The Impact of Underutilizing Adjuvant CDK4/6 Inhibitors in Node-Positive, HR-Positive/HER2-Negative Early Breast Cancer

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Cyclin-dependent kinase (CDK)4/6 inhibitor-based treatment became available for adjuvant use in node-positive, high-risk, hormone receptor (HR)-positive/HER2-negative early breast cancer (eBC) in 2021. Despite this, new real-world data reveal that many eligible patients, especially patients ≥65 years of age and those with high-risk N1 disease, are not receiving this critical treatment. This newsletter explores updated clinical data that underscore improved survival outcomes for patients treated with available adjuvant CDK4/6 inhibitors, as well as recent real-world findings demonstrating increased recurrence and mortality risks for patients with node-positive, high-risk, HR-positive/HER2-negative eBC treated with endocrine therapy (ET) alone that are comparable with triple-negative breast cancer (TNBC).

CDK4/6 Inhibitors Have Demonstrated Benefits in Preventing Disease Recurrence in the Adjuvant Setting

Currently, there are 2 CDK4/6 inhibitors approved for adjuvant use in node-positive, high-risk, HR-positive/HER2-negative eBC. CDK4/6 inhibitors target cell cycle dysregulation, a key driver of tumor proliferation in HR-positive breast cancer, and have demonstrated significant efficacy in reducing recurrence risk and improving long-term survival outcomes in this high-risk population.

Abemaciclib

Abemaciclib was approved in combination with ET (tamoxifen or an aromatase inhibitor [AI]) for the adjuvant treatment of adult patients node-positive, HR-positive/HER2-negative eBC at high risk of recurrence based on results from the pivotal phase 3 study, monarchE (NCT03155997).¹ Within monarchE, patients were randomized into 2 cohorts receiving either abemaciclib plus ET (tamoxifen or an AI) or ET alone for 2 years. ET was continued for 5 years as appropriate. A significant improvement in invasive disease-free survival (IDFS), the primary endpoint, was observed at 4 years, driven primarily by patients in cohort 1, with IDFS rates of 85.5% for treatment with abemaciclib plus ET, versus 78.6% for ET alone.² Brand new 7-year landmark analysis of monarchE data, with a median follow-up of 76 months, presented at the European Society for Medical Oncology (ESMO) Congress 2025³ and recently published,⁴ showed the addition of 2 years of abemaciclib to ET provided overall survival (OS) benefit, reducing the risk of death by 15.8% compared with ET alone (hazard ratio, 0.84; 95% confidence interval [CI], 0.72-0.98; 2-sided P=.027). IDFS and distant relapse-free survival (DRFS) benefits also persisted with hazard ratios of 0.73 (95% CI, 0.66-0.82; P<.0001) and 0.75 (95% CI, 0.66-0.84), respectively. There were also approximately 30% fewer patients in the abemaciclib arm living with metastatic disease.

Abemaciclib is administered twice daily and may be prescribed in premenopausal patients without the use of co-administered medication for ovarian function suppression (OFS). Specific monitoring of liver function and/or neutropenia is required during the first 2 months.²

The most frequently reported grade 3 or 4 adverse events (AEs) (≥5%) with abemaciclib plus ET were neutropenia, leukopenia, diarrhea, and lymphopenia, with fatal AEs occurring in 0.8% of patients.² Permanent discontinuation of abemaciclib occurred in 19% of patients. Dose interruptions due to AEs were reported in 62%; however, patients could be managed with dose reductions as needed to help most patients remain on therapy without loss of efficacy.^2,5

Ribociclib

Approved by the FDA in September 2024, ribociclib is indicated for use in combination with an AI for the adjuvant treatment of adults with HR-positive/HER2-negative stage II and III eBC at high risk of recurrence based on the result of the pivotal phase 3 study, NATALEE.⁶ High risk of recurrent disease was defined within NATALEE as either stage group IIB to III or stage group IIA and either node-positive or node-negative, or histologic grade 3 or histologic grade 2 with any of the following criteria: Ki67 ≥20% and/or high risk by gene signature testing. Patients were randomized to receive ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) (letrozole or anastrozole), or NSAI for 3 years. An NSAI was administered for at least 5 years and required co-administered goserelin in male patients and to provide OFS in premenopausal women.^7,8

