Giredestrant Plus Everolimus Improves PFS in ER+ Advanced Breast Cancer

Giredestrant (GDC-9545) plus everolimus (Afinitor) significantly improved progression-free survival (PFS) vs standard endocrine therapy plus everolimus in patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer previously treated with a CDK4/6 inhibitor, according to detailed results from the phase 3 evERA Breast Cancer trial (NCT05306340) published in The New England Journal of Medicine (NEJM).¹^,2

The combination reduced the risk of disease progression or death by 44% in the intent-to-treat (ITT) population and by 62% in the ESR1-mutated population.

Giredestrant is an investigational, oral, next-generation selective estrogen receptor degrader (SERD) and full antagonist.

Study Design

evERA is a randomized, open-label, multicenter phase 3 study comparing giredestrant plus everolimus with standard endocrine therapy plus everolimus in patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer who had received a CDK4/6 inhibitor and endocrine therapy in the adjuvant or locally advanced/metastatic setting. The coprimary end points were investigator-assessed PFS in the ITT and ESR1-mutated populations, defined as the time from randomization to disease progression or death from any cause. Key secondary end points included overall survival (OS), objective response rate, duration of response, clinical benefit rate, and safety.

Efficacy and Safety Findings

In the ESR1-mutated population, median PFS was 10.0 months with giredestrant plus everolimus vs 5.5 months in the comparator arm (stratified HR, 0.38; 95% CI, 0.27-0.54; P < .001). In the ITT population, median PFS was 8.8 months vs 5.5 months, respectively (HR, 0.56; 95% CI, 0.44-0.71; P < .001). OS data were immature at the time of analysis. The HR for OS was 0.69 (95% CI, 0.47-1.00) in the ITT population and 0.62 (95% CI, 0.38-1.02) in the ESR1-mutated population, with the upper bound of the confidence interval crossing 1.00 in the latter. Roche, the sponsor, described the findings as a clear positive trend, and follow-up for OS will continue to the next analysis.²

Adverse events with the combination were manageable and consistent with the known safety profiles of the individual agents. No unexpected safety findings were observed, including no photopsia and low rates of bradycardia.^1,2 Additional evERA analyses presented at the 2026 American Society of Clinical Oncology Annual Meeting showed that giredestrant plus everolimus prolonged PFS2, defined as the time from randomization to disease progression following second-line therapy, and chemotherapy-free survival vs standard endocrine therapy. The findings suggest the benefit may extend beyond initial progression.³

Clinical Context

Hormone receptor–positive, HER2-negative disease accounts for approximately 70% of breast cancer cases, and resistance to endocrine therapy, particularly after CDK4/6 inhibitor treatment, increases the risk of progression.² Up to 40% of patients with ER-positive disease have ESR1 mutations in the post–CDK inhibitor setting.²

"Despite advancements with CDK4/6 inhibitor treatment in the first-line setting, many people with advanced breast cancer will eventually experience disease progression as their tumors become resistant to endocrine therapy. The evERA trial demonstrated that the giredestrant combination significantly delayed disease progression, potentially offering a promising all-oral treatment option in a setting where there remains a need for additional treatments to improve patient outcomes,” said Erica L. Mayer, MD, MPH, director of Breast Cancer Clinical Research, Dana-Farber Cancer Institute, in a news release.

Regulatory Status and Giredestrant Development Program

The FDA accepted a new drug application (NDA) for giredestrant plus everolimus in February 2026.⁴ The application covers ER-positive, HER2-negative, ESR1-mutated locally advanced or metastatic breast cancer that has recurred during or after adjuvant endocrine-based therapy or progressed on at least 1 endocrine-based regimen in the metastatic setting, with a Prescription Drug User Fee Act (PDUFA) goal date of December 18, 2026.² The agency has also accepted an NDA under priority review for giredestrant as adjuvant treatment in adults with ER-positive, HER2-negative stage I to III breast cancer, based on the phase 3 lidERA Breast Cancer trial (NCT04961996). The PDUFA goal date for that application is November 30, 2026.² evERA was the first positive phase 3 readout for giredestrant, followed by lidERA. In March 2026, the phase 3 persevERA Breast Cancer trial (NCT04546009), which evaluated giredestrant plus palbociclib vs letrozole plus palbociclib in endocrine-sensitive, recurrent locally advanced or metastatic disease, did not meet its primary PFS end point.⁵

REFERENCES

1. Mayer E, et al. Giredestrant plus everolimus in advanced breast cancer. N Engl J Med. Published online October 2026. doi:10.1056/NEJMoa2602457

2. Roche's giredestrant combination significantly improved progression-free survival in ER-positive advanced breast cancer in phase III evERA data published in The New England Journal of Medicine. News release. Roche. October 1, 2026. Accessed October 1, 2026. https://tinyurl.com/ypssy9sz

3. Jhaveri K, et al. Post-progression treatment analyses 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: 2026 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract 1016.

4. FDA accepts new drug application for giredestrant in advanced breast cancer. Targeted Oncology. February 20, 2026. Accessed October 1, 2026. https://tinyurl.com/56bajdkh

5. Phase 3 trial of giredestrant misses primary PFS end point. Targeted Oncology. March 9, 2026. Accessed October 1, 2026. https://tinyurl.com/ym8jfzkw