Giredestrant Combo Significantly Boosts PFS in ER+ Advanced Breast Cancer

Developers designed giredestrant as an orally available next-generation selective estrogen receptor degrader (SERD) and full antagonist. The agent functions by preventing estrogen from binding to the estrogen receptor, facilitating its degradation while stopping or delaying cancer cell growth.

Treatment with giredestrant plus everolimus (Afinitor) significantly prolonged progression-free survival (PFS) vs endocrine therapy plus everolimus among those with previously treated, estrogen receptor (ER)–positive, HER2-negative, locally advanced or metastatic breast cancer, according to a press release on findings from the phase 3 evERA trial (NCT05306340).1

Data showed that the investigational combination reached both co-primary end points, showing a clinically meaningful and statistically significant PFS improvement in the intention-to-treat (ITT) population as well as those with ESR1-mutated disease. Although overall survival (OS) data were not yet mature at the time of the analysis, the giredestrant regimen demonstrated a positive trend in this end point vs endocrine therapy plus everolimus.

Investigators noted that the novel combination was well tolerated, as adverse effects (AEs) were consistent with prior reports of each individual agent. The study showed no new safety signals.

According to the press release, the evERA study is the first positive head-to-head phase 3 trial assessing an all-oral regimen including a selective ER degrader (SERD) vs a standard-of-care combination in this population. Additionally, investigators plan to submit data from evERA to regulatory health authorities with the aim of expanding access to this potential therapeutic option.

“These results show that the giredestrant combination provided a meaningful benefit for [patients with] ER-positive breast cancer whose disease has progressed following treatment with a CDK inhibitor,” Levi Garraway, chief medical officer and head of Global Product Development at Roche, the developer of giredestrant, stated in the press release.1 “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.”

Developers designed giredestrant as an orally available next-generation SERD and full antagonist. The agent functions by preventing estrogen from binding to the ER, facilitating its degradation while stopping or delaying cancer cell growth.

Investigators of the open-label, multicenter, phase 3 evERA trial assessed the safety and efficacy of giredestrant plus everolimus vs standard-of-care endocrine therapy plus everolimus among those with ER-positive, HER2-negative advanced or metastatic breast cancer who received prior treatment with CDK4/6 inhibitors and endocrine therapy in the adjuvant or locally advanced/metastatic setting. Patients in the investigational arm received giredestrant at 30 mg orally once a day plus everolimus at 10 mg orally every day on each 28-day cycle.2 In the comparator arm, patients received everolimus plus investigator’s choice of exemestane (Aromasin), fulvestrant (Faslodex), or tamoxifen (Soltamox).

The trial’s co-primary end points were investigator-assessed PFS in the ITT and ESR1-mutated populations. Secondary end points included OS, objective response rate, duration of response, clinical benefit rate, health-related quality of life, clinical laboratory test abnormalities, vital sign abnormalities, plasma concentration of giredestrant, and AEs per CTCAE v5.0 criteria.

Patients 18 years and older with locally advanced unresectable or metastatic adenocarcinoma of the breast not amenable to curative therapy, documented ER-positive and HER2-negative status, and the ability to provide a blood sample for circulating tumor DNA ESR1 mutation status via central testing were eligible for study entry. Additional eligibility criteria included having measurable disease per RECIST v1.1 guidelines or evaluable bone metastases and an ECOG performance status of 0 or 1.

Those with prior treatment with another oral SERD, proteolysis targeting chimera, complete ER antagonist, investigational oral selective ER modulator, or everolimus in any setting were ineligible to enroll on the trial. Patients were also unable to enroll if they had prior chemotherapy for locally advanced unresectable or metastatic disease.

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://tinyurl.com/bdurt659
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://tinyurl.com/ya64y4bd