FDA Reviews Giredestrant Plus Everolimus for ESR1-Mutated ER-Positive Breast Cancer

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

The filing acceptance is based on the phase 3 evERA Breast Cancer study (NCT05306340), which showed that giredestrant plus everolimus reduced the risk of disease progression or death by 62% compared with standard-of-care endocrine therapy plus everolimus in patients with ESR1-mutated disease (HR, 0.38; 95% CI, 0.27-0.54; P < .0001). In this population, the median progression-free survival 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%.

Among evaluable patients in the ESR1-mutated population, the overall response rate 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 were 14.88 months (95% CI, 9.10-not evaluable; n = 25) vs 7.33 months (95% CI, 3.84-NE; n = 13), respectively.

In the intention-to-treat 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). 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 overall survival data were not mature at the time of analysis, a positive trend was observed 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). Follow-up for OS is planned to continue.

The evERA Breast Cancer study was an open-label, multicenter study that 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. The coprimary end points were investigator-assessed PFS in the ESR1-mutated and intention-to-treat populations. Key secondary end points included overall survival, ORR, DOR, clinical benefit rate, and safety.

If approved, giredestrant plus everolimus could be the first and only oral selective estrogen receptor degrader combination approved in the post-CDK4/6 inhibitor setting. Giredestrant is a next-generation, nonsteroidal oral SERD and full antagonist designed to achieve deep and sustained inhibition of ER signaling. 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.

The adverse effects observed in the giredestrant/everolimus arm were deemed manageable and consistent with the known safety profiles of the individual agents. No unexpected safety findings were observed, 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.

ER-positive breast cancer accounts for approximately 70% of breast cancer cases. Resistance to endocrine therapies, particularly in the post-CDK inhibitor setting, increases the risk of disease progression and is associated with poor outcomes. Mutations in the ESR1 gene occur in up to 40% of patients with advanced ER-positive disease and are a hallmark of this resistance, rendering traditional aromatase inhibitors less effective.

The NDA acceptance for advanced disease follows positive readouts from the phase 3 lidERA study (NCT04961996) in the early-stage setting, which were presented in December 2025. Other ongoing phase 3 investigations include the persevERA trial (NCT04546009), evaluating giredestrant plus palbociclib in the first-line metastatic setting, and the pionERA trial (NCT06065748), comparing giredestrant to fulvestrant 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.