Giredestrant Combo Improves Efficacy vs SOC in ER+, HER2- Breast Cancer

Giredestrant plus everolimus doubled the ORR and prolonged the DOR in patients with ER-positive, HER2-negative advanced breast cancer previously treated with a CDK4/6 inhibitor.

The all-oral combination of the selective estrogen receptor degrader (SERD) giredestrant with everolimus significantly reduced the risk of progression or death compared with standard of care (SOC) endocrine therapy plus everolimus in patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer previously treated with a CDK4/6 inhibitor. Primary results from the phase 3 evERA trial (NCT05306340) were presented at the 2025 European Society for Medical Oncology (ESMO) Congress.1

In the intent-to-treat population, the median progression-free survival (PFS) was 8.77 months (95% CI, 6.60-9.59) with giredestrant plus everolimus compared with 5.49 months (95% CI, 4.01-5.59) with SOC (HR, 0.56; 95% CI, 0.44-0.71; P <.0001). In a sub-population defined by the presence of the ESR1 mutation, the giredestrant combination elicited a median PFS of 9.99 months (95% CI, 8.08-12.94) compared with 5.45 months (95% CI, 3.75-5.62) for those treated with SOC (HR, 0.38; 95% CI, 0.27-0.54; P <.0001).

"The combination of giredestrant and everolimus—an oral SERD and an oral mTOR inhibitor—may represent a new, effective, all-oral treatment option in the post-CDK 4/6 inhibitor setting for patients with ER-positive, HER2-negative advanced disease," lead investigator Erica L. Mayer, MD, MPH, medical oncologist and clinical investigator in the Breast Oncology Center at the Dana-Farber Cancer Institute, said during a presentation of the results. "Consistent benefit with this regimen was seen across key subgroups. Overall response and duration of response benefits were observed in all patients. Overall survival is immature yet favorable."

The evERA study enrolled 373 patients and randomly assigned them to giredestrant plus everolimus (n = 183) or SOC endocrine therapy plus everolimus (n = 190). Giredestrant was administered at 30 mg and everolimus was given at 10 mg in both arms. Patients were stratified based on their ESR1 status, site of disease, and prior treatment with fulvestrant. Of note, ESR1 mutations were present in 102 of those in the giredestrant arm and for 105 in the SOC group at baseline. The most common SOC therapy was exemestane (n = 141) followed by fulvestrant (n = 39) and tamoxifen (n = 6).

Baseline demographics and characteristics were balanced across the groups, Mayer mentioned. In the giredestrant arm, the median age was 62 years. Visceral disease was present for 68.9% of patients, most commonly in the liver (n = 89). Bone only metastases were present for 13.1% of patients. Most patients (76.5%) had received at least 1 prior line of therapy for advanced breast cancer, with 21.9% having received 2 and 1.6% having received none. All patients had received a prior CDK4/6 inhibitor. Nearly half of patients had received prior fulvestrant (47%).

Investigator assessed PFS in the ESR1 subgroup and in the full intent-to-treat (ITT) population were the co-primary end points of the study. Secondary end points included overall survival (OS), objective response rate (ORR), and duration of response (DOR).

The PFS Kaplan-Meier curves separated early and continued to widen, Mayer noted. In the ESR1 group, at 6 months, 66.1% of those in the giredestrant group remained progression free compared with 38.1% in the control arm. At month 12, the PFS rates were 40.5% and 15.2%, respectively. In the ITT population, the 6-month PFS rate was 57.4% with giredestrant compared with 39.6% for SOC. At 12 months, the PFS rates were 34.1% and 18.1%, respectively.

An exploratory analysis found similar PFS rates regardless of the endocrine therapy used in the SOC arm. In the ESR1 group, the hazard ratios for giredestrant/everolimus compared with exemestane/everolimus and fulvestrant/everolimus were 0.40 (95% CI, 0.28-0.58) and 0.44 (95% CI, 0.28-0.69), respectively. For those in the ITT, the HRs were 0.55 (95% CI, 0.43-0.71) and 0.59 (95% CI, 0.40-0.86), respectively.

