Ribociclib Offers Consistent Benefit in HR+ Early Breast Cancer Across All Ages and Menopausal Statuses

Data from the phase 3 NATALEE trial confirms ribociclib plus NSAI consistently improves survival outcomes in stage II/III HR+/HER2– early breast cancer patients, regardless of age or menopausal status.

According to results from the phase 3 NATALEE trial (NCT03701334) shared at the 2025 American Society of Clincial Oncology (ASCO) Annual Meeting, ribociclib (Kisqali), when combined with a nonsteroidal aromatase inhibitor (NSAI), has demonstrated consistent and sustained benefits across various survival endpoints—including invasive disease-free survival (iDFS), distant disease-free survival (DDFS), recurrence-free survival (RFS), and distant relapse-free survival (DRFS)—for patients with stage II/III hormone receptor–positive, HER2-negative early breast cancer.¹

At a median follow-up of 44.2 months, results showed that the 4-year iDFS rates in premenopausal patients were 90.6% with the ribociclib-plus-NSAI regimen with letrozole or anastrozole (n = 1115) vs 85.3% with a NSAI alone (n = 1123), leading to an absolute improvement of Δ5.3% (HR, 0.671; 95% CI, 0.518-0.870). In postmenopausal patients, the 4-year iDFS rates were 86.8% with the ribociclib-plus-NSAI regimen vs 82.2% with NSAI alone, which was a Δ4.6% absolute improvement (HR, 0.746; 95% CI, 0.607-0.917).

“This analysis showed that ribociclib in combination with letrozole or anastrozole lowered the chance of the cancer returned was safe to use in a broad population of patients with HR-positive, HER2-negative early breast cancer,” lead study author Kevin Kalinsky, MD, MS, FASCO, professor and director in the Division of Medical Oncology of the Department of Hematology and Medical Oncology at Emory University School of Medicine, and the director of the Glenn Family Breast Center at Winship Cancer Institute, said in an oral presentation during the meeting. “Ribociclib plus a NSAI provides treatment benefit to a broad range of patients with stage II/stage III HR-positive, HER2-negative early breast cancer across menopausal status and age.”

Although survival outcomes in patients with hormone receptor–positive, HER2-negative early breast cancer have improved with the use of adjuvant endocrine therapy, there is still a risk of recurrence, influenced by menopausal status and age, Kalinsky explained.

To be eligible for NATALEE, patients must have had hormone receptor–positive/HER2-negative early breast cancer and prior endocrine therapy was permitted within 12 months prior to randomization. Patients had to have:

1. anatomical stage IIA disease, which could be N0 with grade 2 and evidence of high risk, a Ki-67 of at least 20%, Oncotype DX Breast Recurrence Score at least 26 or high risk via genomic risk profiling, or grade 3, or N1 disease;
2. anatomical stage IIB, which was N0 or N1;
3. or anatomical stage III, which was N0, N1, N2, or N3.

Patients who were premenopausal were required to undergo ovarian suppression.

A total 5101 patients were randomized 1:1 to receive 400 mg of daily ribociclib on a 3-weeks-on/1-week-off schedule for 3 years plus an NSAI regimen of letrozole or anastrozole for at least 5 years plus goserelin in men and premenopausal women, or the NSAI regimen alone.

The primary end point was iDFS using STEEP criteria; secondary end points were RFS, DDFS, overall survival, safety and tolerability, patient-reported outcomes, and pharmacokinetics.

Stratification factors included anatomical stage (II vs III), menopausal status (men and premenopausal women vs postmenopausal women), receipt of prior neo(adjuvant) chemotherapy (yes vs no), and geographic location (North America/Western Europe/Oceania vs rest of world).

Prior NATALEE data showed a statistically significant benefit with iDFS with ribociclib plus NSAI vs NSAI alone in a larger population of patients with hormone receptor–positive/HER2-negative early breast cancer at risk of recurrence.² Additionally, the absolute iDFS benefit had increased to 4.9% in a 4-year landmark analysis and was observed across subgroups.³

In the analysis presented at the 2025 ASCO Annual Meeting, investigators reported on 4-year efficacy, safety, and quality-of-life (QOL) outcomes with ribociclib plus NSAI specific to menopausal status and age from the NATALEE study.¹

Kalinsky noted that more premenopausal patients vs postmenopausal had an ECOG performance status of 0 (86.8% vs 80.1%, respectively), Ki-67 greater than 20% (39.9% vs 34.4%), stage III (62.2% vs 58.3%), N1 to N3 nodal stage (63.4% vs 56.9%), and T3/T4 tumors (28.7% vs 24.0%) at diagnosis.

The data cutoff date was April 29, 2024. Efficacy outcomes were further explored via menopausal status and then grouped by age. Overall, in premenopausal patients, the 4-year DDFS rates were 91.6% with ribociclib/NSAI and 86.6% with NSAI alone (Δ5.0%; HR, 0.655; 95% CI, 0.498-0.861), 4-year RFS rates were 92.0% and 86.6%, respectively (Δ5.4%; HR, 0.641; 95% CI, 0.486-0.845), and 4-year DRFS rates were 92.7% and 87.6%, respectively (Δ5.1%; HR, 0.627; 95% CI, 0.469-0.837).

When examined in premenopausal patients younger than 40 years, the absolute benefit rate with ribociclib (n = 237) vs NSAI alone (n = 276) across iDFS, DDFS, RFS, and DRFS end points were Δ6.3% (HR, 0.690; 95% CI, 0.419-1.137), Δ7.0% (HR, 0.647; 95% CI, 0.383-1.091), Δ5.5% (HR, 0.723; 95% CI, 0.429-1.220), and Δ6.5% (HR, 0.659; 95% CI, 0.386-1.126), respectively.

