Giredestrant Plus Everolimus Extends Survival in ER+, HER2- Advanced Breast Cancer

Giredestrant (GIRE; Roche) plus everolimus (E, Zortress; Novartis Pharmaceuticals) after CDK4/6 inhibitor therapy led to clinically meaningful survival benefits in patients with estrogen receptor-positive (ER+)/HER2-negative (HER2–) advanced breast cancer (aBC). The data were presented at the European Society For Medical Oncology 2025 Congress in Berlin, Germany.

For patients with ER+, HER2– aBC, CDK4/6 inhibitors combined with endocrine therapy (ET) has been the standard of care in the first-line setting. However, once the disease progresses after CDK4/6 inhibitor therapy, effective treatment options remain limited. Data from the phase 3 evERA BC (NCT05306340) trial suggest that GIRE plus E could help fill this gap.^1,2

The evERA BC trial is a global, randomized, open-label study evaluating the efficacy and safety of once-daily oral GIRE (30 mg) combined with E (10 mg) compared with the current standard of care (SOC) ET—exemestane, fulvestrant, or tamoxifen—plus E. All participants had ER+, HER2– aBC that had progressed or relapsed during or after prior CDK4/6 inhibitor therapy with ET.¹

A total of 373 patients were randomized 1:1 to receive either GIRE + E (n = 183) or SOC ET + E (n = 190). Approximately 55% of participants had detectable ESR1 mutations (ESR1m), a common resistance mechanism in hormone receptor–positive BC.¹

The study met its co-primary end points, demonstrating significant and clinically meaningful improvements in investigator-assessed progression-free survival (INV-PFS) in both the ESR1m subgroup and the overall intent-to-treat (ITT) population.¹

Among patients with ESR1 mutations, the median PFS was 9.99 months with GIRE + E versus 5.45 months with SOC ET + E, corresponding to a 62% reduction in risk of progression or death (HR, 0.38; 95% CI, 0.27–0.54; P < .0001). In the ITT population, median PFS was 8.77 months versus 5.49 months, respectively (HR, 0.56; 95% CI, 0.44–0.71; P < .0001).¹

An interim analysis of overall survival (OS) showed trends favoring the GIRE combination. In the ESR1m subgroup, median OS was not yet evaluable (NE) in the GIRE arm compared with 21.03 months in the control arm (HR, 0.62; 95% CI, 0.38–1.02; P = .0566). In the ITT population, median OS was also NE versus 26.87 months, respectively (HR, 0.69; 95% CI, 0.47–1.00; P = .0473).¹

The most common adverse events (AEs) included stomatitis, diarrhea, and anemia, which occurred at similar rates across both study arms. Grade 3 or 4 AEs were infrequent, and treatment discontinuations due to AEs were relatively low (8.2% in the GIRE arm vs 6.5% in SOC ET). Grade 1 bradycardia was reported in a small proportion of patients (3.8%) receiving GIRE but did not lead to treatment interruptions or discontinuations.¹

Overall, GIRE plus everolimus demonstrated robust activity and a manageable safety profile in patients whose disease had progressed on prior CDK4/6 inhibitor therapy. Investigators concluded that this novel regimen could represent a promising new option for patients with ER+, HER2– advanced breast cancer, particularly those harboring ESR1 mutations.

REFERENCES

1. Mayer E, Tolaney S, Martin M, et al. LBA16 - 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: European Society For Medical Oncology 2025 Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA16

2. A study evaluating the efficacy and safety of giredestrant plus everolimus compared with the physician's choice of endocrine therapy plus everolimus in participants with estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer (evERA Breast Cancer). Clinicaltrials.gov. Updated November 12, 2025. Accessed November 12, 2025. https://clinicaltrials.gov/study/NCT05306340