"Treatment with giredestrant and everolimus has consistent benefit across all key subgroups," Mayer said. "This includes patients with visceral disease, liver involvement, prior treatment with fulvestrant, and I would add, in the ESR1-mutant and wild-type populations."

Interim findings were presented for OS, which had reached 59% maturity in the ESR1 population and 67% maturity in the ITT group. In the ESR1 group, median OS was not yet reached in the giredestrant group compared with 21.03 months for those treated with SOC (HR, 0.62; 95% CI, 0.38-1.02; P = .0566). In the ITT population, median OS was not yet reached in the giredestrant arm compared with 26.87 months in the SOC arm (HR, 0.69; 95% CI, 0.47-1.00; P = .0473).

An exploratory analysis was conducted looking at PFS and OS in patients without ESR1 mutations detected. In this subgroup, the median PFS was 5.72 in the giredestrant group compared with 5.52 in the SOC group (HR, 0.84; 95% CI, 0.59-1.18). The median OS in this group was not reached in either arm (HR, 0.79; 95% CI, 0.44-1.40).

In the ESR1-mutant group, the ORR was 26.6% with giredestrant compared with 13.8% with SOC. In the ITT group, the ORR was 23.8% with giredestrant and 11.7% with SOC. In those without the ESR1 mutation, the ORR was 20.0% with giredestrant and 8.7% with SOC.

The median DOR was longer in the giredestrant arm. In the ESR1-mutant population, the median DOR was 14.88 months compared with 7.33 months for SOC. For the ITT group, the DOR was 12.71 months compared with 7.72 months, for giredestrant and SOC, respectively. For those without an ESR1 mutation detected, the median DOR was 12.68 months with giredestrant compared with 7.72 months with SOC.

"Treatment with giredestrant and everolimus led to a consistent doubling in the response rate, seen in the ESR1 population, the ITT population, as well as those without ESR1 mutation," said Mayer. "These were durable responses, as the duration of response was consistently prolonged in all 3 subgroups. Notably, in the ESR1-mutant population, the duration of response doubled from about 7 months with standard of care and everolimus therapy to almost 15 months of disease control with giredestrant."

In the investigational arm, the median treatment duration was 7.11 months with giredestrant and 6.03 months for everolimus. Adverse events led to treatment discontinuation for 17% of those in the giredestrant group compared with 11.8% of those in the SOC arm. The median dose intensity was 95.98% for giredestrant and 84.70% for everolimus. In the control group, the median treatment duration was 4.62 months for endocrine therapy and 4.14 months for everolimus. The median dose intensity was 96.65% for the endocrine therapy and 87.86% for everolimus.

The most common all-grade treatment-emergent adverse events (AEs) in the giredestrant and SOC arms were stomatitis (47.2% vs 48.9%, respectively), diarrhea (26.9% vs 22.6%), and anemia (23.6% vs 21.0%). Of note, Mayer noted that grade 1/2 bradycardia occurred in 3.8% of those treated with giredestrant compared with 0.5% of those in the SOC group. There were no cases of photopsia seen in the study.

"Assessment of toxicity is influenced by the longer median treatment duration in the giredestrant arm," said Mayer. "Overall, however, the toxicity experience was fairly balanced between the 2 arms and reflects the known safety profiles of the individual study agents."

According to Roche, the developer of giredestrant, data from the evERA study would be "shared with health authorities, with the aim of bringing this potential treatment option to people as soon as possible," according to a statement from the company.2

References

1. Mayer E, Tolaney SM, Martin M, et al. Giredestrant (GIRE), an oral selective oestrogen receptor (ER) antagonist and degrader, + everolimus (E) in patients (pts) with ER-positive, HER2-negative advanced breast cancer (ER+, HER2– aBC) previously treated with a CDK4/6 inhibitor (i): Primary results of the phase III evERA BC trial. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA16.
2. Roche’s phase III evERA data showed giredestrant significantly improved progression-free survival in people with ER-positive advanced breast cancer. Roche. October 18, 2025. Accessed October 18, 2025. https://www.roche.com/media/releases/med-cor-2025-10-18