The investigational endocrine therapy giredestrant was one of the highlights at last week’s San Antonio Breast Cancer Symposium (SABCS) 2025, as the first novel hormone therapy in two decades to demonstrate benefit for women with early-stage breast cancer.

Compared with aromatase inhibitors or tamoxifen, adjuvant therapy with giredestrant reduced the risk for disease recurrence or death by 30% over nearly 3 years among patients with nonmetastatic hormone receptor (HR)-positive, HER2-negative breast cancer.

Principle investigator Aditya Bardia, MD, MPH, described the results, from the phase 3 lidERA trial, as “a pivotal moment.”

“Overall, these results support giredestrant as a potential new standard for patients with HR-positive, HER2-negative early breast cancer,” said Bardia, of UCLA Health Jonsson Comprehensive Cancer Center.

But while other experts hailed the findings as an advance, they also highlighted the bigger picture: Adjuvant treatment has changed since lidERA was designed, with the approval of the cyclin-dependent kinase (CDK) 4/6 inhibitors abemaciclib (Verzenio) and ribociclib (Kisqali) to be used in combination with endocrine therapy.

Most patients in the trial would now qualify for one of those medications, noted Kate Lathrop, MD, SABCS program director and a breast medical oncologist at UT Health San Antonio.

At a press briefing, Lathrop pointed to the “most obvious question” at this point: “How are we going to fold this into our current practice?”

What the Trial Found

Giredestrant is an oral selective endocrine receptor antagonist and degrader (SERD). It is designed to “drive deep and sustained” inhibition of both ligand-dependent and ligand-independent estrogen receptor signaling, Bardia said — an advantage over aromatase inhibitors, which block only ligand-dependent signaling.

To test whether giredestrant provides superior patient outcomes, lidERA enrolled 4170 patients with HR-positive, HER2-negative breast cancer (median age, 54 years). All had undergone surgery and about 80% had received prior chemotherapy; 13% of patients had stage I disease, 47.4% had stage II, and 39.6% had stage III, and most patients (nearly 80%) were node-positive.

Half of the study group was randomized to standard endocrine therapy, with 16% receiving tamoxifen and 84% an aromatase inhibitor (anastrozole, exemestane or letrozole). The other half was randomized to giredestrant, at 30 mg once daily.

Over a median follow-up of 32.3 months, giredestrant reduced the risk for invasive disease recurrence or death by 30% (HR, 0.70; P = .0014). Overall, 3-year invasive disease-free survival was 92.4% with the novel drug and 89.6% with standard endocrine therapy.

Lisa Carey, MD, ScD, the discussant for the trial at SABCS, said the absolute benefit with giredestrant was small, but she expects it will grow with more follow-up.

“These are early days,” noted Carey, deputy director of clinical sciences at Lineberger Comprehensive Cancer Center, UNC School of Medicine.

Data on overall survival, a secondary endpoint, were not yet mature but trended in favor of giredestrant, Bardia said. At interim analysis, mortality was 2.7% in the giredestrant group vs 3.4% in the standard endocrine therapy group (HR, 0.79; 95% CI, 0.56-1.12).

As for side effects, the most common ones in both treatment groups were arthralgia, hot flashes, and headache — occurring at similar frequencies in both groups. Despite that, the percentage of patients discontinuing treatment due to side effects was numerically lower in the giredestrant group at 5.3% vs 8.2% in the standard-of-care group.

Practical Takeaways

What’s clear, according to Carey, is that the findings mark the “first improvement in adjuvant endocrine therapy in 20 years.” 

But like Lathrop, she stressed that the trial’s comparison group does not reflect current standard of care, and there are no data on the combination of giredestrant with CDK4/6 inhibition.

She also highlighted the fact that 70% of trial patients were categorized as high-risk, based on factors such as lymph node involvement, tumor grade, and genomic score. The rest, including all patients with node-negative disease, fell into the medium-risk category.

And while giredestrant improved invasive disease-free survival among high-risk patients, Carey said, the medium-risk group had few events and requires more follow-up.

If the SERD wins approval, Carey said she foresees it becoming the “favored” endocrine therapy for patients who will not receive a CDK4/6 inhibitor for any reason.

Otherwise, Carey said, “I believe an AI [aromatase inhibitor] plus a CDK4/6 inhibitor for the initial 2-3 years, as you do now, would be preferred.” From there, a switch to giredestrant could be considered, she added — with the caveat that such an approach would veer from lidERA’s design.

Bardia noted that an ongoing study is assessing giredestrant plus abemaciclib, so there will at least be safety data on the combination in the near future. “And maybe for patients with high-risk disease,” he added, “some physicians will want the best endocrine option along with a CDK4/6 inhibitor.”

In the real world, though, cost is also an issue, Carey said.

She pointed to the list prices of current options: Oral SERDs currently used for metastatic breast cancer, including elacestrant (Orserdu) and imlunestrant (Inluriyo), top $20,000 per month; aromatase inhibitors, which are available as generics, are priced at anywhere from $8 to $367 per month.

“We should all acknowledge that there’s a large potential impact on national healthcare systems, if giredestrant is priced similarly to oral SERDs given in the metastatic setting,” Carey said.

This study was funded by F. Hoffmann-La Roche Ltd. Bardia disclosed financial relationships with Pfizer, Novartis, Genentech, Merck, and Menarini, among others. Lathrop disclosed relationships with TerSera Pharmaceuticals, Novartis, Pfizer, Lilly, and Encore Education. Carey had no personal financial relationships to disclose.