Expanding adjuvant therapy with ribociclib in HR-positive, HER2-negative early breast cancer

Despite advances in adjuvant endocrine therapy (ET), residual recurrence risk remains in patients with hormone receptor (HR)–positive, HER2-negative early breast cancer (eBC). At an industry-sponsored meeting, Professor Michael Untch of the Helios Klinikum Berlin-Buch in Berlin, Germany, and a panel of experts from Hong Kong discussed the survival benefits associated with adding ribociclib, an oral cyclin-dependent kinase (CDK) 4/6 inhibitor, to adjuvant ET in this patient population, and its implications in daily clinical practice.

Unmet needs in HR-positive/HER2-negative eBC management
Recurrence risk in patients with HR-positive, HER2-negative eBC persists beyond the initial 5 years of standard-of-care (SoC) adjuvant ET. In a meta-analysis of clinical trials in­volving women with HR-positive eBC who were disease-free after 5 years of scheduled ET, breast cancer recurrenc­es continued to occur steadily, with 20- year distant recurrence risk of 22–52 percent in N0–N3 patients. [N Engl J Med 2017;377:1836-1846; Ann Oncol 2025;36:149-157]

Despite continued standard adju­vant ET, a substantial unmet need re­mains not only for those with node-pos­itive eBC, but also for those with N0 disease having high-risk tumour fea­tures, because long-term recurrence risks remain persistently significant across these groups. [N Engl J Med 2017;377:1836-1846]

Real-world analysis from the US Flatiron Health eBC database also showed that node-negative patients with high-risk features (eg, T4N0, T3N0, or T2N0 [grade 3 or grade 2 with Ki-67 ≥20 percent or high genomic risk]) have recurrence risks comparable to those with N1 disease (ie, 7-year overall re­currence risk >15 percent). [Jhaveri K, et al, ESMO 2023, abstract 292P]

“These findings challenge the tradi­tional view that N0 disease is uniform­ly low-risk and support potential use of CDK 4/6 inhibition in this patient group,” argued Untch. [Ann Oncol 2015;26:1685-1691; NCCN Clini­cal Practice Guidelines in Oncology, Breast Cancer, version 5.2025]

Rationale for CDK 4/6 inhibition in eBC
The use of adjuvant CDK 4/6 in­hibitors in patients with HR-positive, HER2-negative eBC is increasing­ly being recognized. [Trends Cell Biol 2018;28:911-925; Cancer Treat Rev 2025;136:102944]

While adjuvant ET remains the backbone of treatment for HR-positive, HER2-negative eBC, recurrences con­tinue to occur despite prolonged ET. This highlights the need for additional strategies that can overcome endocrine resistance and improve long-term out­comes, providing the rationale for com­bining ET with CDK4/6 inhibitors in eBC. [N Engl J Med 2017;377:1836-1846; Trends Cell Biol 2018;28:911-925; Can­cer Treat Rev 2025;136:102944]

CDK 4/6 inhibition leads to cell se­nescence, and its combination with ET is expected to improve prevention of mi­crometastatic disease. [Trends Cell Biol 2018;28:911-925; Cancer Treat Rev 2025;136:102944]

Although palbociclib did not show efficacy in eBC setting, the phase III monarchE and NATALEE trials involving abemaciclib and ribociclib, respectively, demonstrated significant improvements in invasive disease-free survival (iDFS) in patients with eBC, which may be attrib­utable to their differences in target spec­ificity. [J Clin Oncol 2021;39:1518-1530; J Clin Oncol 2022;40:449-458; J Clin Oncol 2020;38:3987-3998; N Engl J Med 2024;390:1080-1091; Front Oncol 2021;11:693104]

monarchE and NATALEE: Similarities and key differences
“A key distinction between monarchE and NATALEE is their patient populations and treatment durations,” highlighted Untch. (Table)

monarchE was an open-label, phase III study that evaluated abemaciclib (150 mg BID for 2 years) plus ET in patients with high-risk HR-positive/ HER2-negative eBC. (Table) Interim analysis showed abemaciclib plus ET improved iDFS vs ET alone (hazard ratio, 0.75; 95 percent confidence interval [CI], 0.60–0.93; p=0.01), with 2-year iDFS rates of 92.2 vs 88.7 percent. [J Clin Oncol 2020;38:3987-3998] Ben­efits were sustained at 7 years, sup­porting abemaciclib’s use in high-risk eBC. [Ann Oncol 2025;doi:10.1016/j. annonc.2025.10.005] Meanwhile, NA­TALEE was a phase III trial that com­pared ribociclib plus nonsteroidal aro­matase inhibitor (NSAI; letrozole or anastrozole for ≥5 years) ± ovarian func­tion suppression (OFS) or ET alone in patients with stage II or III HR-positive, HER2-negative eBC (n=5,101). (Table) [N Engl J Med 2024;390:1080-1091]

