Hormone receptor (HR)–positive, ERBB2 (formerly HER2)–negative breast cancer is the most common subtype, accounting for more than 70% of cases. While adjuvant endocrine therapy (ET) remains standard of care, recurrence is a major ongoing challenge — with about half of events occurring within the first five years and risk persisting for decades. Most of these are distant recurrences, which are incurable.
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are firmly established in advanced disease, with ribociclib the only agent in its class to demonstrate both progression-free and overall survival benefit in this setting. In early breast cancer (EBC), both abemaciclib (monarchE) and ribociclib (NATALEE) have shown invasive disease-free survival (iDFS) benefit when added to ET, though trial design and patient populations differed.
The NATALEE Trial: 4-Year Exploratory Analysis
NATALEE enrolled 5,101 patients with stage II–III HR-positive/ERBB2-negative EBC, including both high-risk node-positive and high-risk node-negative disease. Patients were randomised to receive ribociclib (400 mg daily, 3 weeks on/1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI), or NSAI alone.
All patients had completed or discontinued ribociclib treatment by the time of this 4-year exploratory analysis (median follow-up: 44.2 months).
Key findings:
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iDFS benefit sustained: Ribociclib + NSAI reduced the risk of invasive disease recurrence by 28.5% (HR 0.72; 95% CI, 0.61–0.84).
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Absolute benefit increased over time: iDFS rates at 3 years were 90.8% vs 88.1% (difference 2.7 pts); by 4 years this grew to 88.5% vs 83.6% (difference 4.9 pts).
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Distant recurrence reduced: The majority of events were distant recurrences. Ribociclib + NSAI lowered the risk of distant disease-free survival (DDFS) events by 28% (HR 0.72; 95% CI, 0.60–0.85).
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Benefit across subgroups: iDFS and DDFS improvements were consistent across nodal status, stage, menopausal status, Ki-67 status, and prior therapy. High-risk node-negative patients also derived benefit.
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Safety: No new safety signals were observed. The most common adverse events were neutropenia, arthralgia, and nausea. Liver enzyme elevations and QT prolongation remained manageable. Dose reductions were required in 27% of patients, with 20% discontinuing ribociclib early due to adverse events.
What Does This Mean?
The 4-year data show that ribociclib’s benefit persists even after stopping treatment, with Kaplan–Meier curves continuing to separate beyond the planned 3-year ribociclib duration. Importantly, the absolute iDFS benefit increased between years 3 and 4, suggesting a durable effect.
These results reinforce ribociclib + ET as a key adjuvant option for a broad population of patients with HR-positive/ERBB2-negative early breast cancer, including those with high-risk node-negative disease — a group historically underrepresented in adjuvant escalation trials.
A longer follow-up will be critical to determine whether the early improvements in disease-free outcomes translate into an overall survival benefit. Protocol-specified analyses at 5 and 6 years are planned.
Paper: Fasching, P. et al. Ribociclib Plus Endocrine Therapy in Hormone Receptor–Positive/ ERBB2-Negative Early Breast Cancer: 4-Year Outcomes From the NATALEE Randomized Clinical Trial. JAMA Oncol. doi:10.1001/jamaoncol.2025.3700 Published online September 25, 2025. Access online here.
