Giredestrant Plus Everolimus Meets Coprimary PFS End Points in Post–CDK Inhibitor ER+/HER2– Breast Cancer

The investigational, all-oral combination of giredestrant plus everolimus (Afinitor) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs standard-of-care (SOC) endocrine therapy plus everolimus among patients with estrogen receptor (ER)–positive, HER2-negative, locally advanced or metastatic breast cancer who had previously been treated with a CDK4/6 inhibitor plus endocrine therapy in both the intention-to-treat (ITT) and ESR1-mutated patient populations, meeting both co-primary end points of the phase 3 evERA Breast Cancer study (NCT05306340).1

Furthermore, although overall survival (OS) data remain immature, a clear positive trend in favor of the investigational arm was observed, and follow-up will continue in the next OS analysis. Regarding safety, the combination was well tolerated, and adverse effects were consistent with the known safety profiles of the individual study treatments; importantly, no new safety signals were observed.

These positive findings suggest that the combination of giredestrant plus everolimus may offer a meaningful treatment option in the difficult post-CDK inhibitor setting, Roche, the drug’s developer, asserted in a press release.

evERA is the first positive head-to-head phase 3 trial investigating an all-oral selective estrogen receptor degrader (SERD)–containing regimen vs a SOC combination. Data from the study will be presented at an upcoming medical meeting and subsequently shared with health authorities.

“These results show that the giredestrant combination provided a meaningful benefit for ER-positive breast cancer patients whose disease has progressed following treatment with a CDK inhibitor,” Levi Garraway, chief medical officer and head of Global Product Development at Roche, stated in the news release. “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.”

What Is Giredestrant, and Why Administer It in Combination With Everolimus?

Giredestrant is an investigational, oral, next-generation SERD and full antagonist. It was specifically designed to address the challenges of endocrine resistance by directly blocking estrogen from binding to the ER. Upon binding, giredestrant triggers degradation of the ER, which ultimately works to stop or slow down the growth of ER-positive cancer cells.

Combining giredestrant with everolimus, which targets the mTOR pathway, allows 2 different signaling pathways to be targeted simultaneously, offering the potential for improved patient outcomes in resistant disease. Additionally, as an all-oral therapy, this regimen could potentially help increase patient compliance and satisfaction by eliminating the need for injections.

How Was the evERA Trial Designed?

The global, randomized, open-label, multicenter phase 3 study enrolled patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer who had received prior treatment with a CDK4/6 inhibitor and endocrine therapy, regardless of whether previous treatment was given in the adjuvant or locally advanced/metastatic setting.1,2

Patients on the trial were randomly assigned to receive either giredestrant plus everolimus vs exemestane plus everolimus at the following doses2:

• Giredestrant: 30 mg daily by mouth per 28-day cycle
• Everolimus: 10 mg daily by mouth per 28-day cycle
• Exemestane: 25 mg daily by mouth per 28-day cycle

Of note, premenopausal or perimenopausal female patients and male patients received a luteinizing hormone-releasing hormone agonist on day 1 of each 28-day treatment cycle, as determined and supplied by a study investigator. Treatment continued until unacceptable toxicity or disease progression as determined by the investigator according to RECIST 1.1 criteria.

The trial’s coprimary end points were investigator-assessed PFS in the ITT and ESR1-mutant patient populations.1 An enrichment strategy to specifically assess efficacy in the ESR1-mutated patient population was included in the trial design. Key secondary end points included OS, objective response rate, duration of response, clinical benefit rate, and safety.

What Investigations of Giredestrant in Breast Cancer Are Currently Ongoing?

Giredestrant is currently being evaluated in an extensive clinical development program that spans multiple treatment settings and lines of therapy. In addition to evERA, the program includes 4 other company-sponsored phase 3 clinical trials:

• lidERA Breast Cancer (NCT04961996): Giredestrant vs SOC endocrine therapy as adjuvant treatment in ER-positive, HER2-negative early-stage breast cancer.
• persevERA Breast Cancer (NCT04546009): Giredestrant plus palbociclib (Ibrance) vs letrozole plus palbociclib in ER-positive, HER2-negative, endocrine-sensitive, recurrent locally advanced or metastatic breast cancer.
• pionERA Breast Cancer (NCT06065748): Giredestrant plus investigator’s choice of a CDK4/6 inhibitor vs fulvestrant (Faslodex) plus a CDK4/6 inhibitor in ER-positive, HER2-negative advanced breast cancer resistant to adjuvant endocrine therapy.
• heredERA Breast Cancer (NCT05296798): Pertuzumab, trastuzumab, and subcutaneous hyaluronidase-zzxf (Phesgo) alone vs in combination with giredestrant in ER-positive, HER2-positive locally advanced or metastatic breast cancer.

Based on the data from evERA, Roche is moving forward with regulatory submissions for giredestrant plus everolimus.

References

1. Positive phase III results show Roche’s giredestrant significantly improved progression-free survival in ER-positive advanced breast cancer. News release. Roche. September 21, 2025. Accessed September 22, 2025. https://www.roche.com/media/releases/med-cor-2025-09-22
2. A study evaluating the efficacy and safety of giredestrant plus everolimus compared with the physician's choice of endocrine therapy plus everolimus in participants with estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer (evERA Breast Cancer). ClinicalTrials.gov. Updated August 13, 2025. Accessed September 22, 2025. https://clinicaltrials.gov/study/NCT05306340