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Adjuvant abemaciclib (Verzenio) plus endocrine therapy significantly reduced the risk of death by 15.8% compared with endocrine therapy alone in patients with hormone receptor–positive, HER2-negative, high-risk early breast cancer (HR, 0.842; 95% CI, 0.722-0.981; P = .0273), according to findings from the primary overall survival (OS) analysis of the phase 3 monarchE trial (NCT03155997), which were presented at the 2025 ESMO Congress.¹

At a median follow-up of 76 months (6.3 years) and a data cutoff date of July 15, 2025, all patients had stopped receiving abemaciclib for at least 4 years. There were 301 OS events in the abemaciclib arm vs 360 in the endocrine therapy–alone arm. The OS rates at 60, 72, and 84 months were 91.2%, 89.2%, and 86.8% in the abemaciclib arm vs 90.2% (Δ = 1.0), 87.9% (Δ = 1.3), and 85.0% (Δ = 1.8) in the control arm.

“Abemaciclib represents the first CDK4/6 inhibitor to achieve a statistically significant improvement in OS for these high-risk, node-positive patients,” Stephen Johnston, MD, PhD, stated in the presentation.

Johnston is head of the Breast Unit, a professor of breast cancer medicine, and a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research in London, United Kingdom.

What Was the Impetus for Conducting the monarchE Trial?

“Improving OS and cure rates is the goal of adjuvant therapy in early breast cancer, but it’s difficult to prove OS, and we often approve treatments on benefits in reducing risk of recurrence,” Johnston explained.

He summarized key findings from the past several years of investigating endocrine therapy in patients with hormone receptor–positive early breast cancer, including reductions in the risk of death conferred by the use of tamoxifen vs no treatment, the use of an aromatase inhibitor (AI) vs tamoxifen, and the use of extended AI treatment vs 5 years of endocrine therapy. He noted that unlike in prior trials, previously reported data from monarchE indicated that an OS benefit could emerge from the addition of abemaciclib to endocrine therapy vs endocrine therapy alone.

What Was the Design of the monarchE Trial?

monarchE enrolled patients with hormone receptor–positive, HER2-negative, mode-positive, high-risk early breast cancer. Cohort 1 included patients with high-risk disease based on clinical and pathological factors, including at least 4 positive axillary lymph nodes or 1 to 3 positive axillary lymph nodes and grade 3 disease and/or a tumor size of at least 5 cm. Cohort 2 included patients with high-risk disease based on Ki-67 score, defined as 1 to 3 positive axillary lymph nodes plus a Ki-67 score of at least 20%, as well as grade 3 or lower disease and a tumor size of less than 5 cm.

Patients in cohort 1 (n = 5637) were randomly assigned 1:1 to receive abemaciclib at 150 mg twice daily plus endocrine therapy or endocrine therapy alone for the on-treatment study period of 2 years. During the follow-up period, patients received endocrine therapy for 3 to 8 years as clinically indicated. Patients were stratified by prior chemotherapy, menopausal status, and region.

The primary end point was invasive disease–free survival (IDFS). Secondary end points included IDFS in the high Ki-67 populations, distant relapse–free survival (DRFS), OS, safety, pharmacokinetics, and patient-reported outcomes.

What Data Have Been Previously Reported From monarchE?

The initial readout of the monarchE trial showed that patients who received 2 years of adjuvant abemaciclib plus endocrine therapy had significant improvements in IDFS compared with those who received endocrine therapy alone (HR, 0.75; 95% CI, 0.60-0.93; P = .01).² Furthermore, at the 5-year landmark analysis of the trial, at a median follow-up of 54 months (IQR, 49-59), the IDFS (HR, 0.68; 95% CI, 0.599-0.772; nominal P < .001) and DRFS (HR, 0.675; 95% CI, 0.588-0.774; nominal P < .001) benefits with abemaciclib were sustained, and an OS trend favoring the abemaciclib arm had emerged, although it had not yet reached statistical significance (HR, 0.903; 95% CI, 0.749-1.088; P = .284).³ 

What Additional Data Were Seen in the Primary OS Analysis of monarchE?

In the primary OS analysis, the OS benefit with the addition of abemaciclib was consistent across prespecified patient subgroups.¹ However, Johnston emphasized that the point estimates for the individual subgroups should be interpreted with caution because the trial was not powered or controlled to evaluate treatment effects in individual subgroups.

There were approximately 30% fewer patients living with metastatic disease in the abemaciclib arm vs the control arm. In the abemaciclib arm, 2.8% of patients (n = 80) had died from causes unrelated to breast cancer, 7.9% of patients (n = 221) had died due to breast cancer, and 6.4% of patients (n = 180) were alive with metastatic disease. In the control arm, these rates were 2.3% (n = 64), 10.5% (n = 296), and 9.4% (n = 266), respectively.

The addition of abemaciclib to endocrine therapy reduced the risk of IDFS events by 26.6% compared with endocrine therapy alone (HR, 0.734; 95% CI, 0.657-0.820; nominal P < .0001). There were 547 and 722 IDFS events in these respective arms.

During the follow-up period, the respective IDFS rates in the abemaciclib and control arms were as follows:

• 24 months: 92.7% vs 89.9%
• 36 months: 89.2% vs 84.4%
• 48 months: 85.9% vs 80.0%
• 60 months: 83.1% vs 76.5%
• 72 months: 80.0% vs 74.1%
• 84 months: 77.4% vs 70.9%

A consistent IDFS benefit was observed across all prespecified subgroups.