These rates were slightly lower in premenopausal patients 40 years or older with ribociclib (n = 878) vs NSAI alone (n = 847): iDFS (Δ5.0%; HR, 0.662; 95% CI, 0.488-0.897); DDFS (Δ4.4%; HR, 0.659; 95% CI, 0.478-0.908), RFS (Δ5.3%; HR, 0.610; 95% CI, 0.439-0.846), and DRFS (Δ4.7%; HR, 0.615; 95% CI, 0.435-0.869).

The same analysis was conducted in postmenopausal patients. Overall, in this subgroup, the 4-year DDFS rates were 87.7% vs 83.6% with ribociclib or NSAI, respectively (Δ4.1%; HR, 0.759; 95% CI, 0.612-0.941). The 4-year RFS rates were 88.8% vs 84.5% (Δ4.3%; HR, 0.735%; 95% CI, 0.588-0.919), and the 4-year DRFS rates were 89.2% vs 85.6% (Δ3.6%; HR, 0.763; 95% CI, 0.606-0.960).

The outcomes were explored further in postmenopausal patients younger than 60 years. The absolute benefit rate with ribociclib (n = 703) vs NSAI alone (n = 735) across iDFS, DDFS, RFS, and DRFS end points were Δ2.7% (HR, 0.835; 95% CI, 0.619-1.128), Δ2.2% (HR, 0.854; 95% CI, 0.625-1.168), Δ2.8% (HR, 0.811; 95% CI, 0.590-1.114), and Δ2.1% (HR, 0.842; 95% CI, 0.606-1.172), respectively.

These absolute benefit rates were higher in postmenopausal patients 60 years or older with ribociclib (n = 721) vs NSAI alone (n = 685): iDFS (Δ6.4%; HR, 0.673; 95% CI, 0.506-0.896); DDFS (Δ5.9%; HR, 0.681; 95% CI, 0.506-0.916), RFS (Δ5.8%; HR, 0.668; 95% CI, 0.487-0.915), and DRFS (Δ5.0%; HR, 0.693; 95% CI, 0.502-0.956).

Kalinsky emphasized that the trial was not powered to detect differences with these exploratory analyses, adding that the data should be interpreted with caution.

Safety and dose modifications due to adverse effects (AEs) were examined by menopausal status. Kalinsky highlighted that in premenopausal patients overall (n = 2178), the ribociclib discontinuation rate due to AEs was 16.1%, and 75.4% discontinued without dose reductions; in patients younger than 40 years, these respective rates were 10.5% and 52.0%, and in patients 40 years and older, they were 17.5% and 79.2%, respectively.

The ribociclib dose reduction rate due to AEs was 22.4% in all premenopausal patients, followed by 27.0% and 21.1% in patients younger than 40 years and at least 40 years old, respectively.

“Premenopausal women were more likely to discontinue ribociclib without having had a dose reduction,” Kalinsky said.

In postmenopausal patients overall (n = 2771), the ribociclib discontinuation rate was 22.9% and 67.5% stopped treatment without experiencing dose reductions. These rates were 17.8% and 68.0% in patients younger than 60 years and 27.9% and 67.2% in patients 60 years and older. The ribociclib dose reduction rate due to AEs was 23.6% in all postmenopausal patients, followed by 24.2% and 22.9% in patients younger than 60 years and at least 60 years old, respectively.

Time to deterioration (TTD) in global health status (GHS) and physical functioning scales of the EORTC QLQ-C30 was similar between arms for all patient subgroups. The hazard ratio for TTD of GHS was 1.030 (95% CI, 0.928-1.145) in premenopausal patients compared with 1.040 (95% CI, 95% CI, 0.945-1.144) in postmenopausal patients.

The hazard ratios were similar when stratified by age in the premenopausal group: younger than 40 years (HR, 1.085; 95% CI, 0.867-1.356) and 40 years and older (HR, 1.018; 95% CI, 0.903-1.147). In the postmenopausal group, the hazard ratio was 0.996 (95% CI, 0.870-1.141) for patients younger than 60 years and was 1.082 (95% CI, 0.945-1.238) in those who were at least 60 years.

Disclosures: Kalinsky cited employment and stock ownership with EQRx; consulting or advisory roles with AstraZeneca, BioTheranostics, Culinan Oncology, Daiichi Sankyo/AstraZeneca, eFFECTOR Therapeutics, Genentech/Roche, Gilead Sciences, Lilly, Menarini Silicon Biosystems, Merck, Mersana, Myovant Sciences, Novartis, Pfizer, Prelude Therapeutics, ProteinQure, Puma Biotechnology, RayzeBio, Regor, Relay Therapeutics, and Takeda; research funding from Ascentage Pharma (Inst), AstraZeneca (Inst), Daiichi Sankyo (Inst), Genentech/Roche (Inst), Lilly (Inst), Novartis (Inst), and Seagen (Inst).

References

1. Kalinsky K, Reinisch M, Lu Y-S, et al. Efficacy and safety of ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) in NATALEE: analysis across menopausal status and age. J Clin Oncol. 2025;43(suppl 17):516. doi:10.1200/JCO.2025.43.16_suppl.516
2. Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plusendocrine therapy in early breast cancer. N Eng J Med. 2024;390(12):1080-1091.doi:10.1056/NEJMoa2305488
3. Fasching PA, Stroyakovskiy D, Yardley D, et al. Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (Pts) with HR+/HER2− early breast cancer (EBC): 4-year outcomes from the NATALEE trial . AnnOncol. 2024;35(suppl 2):S1207. doi:10.1016/j.annonc.2024.08.2251