A significant improvement in IDFS, the primary endpoint, was observed at 3 years, with IDFS rates of 90.7% in the ribociclib plus NSAI arm versus 87.6% for the NSAI-alone arm.⁷ An updated analysis of NATALEE, with a median follow-up of 56.5 months, which was presented at ESMO Congress 2025⁹ and newly published,¹⁰ showed the addition of 3 years of ribociclib to NSAI provided OS benefit (hazard ratio, 0.80; 95% confidence interval [CI], 0.64-1.003; 1-sided P=.026) and IDFS benefits at a median follow-up of 55.4 months with a hazard ratio of 0.72 (95% CI: 0.62-0.83; P<.0001).⁹ It is worth noting, primary and long-term analyses included patients with node-negative disease. Within total trial enrollment, approximately 14 to 16% of patients had node-negative disease at the time of surgery. A subanalysis of data presented at ESMO examined IDFS by nodal status and found a benefit in all groups (node [N]0: hazard ratio, 0.61; 95% CI, 0.37-0.99; N1-3: hazard ratio, 0.74; 95% CI, 0.63-0.86; P values not reported).⁹ Ribociclib plus NSAI also demonstrated continued benefit DRFS with a hazard ratio of 0.70 (95% CI, 0.59-0.82; P values not reported).⁹ There were fewer patients alive with metastatic disease (n=114) in the ribociclib plus NSAI arm than the NSAI arm (n=169).

Ribociclib is administered on an intermittent schedule (3 weeks on/1 week off) with continuous NSAI co-administration. Use with tamoxifen is contraindicated due to potential cardiac risks; therefore, OFS is required in premenopausal patients.⁷ Specific monitoring of cardiac and liver function and neutropenia is required during the initial cycle and then at the beginning of each 4-week cycle.⁷

The most common grade 3 or 4 AEs (>0.5%) with ribociclib plus NSAI were infections, fatigue, diarrhea, and asthenia, with fatal AEs occurring in 0.6% of patients.⁷ During the pivotal trial, permanent discontinuation of ribociclib occurred in 20% of patients and dose interruptions of both ribociclib plus NSAI due to an AE occurred in 73% of patients. Dose reductions of ribociclib due to an AE occurred in 23% of patients.⁷

Clinical Challenge: Increased Risk of Recurrence and Death in Eligible eBC Patients Not Receiving Adjuvant CDK4/6 Inhibitors Comparable With TNBC

Findings presented at ESMO Breast Cancer 2025 demonstrate that patients with high-risk clinicopathological features, as defined by the monarchE trial, face recurrence and mortality risks not only higher than those observed in non–high-risk patients, but also that are comparable with the risks seen in early TNBC.¹¹ In this retrospective study, using the Flatiron Health database, researchers analyzed electronic health records from approximately 16,000 adult patients diagnosed with eBC between January 2011 and June 2024 who underwent breast cancer surgery. The study focused on data primarily gathered from community settings to provide valuable insights into patient outcomes and care trends. Eligible patients with eBC were categorized into 2 cohorts: HR-positive/HER2-negative, and TNBC (estrogen receptor–negative, progesterone receptor–negative, HER2-negative). Patients with HR-positive/HER2-negative BC had to have initiated adjuvant oral ET without prior targeted therapy and were further divided into 2 groups: node-positive, high-risk, meeting monarchE cohort 1 entry criteria; and non–high-risk. Patients with TNBC were required to have initiated adjuvant chemotherapy.¹¹

This study found that patients meeting the monarchE cohort 1 criteria faced a 5-year mortality risk comparable with patients with TNBC treated with adjuvant chemotherapy. Both groups had significantly higher mortality risks than non–high-risk patients, with the node-positive, high-risk group showing a 12.3% higher risk and the TNBC group showing a 14.7% higher risk.¹¹ Similarly, 5-year recurrence risks for node-positive, high-risk, HR-positive/HER2-negative eBC treated with adjuvant ET align closely with those of early TNBC treated with adjuvant chemotherapy, and are markedly higher than in non–high-risk groups —20.3% higher for the node-positive, high-risk group, and 16.9% higher for early TNBC groups.¹¹

Elevated risks persisted across all node-positive, high-risk, HR-positive/HER2-negative eBC nodal subgroups, with mortality differences of ≥7.4% and recurrence differences of ≥15.5% compared with the non–high-risk group.¹¹ Subanalyses here further revealed that patients with N1 high-risk disease had a 5-year mortality risk (6.3% higher) and a recurrence risk (14.3% higher) compared with those in the N1 non-high-risk group.¹¹ These results underscore the urgent need for all patients with node-positive, high-risk, HR-positive/HER2-negative eBC to receive adjuvant treatment beyond ET alone to reduce the risk of recurrence and death.

