FDA Accepts NDA for Giredestrant/Everolimus in ESR1-Mutated Breast Cancer

The FDA had accepted a new drug application for giredestrant plus everolimus (Afinitor) for the treatment of patients with estrogen receptor–positive, HER2-negative, ESR1-mutated locally advanced or metastatic breast cancer after progression on previous endocrine therapy, according to a press release from Genentech.¹

A Prescription Drug User Fee Act date of December 18, 2026, has been set. If approved, the combination would be the first oral selective estrogen receptor degrader with a CDK4/6 inhibitor in this setting.

Results from the phase 3 evERA Breast Cancer trial (NCT05306340) led to the application’s acceptance. At the 2025 European Society for Medical Oncology (ESMO) Congress, the presentation of the trial showed a median progression-free survival (PFS) of 8.77 months (95% CI, 6.60-9.59) in the combination arm vs 5.49 months (95% CI, 4.01-5.59) in the standard of care (SOC) arm (HR, 0.56; 95% CI, 0.44-0.71; P <.0001).² For those with an ESR1 mutation, the median PFS was 9.99 months (95% CI, 8.08-12.94) compared with 5.45 months (95% CI, 3.75-5.62) between each arm, respectively, (HR, 0.38; 95% CI, 0.27-0.54; P <.0001).

“Resistance to standard-of-care therapies is common in the post-CDK inhibitor setting, and the results from evERA validate using a combination to address this challenge,” lead study author Erica L. Mayer, MD, MPH, medical oncologist at Dana-Farber Cancer Institute, said in a press release on the evERA findings.³ “The clinically meaningful benefit observed with the giredestrant and everolimus all-oral combination is impressive and speaks to its potential to improve outcomes for patients in need of new treatment options.”

A total of 373 patients were enrolled on the trial and randomly assigned to either the giredestrant plus everolimus arm (n = 183) or SOC arm (n = 190). Treatment administration included giredestrant at 30 mg and everolimus at 10 mg. ESR1 mutations occurred in 102 patients in the combination arm and 105 in the SOC arm.

The co-primary end points of the trial were investigator-assessed PFS in the ESR1 subgroup and in the full intent-to-treat (ITT) group. Secondary end points included overall survival (OS), objective response rate (ORR), and duration of response (DOR).

In the ESR1 group, the 6-month PFS rate was 66.1% for those in the combination arm and 38.1% in the SOC arm. The 12-month PFS rates were 40.5% and 15.2%, respectively. For those in the ITT population, the PFS rates at 6 and 12 months were 57.4% vs 39.6% and 34.1% vs 18.1%.

Regarding OS, interim findings showed a 59% maturity in the ESR1 population and 67% in the ITT population. For the ESR1 group, the median OS was not yet reached in the combination arm compared with 21.03 months in the SOC arm (HR, 0.62; 95% CI, 0.38-1.02; P = .0566). The median OS was also not reached in the ITT population within the combination arm but was 26.87 months in the SOC arm (HR, 0.69; 95% CI, 0.47-1.00; P = .0473).

The ORR in the ESR1 group was 26.6% for the combination arm vs 13.8% for the SOC arm. In the ITT group, the ORRs were 23.8% vs 11.7%, respectively. For patients who did not have an ESR1 mutation, the ORR was 20.0% vs 8.7%.

Regarding DOR, in the ESR1 population, the median DOR was 14.88 months in the combination arm compared with 7.33 months for the SOC arm. In the ITT group, the median DOR was 12.71 months compared with 7.72 months, respectively. For patients without an ESR1 mutation detected, the median DOR was 12.68 months with giredestrant compared with 7.72 months with SOC.

The most common all-grade treatment-emergent adverse effects were stomatitis (47.2% vs 48.9%, respectively), diarrhea (26.9% vs 22.6%), and anemia (23.6% vs 21.0%) between the arms, respectively.

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/yep68x53
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. Ann Oncol. 2025;36(suppl 2):S1561-S1562. doi:10.1016/j.annonc.2025.09.026
3. Roche’s phase III evERA data showed giredestrant significantly improved progression-free survival in people with ER-positive advanced breast cancer. News release. Roche. October 17, 2025. Accessed February 20, 2026. https://tinyurl.com/26xcmfds