Five-Year NATALEE Data Show Ribociclib Improves Outcomes in High-Risk HR+/HER2– Early Breast Cancer

Five-year follow-up data show adjuvant ribociclib plus nonsteroidal anti-inflammatory drugs (NSAIDs) led to meaningful invasive disease–free survival (iDFS) benefit in patients with stage 2 and 3 hormone receptor-positive (HR+)/HER2-negative (HER2−) early breast cancer (eBC). The data, presented at the European Society of Medical Oncology 2025 Congress, are from the phase 3 NATALEE trial (NCT03701334).¹

In 2024, an estimated 300,000 women in the United States will be diagnosed with breast cancer, and more than 42,000 are projected to die from the disease. Approximately 70% of these new cases involve the most common subtype—HR+/HER2– breast cancer. Although many patients initially respond to therapy, this subtype carries a notable risk of recurrence, often manifesting as metastatic disease that is difficult to treat, underscoring the critical importance of therapies that can prevent relapse.²

Ribociclib is a selective cyclin-dependent kinase (CDK) 4/6 inhibitor designed to slow the uncontrolled growth of cancer cells driven by overactivation of these proteins. By targeting CDK4 and CDK6, the therapy helps halt cell cycle progression and tumor proliferation. When used with an aromatase inhibitor, ribociclib is taken orally once daily for 3 weeks, followed by a 1-week break.²

The agent received its first FDA approval in 2017 in combination with an aromatase inhibitor as initial endocrine-based therapy for treatment of postmenopausal women with HR+/HER2– advanced or metastatic breast cancer. In 2018, the indication expanded to include women with HR+/HER2– advanced or metastatic breast cancer.^3,4

In 2024, ribociclib received a third approval for combination with an aromatase inhibitor for the adjuvant treatment of individuals with HR+/HER2– stage 2 and 3 eBC at high risk of recurrence, including those with node-negative disease.⁵

“Ribociclib, in combination with an aromatase inhibitor,” explained John Paul Crown, MD, medical oncologist, and professor of oncology at St. Vincent's University Hospital in Dublin, Ireland, “is indicated as adjuvant treatment for patients in stages 2 and 3 [HR+/HER2– eBC] who are at high risk of recurrence.”

In the phase 3 NATALEE trial, researchers assessed the efficacy and safety of ribociclib plus an NSAID for patients with HR+/HER2– eBC. They were randomly assigned in a 1:1 ratio to receive either ribociclib (400 mg daily, 3 weeks on and 1 week off for 3 years) plus an NSAI (letrozole 2.5 mg daily or anastrozole 1 mg daily for 5 years), or NSAI alone.⁶

Men and premenopausal women also received goserelin for ovarian suppression. Eligible patients had anatomical stage IIA disease (if node-positive with 1 to 3 axillary lymph nodes or node-negative with additional high-risk features), stage 2B, or stage 3 disease.⁶

The primary end point was iDFS, with secondary end points including distant disease–free survival (DDFS), distant relapse–free survival (DRFS), and OS. Time-to-event outcomes were analyzed using Kaplan-Meier methods, and treatment comparisons were made using a stratified log-rank test.⁶

As of the data cutoff on May 28, 2025, all patients had completed ribociclib treatment, and a similar proportion in both groups had finished 5 years of NSAI therapy (36.5% with ribociclib plus NSAI vs 34.4% with NSAI alone).⁶

“The percentage of patients that completed 5 years of aromatase inhibitor treatment was similar between the 2 arms, indicating that the addition of ribociclib did not impact the patient's ability to complete 5 years of endocrine therapy,” said Crown.

After a median follow-up of 55.4 months, ribociclib plus NSAI maintained a significant iDFS advantage compared with NSAI alone (HR, 0.716; 95% CI, 0.618–0.829; nominal one-sided P < .0001). The absolute iDFS rates for ribociclib plus NSAI versus NSAI alone were 90.8% vs 88.0% at 3 years, 88.3% vs 83.9% at 4 years, and 85.5% vs 81.0% at 5 years—reflecting absolute improvements of 2.7%, 4.4%, and 4.5%, respectively.⁶

The iDFS benefit was consistent across all subgroups, including patients with node-negative disease (HR, 0.606; 95% CI, 0.372–0.986). Ribociclib and NSAI also showed sustained benefits in DDFS (HR, 0.709; 95% CI, 0.608–0.827) and DRFS (HR, 0.699; 95% CI, 0.594–0.824) compared with NSAI alone.⁶

A positive trend favoring ribociclib plus NSAI for OS (HR, 0.800; 95% CI, 0.637–1.003; nominal one-sided P = .026) continues to emerge. No new or unexpected safety concerns were identified with a median of approximately 2 years of follow-up after completion of ribociclib treatment.⁶

“This combination produced a statistically significant improvement in [iDFS] versus aromatase inhibitor alone at the primary analysis of the NATALEE study, with a median [iDFS] follow-up of 27 months and a hazard ratio of 0.75,” explained Crown.

In this 5-year landmark analysis with mature efficacy data, ribociclib in combination with NSAI significantly reduced the risk of invasive and distant disease recurrence compared with NSAI alone, including among patients with high-risk node-negative disease. A favorable trend in OS continues to emerge, supporting the long-term benefit of ribociclib in the adjuvant setting.⁶

REFERENCES

1. A trial to evaluate efficacy and safety of ribociclib with endocrine therapy as adjuvant treatment in patients with HR+/​HER2- early breast cancer (NATALEE). Clinicaltrials.gov. Updated November 14, 2024. Accessed October 17, 2025. https://clinicaltrials.gov/study/NCT03701334

2. Gerlach A. Ribociclib With Nonsteroidal Aromatase Inhibitor Does Not Reduce Quality of Life in HR+/HER2- Early Breast Cancer. Pharmacy Times. April 24, 2025. Accessed October 17, 2025. https://www.pharmacytimes.com/view/ribociclib-with-nonsteroidal-aromatase-inhibitor-does-not-reduce-quality-of-life-in-hr-her2--early-breast-cancer

3. FDA Approves Kisqali, Drugs.com. March 13, 2017. Accessed October 17, 2025. https://www.drugs.com/newdrugs/fda-approves-kisqali-ribociclib-hr-her2-metastatic-breast-cancer-4496.html

4. Kisqali (ribociclib) Approved for Additional Indications in HR+/HER2- Advanced Breast Cancer. Drugs.com. July 18, 2019. Accessed October 17, 2025. https://www.drugs.com/newdrugs/kisqali-ribociclib-approved-additional-indications-hr-her2-advanced-breast-cancer-4783.html

5. FDA Approves Kisqali to Reduce Risk of Recurrence in People with HR+/HER2- Early Breast Cancer. Drugs.com. September 17, 2024. Accessed October 17, 2025. https://www.drugs.com/newdrugs/fda-approves-kisqali-reduce-risk-recurrence-hr-her2-early-breast-cancer-6369.html

6. Crown J, Stroyakovskiy D, Yardley D, et al. LBA14 - Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+/HER2− early breast cancer (EBC): NATALEE 5-year outcomes. Presented at: European Society of Medical Oncology. October 17, 2025, to October 21, 2025. Abstract LBA14.