Clinical Summary: 

• Design/Population: Subgroup analysis from the phase 3 lidERA trial evaluating giredestrant versus standard endocrine therapy in 4,170 patients with intermediate- to high-risk ER-positive, HER2-negative early breast cancer. The analysis examined outcomes according to menopausal status and endocrine therapy backbone.
• Key Outcomes: Giredestrant improved invasive disease-free survival and distant recurrence-free survival in both premenopausal and postmenopausal patients, with consistent benefit regardless of whether patients received aromatase inhibitors or tamoxifen. The safety profile was similar across menopausal groups and was associated with fewer treatment discontinuations than standard endocrine therapy.
• Clinical Relevance: These findings demonstrate that the efficacy and tolerability benefits of giredestrant extend across key patient subgroups, supporting its potential role as a new endocrine treatment option for early-stage ER-positive breast cancer.

Peter Schmid, MD, PhD, Barts Cancer Institute, London, United Kingdom, discusses subgroup analyses from the phase 3 lidERA trial, the first study of an oral selective estrogen receptor degrader to report positive results in early-stage ER-positive, HER2-negative breast cancer. The trial previously demonstrated significant improvements in invasive disease-free survival and distant recurrence-free survival compared with standard endocrine therapy. 

The current analysis showed that these benefits were maintained regardless of menopausal status, with similar efficacy observed in both premenopausal and postmenopausal women. Giredestrant also demonstrated favorable tolerability, with fewer treatment discontinuations overall and lower rates of discontinuation due to musculoskeletal symptoms compared with standard endocrine therapy.

Dr Schmid presented these results at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

Transcript:

I'm Peter Schmid, I'm a medical oncologist and work at Barts Hospital in London. I had the pleasure of presenting data from the lidERA trial here at ASCO 2026.

The lidERA trial is the first trial of an oral SERD to be read out in early-stage ER-positive, HER2-negative breast cancer. It compared 5 years of treatment with the oral SERD giredestrant versus standard-of-care endocrine therapy. Standard-of-care endocrine therapy included tamoxifen or an aromatase inhibitor, specifically letrozole, anastrozole, or exemestane. 

The focus of this presentation at ASCO was the outcomes according to menopausal status, specifically comparing premenopausal and postmenopausal women. The trial enrolled 4,170 patients who were randomized 1:1. It focused on patients with an intermediate- to high-risk of recurrence. This was defined primarily by node-positive disease. Patients with node-negative disease were also eligible if they had additional risk factors, such as tumors larger than 1 cm, grade 3 disease, high Ki-67, or a high-risk genomic profile. 

All patients had completed local therapy and, if indicated, chemotherapy, which was given to the majority of patients. Importantly, premenopausal patients who received giredestrant or an aromatase inhibitor were required to receive ovarian function suppression. For patients receiving tamoxifen, ovarian function suppression was optional.

We previously demonstrated, with just under 3 years of follow-up, that giredestrant significantly improved invasive disease-free survival compared with standard endocrine therapy, with a hazard ratio of 0.70, corresponding to approximately a 3% absolute improvement in 3-year invasive disease-free survival. We also previously demonstrated a significant improvement in distant recurrence-free interval, with a hazard ratio of 0.69. 

In this analysis, we focused on outcomes according to menopausal status. Forty-one percent of patients were premenopausal and 59% were postmenopausal. Within each subgroup, the control and experimental arms were very well balanced for all key prognostic factors. 

Looking first at the premenopausal population, approximately two-thirds of patients received an aromatase inhibitor and about one-third received tamoxifen. Of those receiving tamoxifen, approximately 69% also received ovarian function suppression. In other words, only about 10% of all premenopausal patients received tamoxifen alone. Interestingly, and perhaps not surprisingly, patients treated with tamoxifen generally had somewhat more favorable prognostic features than those receiving aromatase inhibitors. When we look at invasive disease-free survival according to menopausal status, the benefit of giredestrant was consistent across both groups. In premenopausal women, the hazard ratio was 0.65 in favor of giredestrant. In postmenopausal women, the hazard ratio was 0.74. Looking at distant recurrence-free interval, again the benefit was consistent. The hazard ratio was 0.56 in premenopausal women and 0.70 in postmenopausal women.

We also explored whether the benefit of giredestrant differed according to the endocrine therapy comparator, particularly in premenopausal women where patients could receive either tamoxifen or an aromatase inhibitor. Interestingly, the benefit was very consistent regardless of comparator therapy. The hazard ratio was 0.66 when compared with aromatase inhibitors and 0.62 when compared with tamoxifen. 

We also examined safety according to menopausal status. The safety profile was very similar between premenopausal and postmenopausal women. As we have seen in the overall study, the most common adverse events were hot flushes and musculoskeletal pain. Importantly, fewer patients receiving giredestrant switched treatment because of tolerability issues. Just over 5% of patients receiving giredestrant changed therapy compared with just over 10% receiving standard endocrine therapy. 

Similarly, fewer patients discontinued treatment entirely. Just over 5% of patients receiving giredestrant stopped treatment compared with approximately 8% of patients receiving standard endocrine therapy. One of the most common reasons for treatment discontinuation was musculoskeletal pain, so we looked more closely at that. The overall rates of musculoskeletal pain were relatively similar across treatment groups. However, discontinuation because of musculoskeletal pain was substantially lower with giredestrant. Approximately 1.5% of patients discontinued giredestrant because of musculoskeletal pain, compared with about 4.5% to 5% of patients treated with aromatase inhibitors. I think that is an important reflection of treatment tolerability from the patient perspective.

In summary, the significant and clinically meaningful benefits observed with giredestrant compared with standard endocrine therapy were consistent across both premenopausal and postmenopausal women. The hazard ratio for invasive disease-free survival was 0.65 in premenopausal women and 0.74 in postmenopausal women. Similarly, the benefits in distant recurrence-free intervals were consistent across both groups.  Finally, there were no major differences in safety between premenopausal and postmenopausal patients, and giredestrant appeared to be associated with lower rates of treatment discontinuation due to musculoskeletal toxicity. 

Source:

Schmid P, Geyer CE, Martin 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. Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. Abstract 502.