FDA Accepts New Drug Application for Giredestrant in Advanced Breast Cancer

The FDA has accepted a new drug application (NDA) for giredestrant, an investigational oral selective estrogen receptor degrader (SERD), for the treatment of adult patients with estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated locally advanced or metastatic breast cancer.¹ The application seeks approval for giredestrant in combination with everolimus for patients whose disease has progressed following treatment with a CDK4/6 inhibitor and endocrine therapy. The FDA is expected to reach a regulatory decision by December 18, 2026.

The filing is primarily supported by results from the phase 3 evERA study (NCT05306340), which evaluated the efficacy and safety of the giredestrant-everolimus combination compared with physician's choice of endocrine therapy plus everolimus. If approved, this would represent the first and only all-oral SERD-containing combination therapy available for patients in the post-CDK4/6 inhibitor setting.

Clinical Data from the evERA Trial

Data from the evERA trial demonstrated that giredestrant plus everolimus significantly improved progression-free survival (PFS) in both the intention-to-treat (ITT) and ESR1-mutated populations.² In the ITT population, the combination reduced the risk of disease progression or death by 44% compared with standard-of-care endocrine therapy plus everolimus (HR 0.56; 95% CI, 0.44-0.71; P <.0001). The benefit was even more pronounced in the ESR1-mutated subgroup, where the combination achieved a 62% reduction in the risk of progression or death (HR, 0.38; 95% CI, 0.27-0.54; P <.0001).

Median PFS in the ESR1-mutated population reached 9.99 months for those receiving giredestrant, compared with 5.45 months in the comparator arm. Although overall survival (OS) data were immature at the time of the primary analysis presented at the 2025 ESMO Congress, investigators observed a positive trend favoring the giredestrant arm in both the ITT (HR, 0.69) and ESR1-mutated (HR, 0.62) groups. Follow-up for OS remains ongoing.

"The combination of giredestrant and everolimus—an oral SERD and an oral mTOR inhibitor—may represent a new, effective, all-oral treatment option in the post-CDK 4/6 inhibitor setting for patients with ER-positive, HER2-negative advanced disease," lead investigator Erica L. Mayer, MD, MPH, medical oncologist and clinical investigator in the Breast Oncology Center at the Dana-Farber Cancer Institute, said during a presentation of the results. "Consistent benefit with this regimen was seen across key subgroups. Overall response and duration of response benefits were observed in all patients. Overall survival is immature yet favorable."

Addressing Resistance and Therapeutic Gaps

ER-positive breast cancer accounts for approximately 70% of all breast cancer diagnoses.³ While CDK4/6 inhibitors have transformed the first-line treatment paradigm, resistance eventually develops in nearly all cases. Mutations in the ESR1 gene, which occur in up to 40% of patients with advanced ER-positive disease, are a hallmark of this resistance, rendering traditional aromatase inhibitors less effective.

Giredestrant is a next-generation, nonsteroidal oral SERD and full antagonist designed to achieve deep and sustained inhibition of ER signaling.¹ By triggering the degradation of the estrogen receptor, it blocks both ligand-dependent and ligand-independent signaling, the latter of which is often driven by ESR1 mutations. Unlike intramuscularly administered SERDs, giredestrant’s oral formulation offers a potentially more convenient option for patients while maintaining potent antagonistic activity.

Safety Profile and Tolerability

The safety profile of giredestrant in combination with everolimus was consistent with the known safety signals of the individual agents. No new or unexpected safety concerns were identified in the evERA study. Notably, the trial reported no instances of photopsia, a visual side effect that has been observed with some other investigational agents in the SERD class. Adverse events were described as manageable, supporting the potential for long-term administration in the metastatic setting.

The Giredestrant Development Program

The NDA acceptance for advanced disease follows a string of positive readouts for the molecule. In December 2025, results from the phase 3 lidERA study (NCT04961996) were presented at the 2025 San Antonio Breast Cancer Symposium which showed that giredestrant as an adjuvant treatment reduced the risk of invasive disease recurrence or death by 30% (HR, 0.70) in patients with medium-to-high risk early-stage ER-positive/HER2-negative breast cancer.⁴

Other ongoing phase 3 investigations include the persevERA trial (NCT04546009), evaluating giredestrant plus palbociclib (Ibrance) in the first-line metastatic setting, and the pionERA trial (NCT06065748), comparing giredestrant to fulvestrant (Faslodex) in combination with a CDK4/6 inhibitor for patients with resistance to adjuvant endocrine therapy. Data from the persevERA study are expected within the first half of 2026.¹

REFERENCES

1. FDA accepts new drug application for Genentech’s giredestrant in ESR1-mutated, ER-positive advanced breast cancer. News release. Genentech. February 19, 2026. Accessed February 20, 2026. https://tinyurl.com/ytf5t36m

2. 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.

3. Breast cancer hormone receptor status. American Cancer Society. Accessed February 20, 2026. https://tinyurl.com/5sbhc4yc

4. Bardia A, Schmid P, Martín M, et al. Giredestrant vs standard-of-care endocrine therapy as adjuvant treatment for patients with estrogen receptor-positive, HER2-negative early breast cancer: results from the global Phase III lidERA Breast Cancer trial. Presented at: 2025 San