“NATALEE had broader inclusion criteria, encompassing not only those with 1–3 positive nodes but also node-negative patients with high-risk features [ie, T2 (grade 2 and high genomic risk or Ki-67 ≥20 percent, or grade 3), T3 or T4],” he explained. “Patients received riboci­clib 400 mg/day for 3 years – a reduced dose compared with the recommended 600 mg dose for patients with advanced disease, aiming to improve safety and adherence.” (Table) [N Engl J Med 2024;390:1080-1091; Ther Adv Med Oncol 2025;17:17588359251326710]

“The inclusion of node-negative, high-risk patients in NATALEE represents a major advance over monarchE, ad­dressing a previously unmet need by broadening the therapeutic scope of CDK 4/6 inhibition,” highlighted Untch. “These patients were traditionally ex­cluded from treatment escalation trials. However, their recurrence risk was com­parable to node-positive patients in NA­TALEE, suggesting that recurrence risk is not solely determined by nodal status, but also by tumour biology and other high-risk features.” (Figure 1) [Fasching PA, et al, ESMO 2024, abstract LBA13; J Clin Oncol 2020;38:3987-3998]

NATALEE: Ribociclib’s benefits
Prespecified interim analysis results at 3 years showed a significant iDFS benefit associated with ribociclib plus an NSAI vs NSAI alone. [N Engl J Med 2024;390:1080-1091]

Sustained benefit at 5 years, across subgroups
Notably, these results remained con­sistent in an exploratory analysis 5 years later, when all patients were no longer on ribociclib (data cut-off, 28 May 2025). [ESMO Open 2025;doi:10.1016/j.es­moop.2025.105858]

At 5 years (median follow-up, 55.4 months), ribociclib plus NSAI continued to improve iDFS vs NSAI alone (85.5 vs 81.0 percent; hazard ratio, 0.716; 95 percent CI, 0.618–0.829; p<0.0001). This iDFS benefit was consistent across a broad range of prespecified subgroups, includ­ing node-positive and node-negative sub­groups. (Figures 1 & 2)
 

The 5-year follow-up of NATALEE also showed that ribociclib was associ­ated with a distant disease-free survival benefit (hazard ratio, 0.709; 95 percent CI, 0.608–0.827) vs NSAI alone.

As overall survival data are emerging (not yet mature), a trend favouring ribo­ciclib (hazard ratio, 0.800; 95 percent CI, 0.637–1.003; p_nominal=0.026) was observed.

ET partner optimization: AI vs tamoxifen
“In monarchE, the benefit of abe­maciclib was greater when combined with tamoxifen than with an aromatase inhibitor [AI] as the first ET [iDFS hazard ratios, 0.537 vs 0.760],” noted Untch. “In NATALEE, tamoxifen was not al­lowed as SoC. Instead, it included an NSAI plus OFS for premenopausal women and NSAI for postmenopaus­al women in addition to ribociclib, which represents the SoC in this high-risk population.” (Table) [J Clin Oncol 2020;38:3987-3998; Verzenios EMA Assessment report, February 2022; N Engl J Med 2024;390:1080-1091]

This shift reflects a broader princi­ple of ET partner optimization: Whereas monarchE permitted both tamoxifen and AI partners, contemporary treat­ment practice increasingly favours AI-based backbones, as in NATALEE, given their proven efficacy when com­bined with OFS in higher-risk patients. [J Clin Oncol 2020;38:3987-3998; N Engl J Med 2024;390:1080-1091]

AIs are increasingly preferred vs tamoxifen when combined with OFS be­cause multiple major trials, such as the SOFT (Suppression of Ovarian Function Trial), TEXT (Tamoxifen and Exemes­tane Trial), and BIG (Breast International Group) 1-98S trials, have demonstrated that AIs plus OFS provide superior effi­cacy and reduce recurrence risk more effectively in eBC patients at increased risk of recurrence than tamoxifen + OFS. [N Engl J Med 2018;379:122-137; Lan­cet Oncol 2011;12:1101-1108]