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Giredestrant Plus Everolimus NDA Is Under FDA Review for ESR1-Mutated, ER+ Advanced Breast Cancer

Author(s)Ashling Wahner

Fact checked by: Chris Ryan

  • In ESR1-mutated tumors, giredestrant/everolimus cut progression or death risk 62% (HR 0.38) and achieved median PFS 9.99 months versus 5.45 months.
  • Across the ITT population, PFS improved with giredestrant/everolimus (HR 0.56), extending median PFS to 8.77 months and raising 12‑month PFS to 34.1%.
  • Objective responses were more frequent and durable, with ORR 26.6% and median DOR 14.88 months in ESR1‑mutated disease compared with 13.8% and 7.33 months.
  • Trial design was open‑label and multicenter after prior CDK4/6 inhibitor plus endocrine therapy; coprimary endpoints were investigator‑assessed PFS in ESR1‑mutated and ITT cohorts.
  • Safety reflected known everolimus and SERD toxicities; discontinuations occurred (giredestrant 8.2%, everolimus 17.0%), grade 1/2 bradycardia was uncommon, and OS showed an immature favorable trend.

The FDA has accepted for review a new drug application (NDA) seeking the approval of giredestrant (GDC-9545) in combination with everolimus (Afinitor) for the treatment of patients with ESR1-mutated, estrogen receptor (ER)–positive, HER2-negative locally advanced or metastatic breast cancer following recurrence or progression on a prior endocrine therapy–based regimen.1

The NDA was based on findings from the phase 3 evERA Breast Cancer trial (NCT05306340), in which giredestrant plus everolimus (n = 102) reduced the risk of disease progression or death by 62% compared with standard-of-care (SOC) endocrine therapy plus everolimus (n = 105) in patients with ESR1-mutated disease (HR, 0.38; 95% CI, 0.27-0.54; P < .0001).1,2 In this population, the median progression-free survival (PFS) was 9.99 months (95% CI, 8.08-12.94) vs 5.45 months (95% CI, 3.75-5.62), respectively. The 12-month PFS rates in these respective arms were 40.5% and 15.2%.2

Among evaluable patients in the ESR1-mutated population, the overall response rate (ORR) was 26.6% in the giredestrant arm (n = 94) vs 13.8% in the SOC arm (n = 94; difference, 12.8%; 95% CI, 0.48%-24.7%). The median durations of response (DORs) were 14.88 months (95% CI, 9.10-not evaluable [NE]; n = 25) vs 7.33 months (95% CI, 3.84-NE; n = 13), respectively.

The FDA has set a Prescription Drug User Fee Act target action date of December 18, 2026.1

“The clinically meaningful benefit seen with giredestrant could enable an important new treatment option to help delay disease progression or death in people with advanced ER-positive breast cancer,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Roche, stated in a news release. “This [FDA] acceptance marks a first step towards establishing the giredestrant combination as a new SOC in this population.”

What was the design of the evERA Breast Cancer trial?

This open-label, multicenter study enrolled patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer who had received prior therapy with a CDK4/6 inhibitor and endocrine therapy in either the adjuvant or locally advanced/metastatic setting.1,2 The coprimary end points were investigator-assessed PFS in the ESR1-mutated and intention-to-treat (ITT) populations. Key secondary end points included overall survival (OS), ORR, DOR, clinical benefit rate, and safety.

What additional findings were reported from evERA Breast Cancer?

In the ITT population, the giredestrant-based regimen (n = 183) reduced the risk of disease progression or death by 44% compared with the control arm (n = 190; HR, 0.56; 95% CI, 0.44-0.71; P < .0001).2 The median PFS values in these respective arms were 8.77 months (95% CI, 6.60-9.59) vs 5.49 months (95% CI, 4.01-5.59). The 12-month PFS rates in these respective arms were 34.1% and 18.1%.

Although OS data were not mature at the time of analysis, investigators noted a positive trend in favor of the giredestrant arm in both the ESR1-mutated population (HR, 0.62; 95% CI, 0.38-1.02; P = .0566) and ITT population (HR, 0.69; 95% CI, 0.47-1.00; P = .0473).1,2 Follow-up for OS is planned to continue.

Regarding safety, the adverse effects (AEs) observed in the giredestrant/everolimus arm were deemed manageable and consistent with the known safety profiles of the individual agents. The investigators noted no unexpected safety findings, including no reports of photopsia.

Among safety-evaluable patients in the giredestrant arm (n = 182), 2.7% had AEs with fatal outcomes, and 30.8% experienced AEs leading to everolimus dose reduction. AEs leading to discontinuation from giredestrant (8.2%), everolimus (17.0%), or either drug (17.0%) were also reported. Notably, grade 1/2 bradycardia was observed in 7 patients, and no grade 3/4 bradycardia was reported.

References

  1. FDA accepts new drug application for Roche’s giredestrant in ESR1-mutated, ER-positive advanced breast cancer. News release. Roche. February 19, 2026. Accessed February 20, 2026. https://www.roche.com/media/releases/med-cor-2026-02-20
  2. 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: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, Texas. Abstract GS3-09.