Giredestrant + Everolimus Delivers New Hope in ER+ Breast Cancer Post-CDK4/6 Treatment

Recent phase 3 data from the evERA trial (NCT05306340)¹ demonstrate that a combination of giredestrant (Roche) and everolimus (Afinitor; Novartis) extends progression-free survival (PFS) significantly over a standard endocrine therapy plus everolimus in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, after a CDK4/6 inhibitor and endocrine therapy have been passed.²

This study achieved its two co-primary endpoint goals both in the intention-to-treat population and in the group of patients with ESR1-mutated tumors. The findings suggest a clinically significant advantage of postponing disease progression in the challenging case of treatment.²

One of the compelling features of the evERA study is its design. The study was enriched for patients with ESR1 mutations, a known driver of resistance to endocrine therapies in breast cancer. Up to 40% of patients with ER-positive breast cancer are reported to develop ESR1 mutations after treatment with CDK4/6 inhibitors and endocrine therapy; therefore, this is a crucial subgroup for therapeutic targeting.² In evERA, the combination of giredestrant, a selective oral estrogen receptor degrader (SERD), plus everolimus showed a better PFS in the two groups, the ESR1-mutant population as well as the all-comer population, thus indicating its possible wide use regardless of the molecular heterogeneity of advanced ER-positive disease.³

The safety and tolerability of the treatment were as expected. Side effects in the giredestrant plus everolimus group were in line with the known adverse effects of everolimus and SERD treatments, and there were no indications of new safety issues.²

This safety stability is essential for patients who have been through several treatment regimens, where the issue of cumulative toxicity is at the forefront. In addition, the oral form of giredestrant gives a transport advantage over injectable SERDs like fulvestrant (Faslodex; AstraZeneca), thus the ease of use and patient compliance.²

“These results show that the giredestrant combination provides a meaningful benefit for ER-positive breast cancer patients whose disease has progressed following treatment with a CDK inhibitor,” said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. “We look forward to discussing these results with regulatory authorities with the goal of making this giredestrant-based regimen available to many people with advanced ER-positive breast cancer.”

Clinical Implications and Unmet Needs

ER+, HER2- breast cancer is the most common hormone receptor subtype, making up about 70% of breast cancer cases. Treatment with aromatase inhibitors, selective estrogen receptor modulators (SERMs), SERDs, and CDK 4/6 inhibitors has improved significantly, but resistance is still developed in most patients.² Prior studies have pointed out that ESR1 mutations can be present even before metastasis and become more common under endocrine therapy pressure.⁴ The evERA outcomes are particularly encouraging, as they demonstrate activity in both ESR1-mutated and wild-type patients; thus, a treatment that may be beyond mutation status, depending on the regulatory and subgroup groups.³

Looking forward, the secondary endpoints of the trial, such as overall survival, objective response rate, duration of response, clinical benefit rate, and quality of life metrics, will be critically important in determining how this regimen fits into clinical practice.² Although OS data are currently immature, a favorable trend has been detected, with follow-up planned until the next OS analysis.² Besides, the molecular aspects of ESR1 mutation kinds and their responsiveness to this combination will also be key next questions for oncologists and researchers.

Regulatory and Practical Considerations

With these positive data, Genentech (via Roche) plans to present the evERA results to regulatory authorities to seek approval of this regimen for patients with ER-positive, HER2-negative advanced breast cancer after CDK4/6 inhibitor therapy.² If approved, this would represent the first phase 3 evidence for a fully oral SERD-based combination (giredestrant + everolimus) to outperform standard endocrine therapy plus everolimus in the aforementioned setting.^2,4

For pharmacists, advanced practitioners, and oncologists, the implications are significant. The whole treatment process, especially for those with ESR1 mutations, could be altered considerably. Besides that, it is anticipated that the everolimus adverse effects will continue to be addressed rigorously by doctors through patient monitoring. A good point to consider is the patient's health condition, the history of drug tolerance, and other diseases in addition to the ease of taking the medicine orally.

REFERENCES

1. NCT05306340. Clinicaltrials.gov. Published 2025. Accessed September 23, 2025. https://clinicaltrials.gov/study/NCT05306340#study-record-date

2. Positive phase III results show Roche’s giredestrant significantly improved progression-free survival in ER-positive advanced breast cancer. Roche.com. Published 2025. Accessed September 23, 2025. https://www.roche.com/media/releases/med-cor-2025-09-22

3. Taylor NP. Roche reports phase 3 breast cancer victory, starting key period for oral SERD with a win. Fierce Biotech. Published September 22, 2025. Accessed September 23, 2025. https://www.fiercebiotech.com/biotech/roche-reports-phase-3-breast-cancer-victory-starting-key-period-oral-serd-win

4. Patel R, Klein P, Tiersten A, Sparano JA. An emerging generation of endocrine therapies in breast cancer: a clinical perspective. NPJ Breast Cancer. 2023;9(1):20. Published 2023 Apr 5. doi:10.1038/s41523-023-00523-4