Clinical Relevance

  • Giredestrant is currently the only oral SERD to demonstrate a clear improvement in invasive disease-free survival in the adjuvant setting, representing the first major step forward in endocrine therapy for early breast cancer in more than two decades.
  • The magnitude and consistency of benefit seen with giredestrant suggest it could reasonably be positioned as a future standard-of-care option for patients with early-stage HR-positive disease.
  • Estrogen receptor–positive breast cancer makes up around 70% of all breast cancer diagnoses, and as many as one in three of these patients will ultimately experience disease recurrence during or after adjuvant endocrine therapy.

The LIDERA trial made one of the biggest impacts at the 2025 San Antonio Breast Cancer Symposium, marking the first time an oral selective estrogen receptor degrader (SERD) has shown a statistically significant improvement in adjuvant disease-free survival (DFS) for early-stage hormone receptor–positive (HR+), HER2-negative breast cancer.

For a field that has not had a new adjuvant endocrine agent in nearly two decades, the implications are substantial.

“This was the most important study presented this morning… a significant improvement in DFS with a hazard ratio of 0.70,” said Dr.Francisco Esteva, chief of breast medical oncology at Northwell Health in New York. “It’s in the same range as CDK4/6 inhibitors; this is the first oral SERD to do that.”

The Trial – What LIDERA Actually Studied?

LIDERA is a large, randomized, open-label, phase 3 trial evaluating giredestrant, an oral SERD, compared with standard adjuvant endocrine therapy (tamoxifen or aromatase inhibitors) in patients with medium- or high-risk stage I-III HR+, HER2-negative breast cancer.  Over 4,100 patients were enrolled in the protocol.

Key outcomes:

  • DFS improvement: HR 0.70, translating to a reduced risk of invasive disease recurrence or death by 30%, comparable to adjuvant CDK4/6 trials like NATALEE.
  • Invasive DFS >92% in both arms, demonstrating a favorable prognosis but with a measurable incremental benefit for the SERD arm.
  • Safety: Low discontinuation rates and a toxicity profile comparable to standard endocrine therapy.

“It’s very intriguing. We haven’t had a new adjuvant endocrine therapy in 20 years,” noted Dr. Kristina Fanucci, a Breast Oncologist at Dana-Farber Cancer Institute in Boston, Massachusetts.

While the DFS benefit is statistically and clinically meaningful, experts emphasized that LIDERA is not yet practice-changing and may not immediately alter management even upon approval. Many patients in LIDERA would also have been eligible for adjuvant CDK4/6 inhibitors, and LIDERA does not answer how oral SERDs should be sequenced or integrated with CDK4/6 therapy.

“Even if FDA approved tomorrow, I don’t think it would change my practice, at least for the higher risk populations that were captured in the adjuvant CDK4/6 studies. I think we need a little bit more follow-up from this study, just as we did with Natalie before it became broadly adopted,” adds Dr. Heather McArthur, a clinical director of the Breast Cancer Program at Simmons Comprehensive Cancer Center in Dallas, Texas.

Overall survival (OS) results remain immature, but early analyses show a consistent, favorable trend for the giredestrant arm, with additional follow-up planned for the next data readout. Importantly, giredestrant also achieved a 31% reduction in the risk of distant recurrence (HR 0.69; 95% CI, 0.54–0.89), reinforcing its impact on one of the trial’s most clinically meaningful secondary endpoints.

Future Directions

Looking ahead, many experts see LIDERA as the first step toward a more risk-adapted framework for adjuvant endocrine therapy rather than a one-size-fits-all change. In this vision, low-risk patients would likely continue on conventional endocrine therapy alone; intermediate-risk patients might be candidates for oral SERD monotherapy once we have longer follow-up; and high-risk patients could ultimately be treated with a combination of an oral SERD plus a CDK4/6 inhibitor.

As Dr. McArthur put it, “My forecast is low-risk stays with standard therapy, intermediate-risk gets an oral SERD, and very high-risk eventually gets a CDK4/6 + SERD combination.” Several discussants agreed that the SERD + CDK4/6 doublet is probably the most promising direction going forward, offering the best chance to balance efficacy and tolerability in the curative-intent setting.

One of the strongest selling points for giredestrant is its favorable toxicity profile. Although arthralgia rates were similar between the SERD and AI arms, dropout due to arthralgia was lower in the SERD group. That alone may position oral SERDs as attractive alternatives for patients struggling with standard endocrine therapy adherence.

“Discontinuation was very low in both groups… shocking, because in the real world more than 50% of women don’t adhere to endocrine therapy,” said Dr. McArthur. “If someone starts on tamoxifen and has a lot of toxicity, I’d be happy to switch to giredestrant once approved,” added Dr. Esteva.

Dr. Kaique Filardi is a board-certified general surgeon and gastrointestinal (GI) surgeon from the University of São Paulo. He is currently an oncologic surgery research fellow at Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, and serves as a teaching assistant in the Principles and Practice of Clinical Research (PPCR) program at Harvard Medical School.

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