At the European Society for Medical Oncology (ESMO) 2025 congress, the late-breaking five-year outcomes from the phase III NATALEE trial confirmed the sustained benefit of adding adjuvant ribociclib (RIB) to a nonsteroidal aromatase inhibitor (NSAI) in hormone receptor-positive, HER2-negative early breast cancer (HR+/HER2− EBC). The updated analysis demonstrated a durable, clinically meaningful improvement in invasive disease-free survival (iDFS) that persisted beyond the three-year ribociclib treatment period. Prof John Crown (St. Vincent’s University Hospital, Dublin, Ireland) discussed the key findings, trial design and the potential implications for real-world clinical practice.
The late-breaking abstract, ‘Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+/HER2− early breast cancer (EBC): NATALEE 5-year outcomes’ (LBA14) was presented at the European Society for Medical Oncology (ESMO) congress on 17th-21st October 2025 in Berlin, Germany.
Q1. What are the current limitations and unmet needs in treatment for early HR+/HER2– breast cancer?
Early HR+/HER2− breast cancer is the most common biological subtype of breast cancer. It is, in some ways, the least aggressive – recurrences tend to be slower and occur later. However, despite generally better outcomes, many patients, especially those with lymph-node-positive disease, will still unfortunately die from their cancer. Even among node-negative patients, the mortality is appreciable. For several decades, we’ve made relatively modest progress in improving adjuvant outcomes for this group, particularly when compared with the dramatic advances in HER2-positive and triple-negative disease. That’s why there’s been so much interest in exploring new strategies such as CDK4/6 inhibition in the adjuvant setting.
Q2. What made CDK4/6 inhibition – and ribociclib specifically – a compelling approach to test?
CDK4/6 inhibitors have been used in metastatic HR+/HER2− disease for more than a decade. Ribociclib has demonstrated not only improvements in progression-free survival but, importantly, consistent overall survival benefits across several phase III trials. That gave us a strong biological and clinical rationale to move these agents earlier in the disease course.
The NATALEE trial was designed to determine whether adding ribociclib to standard endocrine therapy could reduce the risk of recurrence in early-stage disease – essentially to test if we could alter the natural history of HR+/HER2− breast cancer.
Q3. Please can you summarize the design and eligibility criteria of the NATALEE study?
NATALEE is a large, global, phase III trial enrolling 5,101 patients, randomized 1:1 to receive ribociclib plus NSAI versus NSAI alone. One of its key strengths is its broad eligibility criteria, making it highly representative of real-world early breast cancer.
Patients with node-positive disease were all eligible, as were selected node-negative patients with other high-risk features – such as grade 3 tumours, high Ki-67, or high genomic risk scores. This inclusion allows us to better understand the potential benefit across a spectrum of risk.
Importantly, ribociclib was administered at a lower dose (400mg daily) than in the metastatic setting and for a longer duration – three years – to balance efficacy and tolerability. The rationale was to maintain cell-cycle arrest for an extended period and potentially push residual tumour cells toward senescence or death.
Q4. What were the key findings from the five-year analysis presented at ESMO 2025?
At this five-year mark, all patients had completed their ribociclib therapy. The results confirm and extend our earlier reports. The invasive disease-free survival (iDFS) benefit has not only been sustained, but has increased over time.
- The absolute iDFS improvement grew from 2.7% in the initial readout to 4.5% at five years
- The hazard ratio (HR) for iDFS was 0.716 (95% CI 0.618–0.829), representing about a 28% reduction in risk of invasive disease recurrence
- The five-year iDFS rates were 85.5% with ribociclib + NSAI versus 81.0% with NSAI alone
- Importantly, for the first time, the benefit in node-negative patients reached statistical significance (HR ≈ 0.606)
We also saw consistent improvements in distant disease-free survival, with no new safety signals emerging.
Q5. How do you interpret these findings in terms of long-term benefit?
The most reassuring aspect is that the benefit continues to widen even after the three-year ribociclib treatment period. That tells us there’s a durable biological effect – perhaps a ‘legacy’ benefit from sustained CDK4/6 inhibition early on.
Clinically, it reinforces that ribociclib plus endocrine therapy offers a meaningful reduction in recurrence risk, including for patients who are node-negative but biologically high-risk. It’s an important step forward in closing the survival gap for HR+/HER2− disease. There were around 300 deaths across the entire study population, which means the trial isn’t yet statistically powered for overall survival. The hazard ratio for death was 0.80, which is an improvement over previous analyses, but hasn’t yet crossed the threshold for significance.
The encouraging news is that the follow-up will continue for several more years, allowing us to determine whether this survival trend becomes significant. It’s certainly moving in the right direction.
Q6. What are the next steps for the NATALEE trial and for clinical practice?
The sponsor has agreed to extend follow-up, which will give us valuable insight into long-term survival and durability. For clinicians, the data already support offering adjuvant ribociclib to node-positive and high-risk node-negative patients.
As we integrate this into practice, discussions around patient selection, cost-effectiveness and management of side-effects will be important. But overall, this represents one of the most meaningful advances we’ve seen in this subtype in many years. We now have, I believe, the option of offering our patients with higher-risk or even node-negative HR+/HER2− early breast cancer a treatment that can substantially reduce their risk of relapse. The five-year NATALEE data provide a reassuring and consistent signal – the benefit is real, and it’s enduring.
Disclosure: John Crown is a member of the Advisory Board for Novartis and has received financial or material support from Novartis.
This content has been developed independently by Touch Medical Media for touchONCOLOGY. It is not affiliated with the European Society for Medical Oncology (ESMO). Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.
Cite: ESMO25: Five-year NATALEE trial data confirm lasting benefit with adjuvant ribociclib in HR+/HER2− early breast cancer. touchONCOLOGY. November 11th, 2025
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