Giredestrant/Everolimus Drives PFS2, Chemotherapy-Free Survival Benefits in ER+, HER2– Advanced Breast Cancer

Giredestrant plus everolimus (Afinitor) improved progression-free survival (PFS) after next-line therapy (PFS2) and prolonged chemotherapy-free survival compared with standard-of-care (SOC) endocrine therapy (ET) plus everolimus in patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer previously treated with a CDK4/6 inhibitor, according to exploratory post-progression analyses from the phase 3 evERA BC trial (NCT05306340) presented at the 2026 ASCO Annual Meeting.¹

Findings showed that in the overall study population, the median PFS2 was 19.02 months (95% CI, 15.51-not estimable [NE]) with giredestrant plus everolimus (n = 183) vs 13.17 months (95% CI, 11.70-15.57) with SOC ET plus everolimus (n = 190; HR, 0.69; 95% CI, 0.51-0.92).

Chemotherapy-free survival was 11.10 months (95% CI, 9.50-12.59) with giredestrant vs 7.89 months (95% CI, 6.53-9.49) with SOC (HR, 0.61; 95% CI, 0.47-0.79).

“Subsequent therapies were generally balanced across the treatment arms and representative of the current SOC,” lead study author Komal Jhaveri, MD, FACP, said in a presentation of the data. “Improved PFS2 and chemotherapy-free survival were consistent with favorable overall survival [OS] data at this interim OS analysis.”

Jhaveri is the section head of the Endocrine Therapy Research Program, clinical director of the Early Drug Development Service, and the Patricia and James Cayne Chair for Junior Faculty at Memorial Sloan Kettering Cancer Center in New York, New York.

What were the primary evERA results?

The evERA BC trial enrolled 373 patients with ER-positive, HER2-negative advanced breast cancer who experienced disease progression during or following a CDK4/6 inhibitor plus ET.

Patients were randomly assigned 1:1 to receive oral giredestrant at 30 mg once daily plus everolimus at 10 mg or SOC ET (exemestane, fulvestrant, or tamoxifen) plus everolimus at 10 mg per day.

The co-primary end points were investigator-assessed PFS in the overall intent-to-treat (ITT) population and in patients with ESR1-mutant tumors.

Primary results presented at the 2025 ESMO Congress showed a statistically significant PFS benefit for giredestrant plus everolimus in both populations. In the ITT population, the median investigator-assessed PFS was 8.77 months vs 5.49 months with SOC (HR, 0.56; 95% CI, 0.44-0.71; P < .0001).² Among patients with ESR1-mutant tumors, the median PFS was 9.99 months vs 5.45 months, respectively (HR, 0.38; 95% CI, 0.27-0.54; P < .0001).

The safety profile was manageable and consistent with the known profiles of each agent. The most common all-grade treatment-emergent adverse effects (AEs) were stomatitis (47.2% with giredestrant vs 48.9% with SOC), diarrhea (26.9% vs 22.6%), and anemia (23.6% vs 21.0%). Grade 1/2 bradycardia occurred in 3.8% of patients in the giredestrant arm vs 0.5% in the SOC arm, with no cases of photopsia observed. Treatment discontinuation due to AEs occurred in 17.0% and 11.8% of patients, respectively.

What Did the PFS2 Data Show Across ESR1 Subgroups?

PFS2 benefits were observed in both the ESR1-mutant and ESR1-mutation-not-detected subgroups.¹ Among patients with ESR1-mutant tumors, the median PFS2 was 19.02 months (95% CI, 15.51-NE) with giredestrant plus everolimus (n = 102) vs 12.54 months (95% CI, 11.70-17.51) with SOC ET (n = 105; HR, 0.61; 95% CI, 0.40-0.93). In patients without a detected ESR1 mutation, the median PFS2 was 17.25 months (95% CI, 13.91-NE) with giredestrant (n = 81) vs 12.59 months (95% CI, 9.79-20.82) with SOC (n = 85; HR, 0.77; 95% CI, 0.51-1.17).

What were the chemotherapy-free survival and OS Findings?

The chemotherapy-free survival benefit with giredestrant plus everolimus was most pronounced in patients with ESR1-mutant tumors. In this subgroup, the median chemotherapy-free survival was 12.59 months with giredestrant plus everolimus vs 8.54 months with SOC ET (HR, 0.46; 95% CI, 0.32-0.66). In the ESR1-mutation-not-detected subgroup, the median chemotherapy-free survival was 9.53 months vs 7.29 months, respectively (HR, 0.80; 95% CI, 0.57-1.14)

Updated interim OS data remained consistent with the favorable signal from the primary analysis. In the ITT population, the median OS was NE (95% CI, NE-NE) with giredestrant vs 26.87 months (95% CI, 22.21-NE) with SOC (HR, 0.69; 95% CI, 0.47-1.00).

In the ESR1-mutant subgroup, the median OS was NE (95% CI, 20.17-NE) in the giredestrant arm vs 21.03 months (95% CI, 14.78-26.87) with SOC (HR, 0.62; 95% CI, 0.36-1.02).

References

1. Jhaveri KL, Rugo HS, Tolaney SM, et al. Post-progression treatment analyses of evERA Breast Cancer (BC): a phase III trial of giredestrant (GIRE) + everolimus (E) in patients with ER-positive, HER2-negative advanced BC previously treated with a CDK4/6 inhibitor. Presented at: 2026 ASCO Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract 1016.
2. 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.