Frontline Giredestrant Displays IDFS Improvement vs SOC ET in ER+/HER2– BC

Giredestrant (GDC-9545) displayed an improvement in invasive disease-free survival (IDFS) vs standard-of-care (SOC) endocrine therapy among patients with estrogen receptor (ER)-positive, HER2-negative, medium- and high-risk early breast cancer, according to findings from the phase 3 lidERA Breast Cancer (BC) trial (NCT04961996) presented in a press briefing at the 2025 San Antonio Breast Cancer Symposium (SABCS).

Efficacy data from the trial revealed that in patients treated with giredestrant (n = 2084) or SOC endocrine therapy (n = 2086), a significant and clinically meaningful improvement in IDFS was observed with the investigational therapy, with a 30% reduction in the risk of invasive disease recurrence or death vs SOC (HR, 0.70; 95% CI, 0.57-0.87; P = .0014) after a median follow-up of 32.36 months. Additionally, the respective 12-, 24-, and 36-month IDFS rates in the giredestrant arm were 97.7%, 94.6%, and 92.4%. In the SOC arm, the respective rates were 96.9%, 92.3%, and 89.6%.

An exploratory analysis examining IDFS by SOC endocrine therapy regimens revealed that aromatase inhibitors displayed more favorable efficacy vs tamoxifen, with respective HRs of 0.73 (95% CI, 0.58-0.92) vs 0.53 (95% CI, 0.35-0.80).

A subgroup analysis revealed that the IDFS benefit was consistent across all key prespecified subgroups. Particular benefit was observed among patients 46 to 55 years old (HR, 0.54; 95% CI, 0.36-0.80), patients with AJCC stage II disease at surgery (HR, 0.58; 95% CI, 0.39-0.85), patients who did not receive prior chemotherapy (HR, 0.63; 95% CI, 0.33-1.21), and pre-menopausal patients (HR, 0.65; 95% CI, 0.44-0.95).

Additionally, interim overall survival (OS) data revealed a numerically improved advantage with giredestrant, which did not achieve statistical significance (HR, 0.79; 95% CI, 0.56-1.12; P = .1863), although the data were immature at the time of analysis. The respective 12-, 24-, and 36-month OS rates in the giredestrant and SOC arms were 99.5% vs 99.4%, 98.2% vs 97.5%, and 97.0% vs 95.9%, respectively.

“Since the approval of [aromatase inhibitors] in 2000, 25 years later the lidERA [Breast Cancer] is the first trial that has demonstrated benefit with a novel endocrine agent in early breast cancer,” Aditya L. Bardia, MD,MPH, FASCO, a professor in the Department of Medicine, Division of Hematology/Oncology and Director of Translational Research Integration at the University of California, Los Angeles Health, stated in the press briefing. “With a median follow-up of 32.6 months, lidERA demonstrated a clinically meaningful and statistically significant improvement with [frontline] giredestrant over [SOC] endocrine therapy in ER-positive, HER2-negative early breast cancer.”

Those enrolled on the phase 3 trial had stage I to III, ER-positive, HER2-negative disease, had received breast cancer surgery within 12 months of the start of study treatment, and received adjuvant/neoadjuvant chemotherapy if indicated. Patients were stratified by medium- vs high-risk disease, region, receipt of previous chemotherapy, and menopausal status. They were randomly assigned 1:1 to receive 30 mg of daily oral giredestrant or SOC endocrine therapy with tamoxifen, anastrozole, letrozole, or exemestane.

The primary end point of the trial was IDFS excluding second primary non-breast cancer. Secondary end points included disease-free survival, distant recurrence-free survival, IDFS including second primary non-breast invasive cancer, OS, and safety.

In the safety evaluable population of the giredestrant and ET arms, the most common treatment-emergent adverse effects (TEAEs) included arthralgia (46.5% vs 45.3%), hot flush (27.1% vs 28.5%), and headache (15.2% vs 13.1%). Arthralgias and hot flushes resulting in treatment discontinuations in the respective arms occurred in 1.6% vs 3.7% and less than 0.1% vs 0.8% of patients. Of note, no patients in either arm experienced grade 3/4 bradycardia, and less than 0.1% vs 0.3% of each arm experienced grade 3/4 venous thromboembolic events.

“The safety profile was favorable and consistent with the known profile. The discontinuation rate was lower with giredestrant compared with standard-of-care endocrine therapy,” Bardia concluded.

Disclosures: Bardia disclosed financial relationships with Alyssum, BMS, Daiichi Pharma/AstraZeneca, Eli Lilly, Genentech Inc., Gilead, Menarini, Merck, Novartis, Pfizer, Sanofi, and Vyome.

Reference

Bardia A, Schmid P, Martín M, et al. Giredestrant vs standard-of-care endocrine therapy as adjuvant treatment for patients with estrogen receptor-positive, HER2-negative early breast cancer: results from the global Phase III lidERA Breast Cancer trial. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract GS1-10