among patients whose most recent line of CDK4/6 inhibitor therapy in the metastatic setting was given for less than 12 months, the HR favoring giredestrant plus everolimus was 0.33 (95% CI, 0.16–0.70) in the ESR1-mutant subgroup (n = 38) and 0.60 (95% CI, 0.38–0.93) in the ITT population (n = 94).

For those whose CDK4/6 inhibitor duration was between 12 to 24 months, the HR was 0.42 (95% CI, 0.25–0.73) in the ESR1-mutant group (n = 74) and 0.66 (95% CI, 0.44–0.99) in the ITT population (n = 121).

Finally, in patients with at least 24 months of prior CDK4/6 inhibitor therapy, the HR was 0.39 (95% CI, 0.23–0.66) in the ESR1-mutant subgroup (n = 92) and 0.50 (95% CI, 0.34–0.75) in the ITT population (n = 150).

Looking at prior CDK4/6 inhibitor use, for those who received palbociclib, the HR was 0.40 (95% CI, 0.26–0.61) favoring giredestrant/everolimus in the ESR1-mutant subgroup (n = 126) and 0.53 (95% CI, 0.39–0.73) in the ITT population (n = 223). For those who received ribociclib (Kisqali), the HR was 0.71 (95% CI, 0.40–1.26) in the ESR1-mutant subgroup (n = 66) and 0.75 (95% CI, 0.49–1.16) in the ITT population (n = 106). For those who received abemaciclib (Verzenio), the HR was 0.29 (95% CI, 0.14–0.61) in the ESR1-mutant subgroup (n = 41) and 0.66 (95% CI, 0.43–1.03) in the ITT population (n = 102).

The overall response rate was 26.6% for giredestrant/everolimus vs 13.8% with ET/everolimus in the ESR1-mutated group, 23.8% vs 11.7%, respectively, in the ITT population, and 20.0% vs 8.7% in the patients with no ESR1 mutation. The respective durations of response were 14.88 months vs 7.33 months in the ESR1-mutant group, 12.71 vs 7.72 months in the ITT population, and 12.68 vs 7.72 months in those with no ESR1 mutation.

Rugo commented that trial was not powered to find significance in the ESR1–wild type subgroup, but said, “It's very encouraging to see that marked improvement in overall response, just without the power to see a difference in PFS in that subset.”

Study Design of evERA BC

In the phase 3 trial, 373 patients were randomly assigned on a 1:1 basis to 30 mg giredestrant plus 10 mg everolimus daily orally or standard-of-care ET (exemestane, fulvestrant, or tamoxifen) plus everolimus until disease progression or unacceptable toxicity. The co-primary end points were investigator-assessed PFS in those with detectable ESR1 mutations by circulating tumor DNA and in the ITT population. Key secondary end points included overall survival and investigator-assessed overall response rate, with exploratory end points including clinical and biomarker subgroup analyses.

The baseline characteristics were well balanced in both the ITT and ESR1-mutated populations. Palbociclib (Ibrance) was the most common CDK4/6 inhibitor given, and prior fulvestrant was used in 47.0% in the giredestrant/everolimus arm and 46.8% in the ET plus everolimus arm, with 29.0% and 22.1%, respectively, being given fulvestrant in the first line with CDK4/6 inhibitor.

Fifty-five percent of patients across both arms (n = 207) had ESR1 mutations, 31% (n = 115) had PIK3CA mutations, and 37% (n = 137) had alterations to the PI3K pathway genes PIK3CA, AKT1, and PTEN. Both ESR1 and PIK3CA mutations were present in 17% (n = 64), and 20% (n = 76) had both ESR1 mutations and PIK3CA, AKT1, or PTEN alterations.

Safety Overview

In terms of safety, Rugo stated that there was no clear difference in toxicity between giredestrant and the ET. The most common adverse event (AE) was stomatitis in 44.5% of grade 1 or 2 and 2.7% grade 3 or 4 in the giredestrant arm and 45.7% of grade 1 or 2 and 3.2% grade 3 or 4 in the standard-of-care ET arm. Bradycardia, an AE of special interest, was reported in 7 patients who received giredestrant vs 1 who received standard ET, all of which were grade 1 or 2. Dose reduction of everolimus were similar between the arms and discontinuation rates were comparable to past studies, according to Rugo.

“Giredestrant and everolimus may represent a new all-oral standard-of-care treatment option in patients following CDK4/6 inhibitor treatment who have hormone receptor–positive advanced breast cancer,” Rugo concluded.

References

1. 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 the 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract GS3-09.
2. Wander SA, Stemmer SM, Rugo HS, et al. Interim analysis (IA) of the giredestrant (G) + everolimus (EVERO) arm in MORPHEUS Breast Cancer (BC): A phase I/II study of G treatment (tx) combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative, locally advanced/metastatic BC (LA/mBC). J Clin Oncol. 2024;42(suppl 16):1059. doi:10.1200/JCO.2024.42.16_suppl.1059
3. Mayer E, Tolaney SM, Martin M, et al. Giredestrant (GIRE), an oral selective oestrogen receptor (ER) antagonist and degrader, + everolimus (E) in patients (pts) with ER-positive, HER2-negative advanced breast cancer (ER+, HER2– aBC) previously treated with a CDK4/6 inhibitor (i): Primary results of the phase III evERA BC trial. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA16.