FDA Accepts Giredestrant Application for ESR1-Mutated Advanced Breast Cancer

The FDA has accepted a new drug application for giredestrant in combination with everolimus for the treatment of adult patients with estrogen receptor-positive, HER2-negative, ESR1-mutated locally advanced or metastatic breast cancer following recurrence or progression on a prior endocrine-based regimen. The FDA has set a Prescription Drug User Fee Act date of December 18, 2026.

If approved, the combination of giredestrant and everolimus would become the first and only oral selective estrogen receptor degrader (SERD) combination therapy available for patients in the post-cyclin-dependent kinase (CDK)4/6 inhibitor setting.

The filing acceptance is based on data from the phase 3 evERA Breast Cancer study, which showed that giredestrant plus everolimus reduced the risk of disease progression or death by 44% in the intention-to-treat (ITT) population compared with standard-of-care endocrine therapy plus everolimus. In patients specifically with ESR1 mutations, the risk reduction was 62%.

In the ESR1-mutated group, the median progression-free survival was 9.99 months for those receiving the giredestrant combination, compared to 5.45 months for those in the comparator arm. For the ITT population, the median progression-free survival reached 8.77 months with giredestrant versus 5.49 months for those receiving the standard-of-care combination.

Overall survival data were immature at the time of analysis, but a positive trend has been observed in the ITT population with a hazard ratio of 0.69, and in the ESR1-mutated population with a hazard ratio of 0.62. Researchers will continue to follow up with participants for further survival analysis.

The evERA Breast Cancer study is a phase 3, randomized, open-label, multicenter trial that included patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer. All participants had previously received treatment with a CDK4/6 inhibitor and endocrine therapy. The primary endpoints of the study were investigator-assessed progression-free survival in both the ITT and ESR1-mutated populations. To ensure a thorough evaluation, the trial was enriched with a higher number of patients with ESR1 mutations than typically found in nature. In the post-CDK inhibitor setting, ESR1 mutations are found in up to 40% of people with ER-positive disease.

According to the study findings, the safety profile of the giredestrant and everolimus combination was manageable. The adverse events reported by participants were consistent with the safety profiles already known for each individual medicine. Researchers reported that there were no unexpected safety findings during the trial.

Giredestrant is an investigational, oral next-generation SERD designed to work as a full antagonist, blocking estrogen from binding to the receptors on cancer cells. This process triggers the breakdown, or degradation, of the receptor, which can stop or slow the growth of the cancer.

Estrogen receptor-positive breast cancer represents approximately 70% of all breast cancer cases. While treatments have advanced, patients often face resistance to endocrine therapies, which increases the risk of the disease progressing.

Data from evERA are being used to support filing submissions to other global health authorities. evERA was the first positive phase 3 readout for giredestrant, followed by lidERA Breast Cancer in the early-stage setting. In the coming weeks, Roche will submit the giredestrant phase 3 lidERA data in early-stage breast cancer to health authorities worldwide, including the FDA.

The persevERA readout in first-line ER-positive breast cancer is expected in the first half of this year. Treatment with the combination of giredestrant and palbociclib generated a numerical but not statistically significant improvement in progression-free survival compared with letrozole plus palbociclib in patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer, missing the primary end point of the phase 3 persevERA trial. In the experimental arm, adverse effects were manageable and consistent with the known safety profiles of the individual agents. Full data will be shared at an upcoming medical meeting.