Clinical trialPhase 3Breast cancer

Giredestrant plus Everolimus in Advanced Breast Cancer

N Engl J Med · 2026373 patients

Mayer EL, Tolaney SM, Martín M, Vidal GA, Moscetti L, Jhaveri KL, et al. N Engl J Med. 2026. 395:1285-1298

Study type: Clinical trial
Study name: evERA Breast Cancer
Phase: Phase 3
Design: Randomised open-label trial, 1:1 ratio
Sample size: 373 patients
Source: N Engl J Med · 2026
Trial registration: NCT05306340

In plain words

In patients with advanced hormone-positive breast cancer whose disease had grown after treatment with CDK4/6 inhibitors, the combination of two tablets, giredestrant and everolimus, delayed the growth of the disease longer than standard hormone therapy plus everolimus; the effect was especially striking in patients whose tumour had an ESR1 mutation, and the side effects of the two treatments were similar.

Key results

10.0 vs 5.5 months

Median progression-free survival – ESR1-mutated

HR 0.38 (95% CI 0.27 to 0.54); P<0.001

8.8 vs 5.5 months

Median progression-free survival – overall population

HR 0.56 (95% CI 0.44 to 0.71); P<0.001

47.3% vs 48.9%

Stomatitis

26.9% vs 22.6%

Diarrhoea

Drugs in this study:Everolimus (Afinitor)Exemestane (Aromasin)Fulvestrant (Faslodex)Tamoxifen (Nolvadex)

Dose and schedule cards

Giredestrant + everolimus

Advanced ER-positive/HER2-negative breast cancer after a CDK4/6 inhibitor + endocrine therapyEach drug’s schedule in the tableOn the page “Hormone-positive breast cancer: an all-oral giredestrant + everolimus regimen delayed progression” · evERA trial regimen (investigational; giredestrant not yet approved)

Advanced ER-positive/HER2-negative breast cancer after a CDK4/6 inhibitor + endocrine therapy

Drug	Dose	Route	Schedule
Giredestrant	30 mg	Oral	Once daily, days 1 to 28, every 28 days
Everolimus	10 mg	Oral	Once daily
Pre- or perimenopausal women and men
LHRH agonist	Per label	Injection	Day 1, every 28 days

Cycle schedule: Giredestrant and everolimus daily, continuous; LHRH agonist every 28 days
Duration: Until disease progression or unacceptable toxicity

Comparator arm: exemestane 25 mg daily, fulvestrant 500 mg intramuscularly (days 1 and 15 of cycle 1, then day 1 of each cycle) or tamoxifen 20 mg daily, with everolimus 10 mg. Stomatitis prevention: an alcohol-free dexamethasone mouthwash (0.5 mg in 5 mL) four times a day for 8 weeks from the start of treatment was strongly recommended. As in the registered protocol.

On the page “Hormone-positive breast cancer: an all-oral giredestrant + everolimus regimen delayed progression” · evERA trial regimen (investigational; giredestrant not yet approved)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Giredestrant + everolimus (183 patients)

Giredestrant 30 mg orally once daily on days 1 to 28 of each 28-day cycle + everolimus 10 mg orally once daily, until progression or unacceptable toxicity. An LHRH agonist for pre/perimenopausal women and men. Alcohol-free dexamethasone mouthwash (0.5 mg in 5 mL) four times daily for 8 weeks was recommended to prevent stomatitis.

2Standard endocrine therapy + everolimus (190 patients)

Exemestane 25 mg orally daily, or fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then day 1 of each cycle, or tamoxifen 20 mg orally daily (physician's choice or per local label) + everolimus 10 mg orally daily.

Source of the regimen details: ClinicalTrials.gov NCT05306340

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer with progression or relapse after a CDK4/6 inhibitor plus endocrine therapy. 207 patients had a tumour with an ESR1 mutation.

Endpoints

Primary endpoint: investigator-assessed progression-free survival, first in patients with ESR1-mutated tumours and then in the overall population.

Safety and side effects

Adverse events occurred in 98.9% of patients receiving giredestrant–everolimus and 96.8% of those receiving standard therapy–everolimus. The most common were stomatitis (47.3% versus 48.9%), diarrhoea (26.9% versus 22.6%) and anaemia (23.6% versus 21.0%).

Clinical significance and place in guidelines

An all-oral SERD-containing regimen with phase 3 superiority after a CDK4/6 inhibitor. Giredestrant is not yet approved; according to the manufacturer, the FDA has accepted its application for ESR1-mutated tumours, and a decision is expected by December 2026.

Limitations

Open-label design; primary endpoint by investigator assessment; overall survival not reported; the benefit in the overall population was driven mainly by the ESR1-mutated subgroup.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.