Adjuvant Giredestrant Improves Invasive DFS in ER+, HER2– Early Breast Cancer

Shared at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, updated results from the phase 3 lidERA Breast Cancer trial (NCT04961996) revealed that adjuvant giredestrant improved invasive disease-free survival (iDFS) vs standard of care (SOC) among patients with estrogen receptor (ER)–positive, HER2-negative early breast cancer regardless of menopausal status.

Among the 1687 premenopausal patients in the trial, giredestrant reduced the risk of invasive disease or death by 35% compared with SOC endocrine therapy (HR, 0.65; 95% CI, 0.44-0.95), with 3-year iDFS rates of 94.0% vs 91.5%. Among 2456 postmenopausal patients, the corresponding hazard ratio was 0.74 (95% CI, 0.57-0.96), with 3-year iDFS rates of 91.3% vs 88.3%. Musculoskeletal-pain-driven treatment discontinuations were less than half as common on giredestrant as on SOC endocrine therapy in both menopausal subgroups.

"Adjuvant giredestrant showed an iDFS benefit over SOC endocrine therapy irrespective of menopausal status," lead investigator Peter Schmid, MD, PhD, FACP, of Queen Mary University of London, said during a presentation of the data. "Patients receiving giredestrant had fewer treatment discontinuations overall due to musculoskeletal pain, regardless of menopausal status."

Adjuvant endocrine therapy with tamoxifen or an aromatase inhibitor (AI) with or without ovarian function suppression (OFS) in premenopausal patients has been the backbone of care for hormone receptor-positive early breast cancer for decades, but treatment-limiting adverse events on AIs and incomplete ER suppression with tamoxifen leave room for improvement. Giredestrant is an oral selective estrogen receptor degrader (SERD) designed to deliver more complete ER blockade without the IV administration burden of fulvestrant. The lidERA Breast Cancer trial is the largest randomized study evaluating an oral SERD in the adjuvant setting.

How was lidERA designed, and who was enrolled onto the trial?

The lidERA Breast Cancer study enrolled 4170 patients with stage I-III, ER+/HER2- early breast cancer who had completed surgery and any indicated neoadjuvant and/or adjuvant chemotherapy. Patients were required to have either node-positive disease (pN1-3) or node-negative tumors larger than 1 cm with grade 3 histology, Ki67 of at least 20%, or a high score on a genomic recurrence assay.

Patients were randomly assigned 1:1 to giredestrant 30 mg orally once daily for 5 years or to investigator's choice of SOC endocrine therapy (tamoxifen, anastrozole, letrozole, or exemestane), stratified by risk category, geographic region, prior chemotherapy use, and menopausal status. OFS with an approved LHRH agonist was required for all men and premenopausal women receiving either giredestrant or an AI. The primary endpoint was iDFS. The key secondary endpoints included distant recurrence-free interval (DRFI), overall survival, and safety.

The 4170-patient population was comprised of 1687 premenopausal patients (41%) and 2456 postmenopausal patients (59%). The median follow-up at the August 8, 2025, data cutoff was 32.4 months. In the premenopausal subgroup, 70.5% of patients had high-risk disease and approximately 91% had received prior chemotherapy. In the postmenopausal subgroup, 66.4% had high-risk disease and approximately 79% had received prior chemotherapy.

The previously reported primary analysis from the 2025 San Antonio Breast Cancer Symposium showed an overall iDFS HR of 0.70 (95% CI, 0.57-0.87; P = .0014) favoring giredestrant, with 3-year iDFS rates of 92.4% vs 89.6% and a 31% reduction in the risk of distant recurrence. Overall survival trended in favor of the giredestrant arm.

What was giredestrant efficacy in premenopausal patients?

Among the 1687 premenopausal patients (giredestrant, n = 849; SOC endocrine therapy, n = 838), 44 iDFS events occurred in the giredestrant arm (5.2%) and 66 in the SOC endocrine therapy arm (7.9%). The benefit was consistent in exploratory analyses by SOC backbone, with hazard ratios of 0.66 (95% CI, 0.43-1.01) when the comparator was an AI plus OFS (n = 563) and 0.62 (95% CI, 0.38-1.03) when the comparator was tamoxifen plus OFS (n = 269).

DRFI showed an even larger separation in premenopausal patients, with 33 distant recurrence events (3.9%) with giredestrant vs 55 (6.6%) for SOC endocrine therapy (HR, 0.58; 95% CI, 0.38-0.90). The 3-year DRFI rates were 95.5% vs 92.6% for giredestrant and SOC, respectively.

What was giredestrant efficacy in postmenopausal patients?

Among the 2456 postmenopausal patients (giredestrant, n = 1220; SOC endocrine therapy, n = 1236), 96 iDFS events occurred for giredestrant (7.9%) and 129 for SOC endocrine therapy (10.4%), for a 26% relative risk reduction (HR, 0.74; 95% CI, 0.57-0.96). The 3-year iDFS rate was 91.3% with giredestrant vs 88.3% with SOC endocrine therapy. Exploratory analyses by SOC backbone showed a hazard ratio of 0.77 (95% CI, 0.59-1.00) in the AI subset (n = 1180) and 0.37 (95% CI, 0.19-0.73) in the 48-patient tamoxifen subset.

DRFI in postmenopausal patients showed 69 events (5.7%) for giredestrant vs 90 (7.3%) for SOC endocrine therapy (HR, 0.76; 95% CI, 0.56-1.04). The 3-year DRFI rate was 93.6% for giredestrant vs 91.6% for SOC.

How did tolerability with giredestrant stack up?

The most common adverse events in both menopausal subgroups were arthralgia and hot flush. In premenopausal patients, any-grade arthralgia occurred in 53.1% on giredestrant vs 47.8% on SOC endocrine therapy, and any-grade hot flush in 34.2% vs 36.2%, with grade 3 or higher rates of 2% or less for both events in either arm. The corresponding any-grade rates in postmenopausal patients were 44.5% vs 46.8% for arthralgia and 22.5% vs 23.8% for hot flush, for giredestrant and SOC, respectively.

Across both menopausal subgroups, 5.7% of patients switched from giredestrant to an alternative endocrine therapy due to adverse events, compared with 10.1% who switched from SOC endocrine therapy. Treatment discontinuations due to adverse events occurred in 5.3% for giredestrant vs 8.2% for SOC endocrine therapy. The most striking tolerability signal was in musculoskeletal-pain-driven discontinuations, Schmid noted. Among premenopausal patients, musculoskeletal pain led to treatment discontinuation in 1.5% on giredestrant vs 3.7% on SOC endocrine therapy overall and 5.0% in the AI-treated subset specifically. Among postmenopausal patients, the corresponding rates were 1.7% on giredestrant, 4.1% on SOC, and 4.3% in the AI subset.

Reference

Schmid P, Geyer CE Jr, Martín M, et al. Efficacy and safety of giredestrant (GIRE) in patients (pts) with estrogen receptor-positive, HER2-negative early breast cancer (ER+, HER2- eBC) in the phase III lidERA BC clinical trial: results by menopausal status. J Clin Oncol. 2026;44(suppl 16):502. doi:10.1200/JCO.2026.44.16_suppl.502