A novel oral treatment combination has demonstrated a significant improvement in progression-free survival for patients with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer, according to results from the phase 3 evERA Breast Cancer study.
The findings, presented by Dr. Erica Mayer of the Dana-Farber Cancer Institute at the annual meeting of the European Society for Medical Oncology (ESMO) in Berlin, offer promising evidence for a new, fully oral therapeutic strategy in this challenging breast cancer subtype.
The Clinical Challenge of ER-Positive, HER2-Negative Disease
Breast tumors that express the estrogen receptor account for approximately 70% of all breast cancer diagnoses. Although endocrine therapies have been effective for many patients, metastatic or advanced forms of ER-positive disease remain difficult to manage, particularly when tumors develop resistance to current treatments. Resistance to endocrine therapy and CDK4/6 inhibitors—both key components of modern breast cancer care—represents one of the most pressing obstacles in oncology today.
“There is a significant need for therapies for metastatic ER-positive breast cancers that are more effective, particularly for patients whose tumors develop resistance to current endocrine therapies,” explained Dr. Mayer. “We also need tolerable therapies that work well with existing targeted agents to improve outcomes for patients in later lines of treatment, when resistance becomes more difficult to overcome.”
Giredestrant: A Next-Generation Oral SERD
At the center of this advancement is giredestrant, a next-generation selective estrogen receptor degrader (SERD) and full antagonist. Giredestrant binds directly to the estrogen receptor, promoting its degradation and preventing estrogen from stimulating tumor growth.
Compared with earlier SERDs, giredestrant has two key advantages:
A novel mechanism of action, which allows it to remain effective in tumors resistant to older hormone therapies.
Oral administration, offering patients greater convenience compared to first-generation SERDs, which require monthly injections.
This dual benefit makes giredestrant a compelling option for patients seeking both efficacy and quality of life.
Inside the evERA Study Design
The evERA Breast Cancer trial is a global, phase 3, randomized, open-label study evaluating the use of giredestrant in combination with everolimus, an mTOR inhibitor, in patients with ER-positive, HER2-negative advanced breast cancer. The study compares this all-oral regimen to the current standard of care: endocrine therapy plus everolimus.
A total of 373 patients were enrolled and randomized to receive either the giredestrant–everolimus combination or standard endocrine therapy with everolimus. Notably, 55% of participants carried ESR1 gene mutations, which are associated with resistance to endocrine therapy and poorer prognoses.
The study’s primary endpoint was progression-free survival (PFS), assessed in both the intention-to-treat (ITT) population and the ESR1-mutant subgroup.
Significant Improvements in Progression-Free Survival
After a median follow-up of 18.6 months, results showed a statistically significant improvement in PFS for patients treated with the giredestrant combination:
In patients with ESR1-mutated tumors, median PFS reached 9.99 months with the giredestrant regimen, compared with 5.45 months for those on standard therapy—a 63% reduction in the risk of disease progression or death.
In the overall ITT population, median PFS was 8.77 months versus 5.49 months, translating to a 44% reduction in disease progression or death risk.
While overall survival (OS) data remain immature, early trends are favoring the giredestrant arm. Importantly, the regimen’s safety profile was consistent with known effects of giredestrant and everolimus, and side effects were manageable across both treatment groups.
Expert Insights and Clinical Implications
“Although we’ve made great progress in treating metastatic ER-positive, HER2-negative breast cancer, resistance to therapy remains a formidable challenge,” Dr. Mayer noted. “The combination of giredestrant and everolimus is designed to address these resistance mechanisms directly. The evERA study is the first to demonstrate that this new combination can significantly improve disease control compared with a standard of care regimen.”
The results are particularly meaningful as evERA represents the first positive, head-to-head phase 3 study of an all-oral SERD-based regimen versus standard endocrine therapy. If validated by longer-term survival data, this approach could reshape the therapeutic landscape for patients with advanced ER-positive, HER2-negative disease.
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