Johnston noted that most IDFS events observed in the trial were distant metastatic disease, and that the addition of abemaciclib reduced the number of patients with metastases at common sites. In the abemaciclib arm (n = 2808), 18.0% of patients in the intent-to-treat (ITT) population had a first recurrence, consisting of distant recurrence (13.6%), local/regional recurrence (2.5%), second primary neoplasm (1.7%), and contralateral breast cancer (0.5%). The sites of initial distant recurrence in this arm included bone (5.9%), liver (3.5%), lung (2.5%), brain/central nervous system (CNS; 1.1%), lymph node (1.0%), and pleura (0.3%).

In the control arm (n = 2829), 24.5% of patients in the ITT population had a first recurrence, consisting of distant recurrence (18.5%), local/regional recurrence (3.9%), second primary neoplasm (1.8%), and contralateral breast cancer (0.8%). The sites of initial distant recurrence in this arm included bone (9.4%), liver (4.7%), lung (2.7%), brain/CNS (1.1%), lymph node (1.6%), and pleura (1.0%).

Overall, investigators observed low rates of second primary neoplasms across both arms.

A sustained DRFS benefit with the addition of abemaciclib was also observed, reducing the risk of DRFS events by 25.4% compared with endocrine therapy alone (HR, 0.746; 95% CI, 0.662-0.840; nominal P < .0001). There were 476 DRFS events in the abemaciclib arm vs 621 DRFS events in the control arm.

During the follow-up period, the respective DRFS rates in the abemaciclib and control arms were as follows:

• 24 months: 94.0% vs 91.5% (Δ = 2.5)
• 36 months: 90.9% vs 86.6% (Δ = 4.3)
• 48 months: 88.2% vs 83.1% (Δ = 5.1)
• 60 months: 85.4% vs 79.5% (Δ = 5.9)
• 72 months: 82.6% vs 77.6% (Δ = 5.0)
• 84 months: 80.0% vs 74.9% (Δ = 5.1)

The investigators also reported a consistent DRFS benefit with abemaciclib across prespecified subgroups.

Among patients in the abemaciclib arm with distant recurrence who entered the post-2-year treatment follow-up period (n = 407), 78.9% received any first systemic therapy in the first-line metastatic setting, 32.7% received chemotherapy, 46.7% received endocrine therapy, 33.2% received targeted therapy (CDK4/6 inhibitor, 30.0%; PI3K/AKT/mTOR inhibitor, 3.2%), and 5.2% received other therapy. These respective rates in the control arm (n = 565) were 83.4%, 23.7%, 58.4%, 484.8% (CDK4/6 inhibitor, 47.3%; PI3K/AKT/mTOR inhibitor, 0.7%), and 4.8%.

Differences in CDK4/6 inhibitor and chemotherapy use between the arms were predominantly seen among patients with early recurrences and were less pronounced among those with later recurrences. Among patients with early recurrences, the rates of chemotherapy and CDK4/6 inhibitor use were 43.5% and 15.2%, respectively, in the abemaciclib arm (n = 191) vs 26.8% and 44.7%, respectively, in the control arm (n = 313). Among patients with late recurrences, the usage rates of these respective classes of therapy were 23.1% and 43.1% in the abemaciclib arm (n = 216) vs 19.8% and 50.4% in the control arm (n = 252).

“This makes clinical sense,” Johnston reported. “Patients relapsing on their adjuvant CDK4/6 inhibitor may be more likely to be offered chemotherapy. Those who have not had it in the adjuvant setting may be offered it for their metastatic disease. Remember, this was a global trial. Investigators could treat the patients as they saw fit. Globally, not all therapies in metastatic disease are equally available around the world, so we do not believe that this analysis confounds the OS impact we’ve seen. If there were more CDK4/6 inhibitors [used] in the endocrine therapy–alone arm, that might diminish the OS benefit, not enhance it.”

What Were the Long-Term Safety Findings From monarchE?

Safety results from long-term follow-up were consistent with those from prior analyses, because all treated patients had completed treatment at least 4 years prior. Investigators observed no relevant differences in adverse effect (AE)–related causes of death between the 2 arms.

Among safety-evaluable patients in the abemaciclib arm (n = 2791), during therapy, 15 deaths occurred; the most common causes of death were infections and infestations (COVID-19, n = 3) and cardiac disorders (n = 5). Following treatment discontinuation in this arm, 197 patients had at least 1 serious AE during late-term follow-up, regardless of causality. There were 44 deaths attributed to AEs, including infections and infestations (n = 13; COVID-19, n = 6), second primary neoplasm (n = 13), and cardiac disorders (n = 6).

Among safety-evaluable patients in the control arm (n = 2800), during therapy, 11 deaths occurred; the most common causes of death were infections and infestations (n = 5; COVID-19, n = 1) and second primary neoplasm (n = 1). Following treatment discontinuation in this arm, 213 patients had at least 1 serious AE during late-term follow-up, regardless of causality. There were 30 deaths attributed to AEs, including infections and infestations (n = 5; COVID-19, n = 2), second primary neoplasm (n = 7), and cardiac disorders (n = 9).

“The 7-year analysis has continued to show a sustained benefit in IDFS and DRFS, and there are no new safety signals,” Johnston concluded.

Disclosures: Johnston reported performing consultant or advisory roles with Eli Lilly and Company, Novartis, AstraZeneca, Roche-Genentech, and Pfizer; receiving grant/research funding from Pfizer, Eli Lilly and Company, and AstraZeneca; receiving honoraria from AstraZeneca, Roche-Genentech, Eli Lilly and Company, Novartis, and Pfizer; and giving expert testimony for Novartis.

References

1. Johnston S, Martin M, O’Shaughnessy J, et al. Overall survival with abemaciclib in early breast cancer. Ann Oncol. Published online October 17, 2025. doi:10.1016/j.annonc.2025.10.005
2. Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol. 2020;38(34):3987-3998. doi:10.1200/JCO.20.02514
3. 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