Adjuvant Ribociclib Improves OS at 6 Years in HR+/HER2- Early Breast Cancer

Adding ribociclib (Kisqali) to a nonsteroidal aromatase inhibitor (NSAI) produced an overall survival (OS) benefit vs NSAI alone in patients with stage II or III hormone receptor-positive, HER2-negative (HR+/HER2-) early breast cancer, according to a prespecified 6-year analysis of the phase 3 NATALEE trial (NCT03701334).

At the 2026 European Society for Medical Oncology (ESMO) Congress, Dennis J. Slamon, MD, PhD, of the David Geffen School of Medicine at the University of California Los Angeles, presented the data during a proffered paper session on early and advanced breast cancer.¹

At a median follow-up of 66.5 months, 178 OS events occurred in the ribociclib arm (n = 2549) vs 205 in the NSAI-alone arm (n = 2552), translating to a 19% reduction in the risk of death (HR, 0.809; 95% CI, 0.661-0.989; nominal 1-sided P = .019). The 6-year OS rate was 91.9% with ribociclib plus NSAI vs 89.7% with NSAI alone, a 2.1% absolute benefit, up from a 1.2% difference at 5 years (93.9% vs 92.7%). The OS HR has remained consistent across successive data cutoffs, at 0.892 at the final invasive disease-free survival (iDFS) analysis, 0.827 at the exploratory 4-year analysis, 0.800 at the prespecified 5-year analysis, and 0.809 at the current readout, with the CI narrowing over time.

Breast cancer-specific survival (BCSS) supported the OS findings, with 126 BCSS events in the ribociclib arm vs 166 in the NSAI-alone arm (HR, 0.706; 95% CI, 0.559-0.890; nominal 1-sided P = .002). The 6-year BCSS rates were 94.2% vs 91.6%, respectively. In addition, fewer patients in the ribociclib arm were alive with metastatic disease (5.0% vs 6.8%), and deaths due to breast cancer occurred in 4.9% vs 6.5% of patients, respectively.

The iDFS benefit continued to deepen with longer follow-up. At a median iDFS follow-up of 66.3 months, the 6-year iDFS rate was 83.2% with ribociclib plus NSAI vs 77.9% with NSAI alone, a 5.3% absolute improvement, compared with a 4.1% difference at 5 years (HR, 0.741; 95% CI, 0.646-0.849; nominal 1-sided P < .0001). Distant recurrence accounted for 242 of 374 iDFS events in the ribociclib arm and 326 of 461 in the NSAI-alone arm. Six-year distant disease-free survival rates were 84.5% vs 79.6% (HR, 0.744; 95% CI, 0.646-0.858), and 6-year distant recurrence-free survival rates were 86.0% vs 81.6% (HR, 0.738; 95% CI, 0.634-0.858), respectively.

The OS benefit was generally consistent across prespecified subgroups. HRs were 0.705 among premenopausal women and men and 0.884 among postmenopausal women, 0.830 for stage II and 0.798 for stage III disease, and 0.790 for node-negative and 0.817 for node-positive disease, with 6-year absolute OS differences ranging from 1.3% to 3.4% across subgroups.

Among patients with distant recurrence, those in the NSAI-alone arm were more likely to receive a CDK4/6 inhibitor after progression, at 44.4% vs 21.0% in the ribociclib arm; this included subsequent ribociclib in 20.3% vs 3.7%, respectively. Endocrine therapy alone (27.9% vs 20.6%) and chemotherapy alone (21.9% vs 14.4%) were more common after recurrence in the ribociclib arm.

All patients were off ribociclib at the time of the analysis, with a median time off treatment of 38 months, and investigators reported that the safety profile of ribociclib remained unchanged. In the ribociclib arm, 62.8% of patients completed 3 years of ribociclib, and 36.3% discontinued early, most commonly because of adverse events (20.0%). Five years of NSAI therapy were completed by 62.1% of patients in the ribociclib arm and 57.0% in the NSAI-alone arm.

In the open-label, multicenter trial, 5101 adult patients with stage II or III HR+/HER2- early breast cancer were randomly assigned 1:1 to receive ribociclib at 400 mg per day on a 3-weeks-on, 1-week-off schedule for 3 years plus letrozole or anastrozole for at least 5 years, or NSAI alone. Men and premenopausal women also received goserelin. Prior endocrine therapy was allowed for up to 12 months. Eligible patients had anatomical stage IIA disease with N1 involvement, or N0 disease that was grade 3 or grade 2 with evidence of high risk (Ki-67 of at least 20%, an Oncotype DX Breast Recurrence Score of 26 or higher, or high risk via genomic profiling); stage IIB disease; or stage III disease. Enrollment of patients with stage II disease was capped at 40%.

The primary end point was iDFS using STEEP criteria. Secondary end points included OS, distant disease-free survival, recurrence-free survival, patient-reported outcomes, safety, and pharmacokinetics. Exploratory end points included distant recurrence-free survival and BCSS. Efficacy outcomes in the 6-year analysis were estimated using the Kaplan-Meier method and are descriptive. The data cutoff was May 15, 2026.

The investigators noted that previous pivotal trials of adjuvant endocrine therapy alone in HR+ early breast cancer generally showed absolute OS differences of 0% to 1% at 4 or 5 years. They concluded that the prespecified 6-year analysis of NATALEE supports the use of ribociclib plus an NSAI to reduce recurrence risk and ultimately improve OS in patients with HR+/HER2- early breast cancer at high risk of recurrence.

Reference

Slamon DJ, Hortobagyi G, Stroyakovskiy D, et al. Adjuvant ribociclib + nonsteroidal aromatase inhibitor in patients with HR+/HER2- early breast cancer: NATALEE 6-year overall survival and efficacy outcomes. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA25