The open-label, multicenter, randomized, phase 3 NATALEE trial (CLEE011O12301C) previously demonstrated that adjuvant ribociclib combined with a nonsteroidal aromatase inhibitor (NSAI) significantly improved invasive disease-free survival (IDFS) compared with NSAI alone in patients with stage II and III hormone receptor (HR)-positive/HER2-negative early breast cancer. A new long-term analysis demonstrates sustained improvements at 5 years with ribociclib plus NSAI compared with NSAI alone.
Patients with HR-positive/HER2-negative early breast cancer were randomized 1:1 to receive ribociclib (400 mg/day, 3 weeks on and 1 week off for 3 years) combined with NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for ≥5 years) or NSAI alone. Premenopausal women and men also received goserelin. Eligible patients included those with anatomical stage IIA disease (with N1 defined as 1-3 positive axillary lymph nodes, or N0 with additional high-risk factors), stage IIB, or stage III disease, as classified by the 8th edition of the American Joint Committee on Cancer staging system. The primary endpoint was IDFS, and secondary endpoints included distant disease-free survival (DDFS), distant relapse-free survival (DRFS), and overall survival (OS). Kaplan−Meier methods were used to evaluate time-to-event endpoints, and statistical comparisons were made using the stratified log-rank test.
By the data cutoff (May 28, 2025), all patients had completed ribociclib treatment at a median of 2 years, and the proportion of patients completing 5 years of NSAI treatment was similar in both arms (ribociclib plus NSAI, 36.5%; NSAI alone, 34.4%). After a median follow-up of 55.4 months, ribociclib plus NSAI demonstrated a sustained and statistically significant IDFS benefit compared with NSAI alone (hazard ratio, 0.72; 95% confidence interval [CI], 0.62-0.83; nominal 1-sided P<.0001). The IDFS rates were higher in the ribociclib plus NSAI arm at 5 years (85.5% vs 81.0%), with absolute improvements of 4.5%, respectively. Subgroup analyses showed consistent IDFS benefits across all prespecified groups, including patients with N0 disease (hazard ratio, 0.61; 95% CI, 0.37-0.99). Most IDFS events were distant recurrences and were more common in the NSAI-alone arm.
In addition to IDFS, ribociclib plus NSAI provided continued benefits in DDFS (hazard ratio, 0.71; 95% CI, 0.61-0.83) and DRFS (hazard ratio, 0.70; 95% CI, 0.5-0.82) compared with NSAI alone. A positive trend in OS favoring ribociclib plus NSAI (hazard ratio, 0.80; 95% CI, 0.64-1.00; nominal 1-sided P=.026) was also observed, although statistical significance was not reached. There were fewer patients alive with metastatic disease (n=114) in the ribociclib plus NSAI arm and the NSAI arm (n=169). Importantly, no new safety signals were reported, and the long-term safety profile remained consistent, with a median follow-up of approximately 2 years after ribociclib discontinuation.
This 5-year landmark analysis of the NATALEE trial demonstrates the long-term efficacy of ribociclib combined with NSAI in reducing the risk of invasive and distant disease recurrence compared with NSAI alone in patients with stage II and III HR-positive/HER2-negative early breast cancer. Benefits were observed across all subgroups, including those with high-risk N0 disease. Additionally, a positive trend favoring OS with ribociclib continues to emerge. These findings reinforce the role of ribociclib plus NSAI as a promising adjuvant therapy for patients with high-risk, HR-positive/HER2-negative early breast cancer.
Source: Crown JP, Stroyakovskiy D, Yardley D, et al. Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+/HER2− early breast cancer (EBC): NATALEE 5-year outcomes. Presented at: ESMO Congress 2025. October 17, 2025; Berlin, Germany. Abstract LBA14.