ESMO 2025: Updated Results From the monarchE Trial in Early Breast Cancer

Sarah Premji, MD Sarah Cannon Research Institute | Matthew Goetz, MD Mayo Clinic, Rochester

Setting the Stage

ESMO 2025 brought a whirlwind of new updates in virtually every tumor type and breast cancer was no exception. One of the most highly anticipated updates was the overall survival analysis from monarchE, which evaluated the use of adjuvant abemaciclib with endocrine therapy (ET) in HR+/HER2– high risk early breast cancer. 

The gold standard for full adoption of any new drug or drug regimen has historically been to improve survival, regardless of the attribution of death. However, in the early-stage estrogen receptor (ER)-positive breast cancer setting, demonstrating an improvement in overall survival (OS) is becoming more difficult, as the risk of a disease event for ER+/HER2– breast cancer tends to be lower than other cancer subtypes, and death may occur from events unrelated to breast cancer. Because of this, endpoints such as invasive disease-free survival (IDFS), relapse free survival (RFS), and distant relapse free survival (DRFS), are often used as surrogates for survival and are accepted by regulatory bodies for drug approval. 

The monarchE investigators evaluated the addition of  abemaciclib, a CDK 4/6 inhibitor (CDK 4/6i) to standard endocrine therapy in both pre and postmenopausal patients with anatomically and/or biologically high-risk disease including patients with ≥ 4 axillary lymph nodes or 1–3 axillary lymph nodes with either grade 3 disease or a tumor size ≥ 5 cm, and a smaller cohort of patients with 1–3 axillary lymph nodes and Ki-6 ≥ 20%. 

In this trial, patients were randomized 1:1 to either ET or ET plus abemaciclib at a dose of 150 mg twice daily for 2 years. Notably, 94%–95% of patients received prior chemotherapy. Previous releases of the data demonstrated that the addition of abemaciclib to ET improved IDFS and DRFS (Hazard Ratio [HR], 0.680; 95% confidence interval [CI], 0.599–0.772; P < 0.001 for IDFS; HR, 0.675; 95% CI, 0.588–0.774; P < 0.001 for DRFS) with an absolute improvement at 5 years of 7.6% and 6.7%, respectively. At the latest update, a trend toward an improvement in OS was observed.¹

The Data

At ESMO 2025, Johnston et al. reported OS results, a key prespecified secondary endpoint. In the intent-to-treat population, with a median follow-up of 76.2 months, abemaciclib-ET resulted in a 15.8% lower risk of death compared with ET alone (661 deaths; HR, 0.842; 95% CI, 0.722–0.981; P = 0.027).  The 7-year OS was 86.8% with abemaciclib-ET and 85% with ET (absolute difference, 1.8%), with consistent OS benefit across pre-specified subgroups. 

The analysis also demonstrated that fewer patients in the abemaciclib and ET were diagnosed with metastatic breast cancer or have passed from metastatic breast cancer (14.3%) compared to 19.9% of patients who had received ET alone. Additionally, IDFS and DRFS continued to be longer in the abemaciclib arm (HR, 0.734; 95% CI, 0.657–0.820, P < 0.001 and HR, 0.746; 95% CI, 0.662-0.840; P < 0.001, respectively). Most IDFS events were distant metastatic disease. Safety results were consistent with previous analyses, and all patients had completed abemaciclib ≥ 4 years prior.² 

Ongoing Questions

The monarchE OS data affirm our ongoing practice, but raise important questions. Dr. Angie DeMichele, a discussant at ESMO 2025, highlighted several important points regarding the quality of the post-relapse period, particularly which disease sites are involved, types of treatments received, and tumor biology in this setting. While there was not a difference in percent development of visceral disease between the arms, there was greater development of bone/soft tissue recurrences in the ET alone arm and more early use of chemotherapy in the abemaciclib arm, raising further questions about tumor biology in the post CDK 4/6i adjuvant setting.³

This issue was partially studied by Corti et al., who identified changes in molecular biology, notably ER loss and P53 alterations.⁴ Ultimately, additional data from both the trial and real-world setting will inform further use of CDK 4/6i and other agents in metastatic disease, including effects on time from prior adjuvant exposure, site of anatomical recurrence, and whether risk factors such as Ki-67, age, and genomic risk predict even greater benefit from adjuvant CDK 4/6i use. Further development and use of additional targeted agents that may combat these various resistance mechanisms in the metastatic setting are imperative as the field continues to evolve.  

The Big Picture

While many questions remain to be explored, the use of adjuvant CDK 4/6 inhibitors in patients that meet the criteria is strongly recommended.  

References

1. Rastogi P, O’Shaughnessy J, Martin M, et al. Adjuvant Abemaciclib Plus Endocrine Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, High-Risk Early Breast Cancer: Results From a Preplanned monarchE Overall Survival Interim Analysis, Including 5-Year Efficacy Outcomes. J Clin Oncol. 2024;42(9):987-993. doi:10.1200/JCO.23.01994
2. Johnston, S., Martin, M., O’Shaughnessy, J., Hegg, R., Tolaney, S. M., Guarneri, V., Del Mastro, L., Campone, M., Sohn, J., Boyle, F., Cortes, J., Rugo, H. S., Goetz, M. P., Hamilton, E. P., Huang, C. S., Senkus, E., Cicin, I., Testa, L., Neven, P.,…Harbeck, N. Overall Survival with Abemaciclib in Early Breast Cancer. Annals of Oncology. https://doi.org/10.1016/j.annonc.2025.10.005 
3. DeMichele, Early Breast Cancer ESMO 2025 Discussion, October 2025 
4. Corti, C., Martin, A. R., Kurnia, P. T., Gómez Tejeda Zañudo, J., Abravanel, D. L., Hughes, M. E., Parker, T., Tarantino, P., Curigliano, G., King, T. A., Mittendorf, E. A., Lin, N. U., & Tolaney, S. M. (2025). Clinicopathological features and genomics of ER-positive/HER2-negative breast cancer relapsing on adjuvant abemaciclib. ESMO Open, 10(6). https://doi.org/10.1016/j.esmoop.2025.105126