MONARCH 3: Adding Abemaciclib to an Aromatase Inhibitor Improves Outcomes in Metastatic Breast Cancer

The addition of the cyclin-dependent kinase (CDK)4/CDK6 inhibitor abemaciclib (Verzenio) to an aromatase inhibitor improved progression-free survival (PFS) over aromatase inhibitor monotherapy in women with hormone receptor (HR)-positive, HER2-­negative advanced breast cancer, according to an interim analysis of the phase 3 MONARCH 3 clinical trial presented at the 2017 European Society for Medical Oncology (ESMO) Congress. The study was also re­cently published in the Journal of Clinical Oncology.1

“This is the third study demonstrating that the combination of endocrine therapy with a CDK4/CDK6 inhibitor is better than endocrine therapy alone. Abemaciclib reduced the rate of disease progression by 46%,” said lead investigator Angelo Di Leo, MD, PhD, Chair of Sandro Pitigliani Medical Oncology Department, Hospital of Prato, Istituto Toscano Tumori, Italy, who presented the study results.

Although patients in the study benefited from abemaciclib, results suggest that approximately 33% of women enrolled in this study may not need a CDK4/CDK6 inhibitor as initial treatment. In the MONARCH 3 clinical trial, patients with higher-risk disease (including liver metastases) derived substantial benefit from the addition of abemaciclib, whereas patients with a better prognosis (ie, bone metastasis only or with indolent disease relapsing years after stopping endocrine therapy) did well with endocrine therapy alone.

“It is well known that these patients have a better prognosis than those with liver or lung metastases, or who relapse early during the course of adjuvant therapy. Now, for the first time, we have insights suggesting that patients with certain clinical characteristics may benefit differently from treatment with a CDK4/CDK6 inhibitor, including the possibility that some patients with a good prognosis may be able to start on endocrine therapy alone. The idea that a CDK4/CDK6 inhibitor could be reserved as a next line of treatment for metastatic disease warrants further study,” said Dr Di Leo.

Avoiding the use of a CDK4/CDK6 inhibitor in patients with good prognosis and preserving it for those with poor prognosis could prevent unnecessary toxicity and reduce treatment costs, he emphasized.


MONARCH 3 was a phase 3, double-blind, randomized clinical trial of 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer in 22 countries; patients did not receive previous treatment for metastatic disease. The patients were randomized in a 2:1 ratio to receive abemaciclib 150 mg twice daily continuously plus an aromatase inhibitor (anastrozole 1 mg daily or letrozole 2.5 mg daily), or an aromatase inhibitor plus placebo as initial therapy, and stratified according to metastatic site (visceral, bone only, other) and previous endocrine therapy (aromatase inhibitor vs no endocrine therapy vs other therapy).

Results of the interim analysis at 18 months showed that the addition of abemaciclib to single-agent endocrine therapy significantly prolonged PFS by 46% (P = .000021). The median PFS was not reached in the abemaciclib arm versus 14.7 months in the placebo arm. The objective response rate was 59% in the abemaciclib arm versus 44% in the placebo arm (P = .004).

The most common adverse events with abemaciclib versus placebo were diarrhea (81.3% vs 29.8%, respectively), neutropenia (41.3% and 1.9%), and fatigue (40.1% vs 31.7%).

Expert Comments

Giuseppe Curigliano, MD, PhD, Director, Division of New Drug Development, European Institute of Oncology, University of Milan, Italy, noted that 3 CDK4/CDK6 inhibitors, including abemaciclib, palbociclib (Ibrance), and ribociclib (Kisqali), are currently being studied in advanced disease.

“The MONARCH 3 trial confirms the role of this new class of agents in combination with endocrine therapy in the treatment of metastatic breast cancer,” said Dr Curigliano.

“Many patients with metastatic disease still receive chemotherapy, despite guidelines and data from clinical trials. This study confirms that we should avoid chemotherapy in hormone receptor–positive, HER2-negative metastatic breast cancer if visceral crisis is not present,” Dr Curigliano added.

The optimal role of CDK4/CDK6 inhibitors and the optimal sequence need to be determined by clinical trials, added Dr Curigliano.


  1. Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35:3638-3646.

Related Article

Verzenio Receives FDA Approval for Metastatic Breast Cancer

On September 28, 2017, a few weeks after ESMO 2017, the FDA approved abemaciclib (Verzenio; Eli Lilly), in combination with fulvestrant, for the treatment of adults with advanced or metastatic HR-positive, HER2-negative breast cancer that progressed after endocrine therapy, or as monotherapy after endocrine therapy and chemotherapy in the metastatic setting.

[ Read More ]

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