Unmet Need: Underutilization of Adjuvant CDK4/6 Inhibitor Treatment in Eligible Patients Following Approval of Abemaciclib

Despite the proven clinical efficacy of abemaciclib, recent findings presented at the Miami Breast Cancer Conference 2025 highlight its underutilization among eligible patients in the adjuvant setting following its approval.¹² The study assessed data from January 2023 to June 2024—a period when abemaciclib was the only CDK4/6 inhibitor approved for use in the adjuvant setting for eBC. Using the Flatiron Health database, the analysis, conducted across approximately 280 US centers, highlights factors contributing to nonutilization and underscores a gap in translating evidence-based treatments into clinical practice.¹² This analysis included patients diagnosed with HR-positive/HER2-negative eBC who met monarchE node-positive, high-risk eligibility criteria, defined by nodal involvement and additional pathological features such as tumor size or tumor grade.¹² A large proportion of eligible patients, 60%, did not receive abemaciclib. The study found key factors impacting abemaciclib utilization which included nodal status, race, and age.¹² Over 2/3 of eligible patients with N1/N1mi with high-risk disease (grade 3 and/or tumor size ≥5 cm) did not receive abemaciclib, and of these, 74% had grade 3 disease. Additionally, 70% of eligible patients aged ≥65 years did not receive abemaciclib, and utilization decreased with age. Therefore, underutilization of adjuvant abemaciclib among patients with N1 high-risk disease or elderly patients remains a significant concern.

Conclusions

Adjuvant treatment of node-positive, high-risk, HR-positive/HER2-negative eBC using CDK4/6 inhibitors has demonstrated significant improvements in IDFS, DRFS, and OS compared with ET alone for patients with high-risk clinicopathological features. Despite the introduction of CDK4/6 inhibitors, real-world evidence highlights a concerning underutilization of these therapies several years following initial approval, particularly in older individuals aged ≥65 and those with N1 disease. Real-world evidence demonstrates that ET alone leaves these patients at elevated risks of recurrence and mortality comparable with patients seen for TNBC. Barriers such as nodal status, age, and race contribute to this underutilization, underscoring the need for greater awareness and adherence to updated clinical guidelines. Ensuring appropriate consideration of available options beyond ET alone is essential for addressing unmet needs and improving long-term outcomes for patients with node-positive, HR-positive/HER2-negative eBC.

References

1. VERZENIO [prescribing information]. 2021. Lilly USA, LLC; Indianapolis, IN.
2. VERZENIO [prescribing information]. 2025. Lilly USA, LLC; Indianapolis, IN.
3. Johnston SR, Martin M, O’Shaughnessy J, et al. monarchE: primary overall survival (OS) results of adjuvant abemaciclib + endocrine therapy (ET) for HR+, HER2-, high-risk early breast cancer (EBC). Presented at: ESMO Congress 2025. October 17, 2025; Berlin, Germany. Abstract LBA13.
4. Johnston S, Martin M, O’Shaughnessy J, et al. Overall survival with abemaciclib in early breast cancer. Ann Oncol. 2025;S0923-7534:049488.
5. Goetz MP, Cicin I, Testa L, et al. Impact of dose reductions on adjuvant abemaciclib efficacy for patients with high-risk early breast cancer: analyses from the monarchE study. NPJ Breast Cancer. 2024;10:34.
6. US Food & Drug Administration. FDA approves ribociclib with an aromatase inhibitor and ribociclib and letrozole co-pack for early high-risk breast cancer [press release]. October 24, 2025. Accessed November 19, 2025. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ribociclib-aromatase-inhibitor-and-ribociclib-and-letrozole-co-pack-early-high-risk
7. KISQALI [prescribing information]. 2025. Novartis Pharmaceuticals Corporation; East Hanover, NJ.
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9. 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.
10. Crown J, Stroyakovskii D, Yardley DA, et al. Adjuvant ribociclib plus nonsteroidal aromatase inhibitor therapy in patients with HR-positive/HER2-negative early breast cancer: 5-year follow-up of NATALEE efficacy outcomes and updated overall survival. ESMO Open. Accessed November 19, 2025. www.esmoopen.com/article/S2059-7029(25)01727-2/fulltext
11. Rugo HS, et al. Real-world survival outcomes by risk features in patients with HR+, HER2- early breast cancer (EBC) in the US. Presented at: European Society for Medical Oncology Breast Cancer Congress. May 14-17, 2025; Munich, Germany. Poster 215P.
12. Sandoval-Leon A, et al. Exploring the treatment gap in high-risk HR+, HER2- early breast cancer (EBC): eligible patients not receiving abemaciclib in the US. Presented at: 42nd Annual Miami Breast Cancer Conference. March 6-9, 2025; Miami, FL. Poster 42.