MONALEESA-3 Expands Endocrine Therapy Options for Advanced Breast Cancer

Lidia Schapira, MD


September 19, 2018

Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: MONALEESA-3

Slamon DJ, Neven P, Chia S, et al
J Clin Oncol. 2018;36:2465-2472

Study Summary

The MONALEESA-3 phase 3 study evaluated ribociclib plus fulvestrant in patients with hormone receptor–positive (HR+) and HER2-negative (HER2-) advanced breast cancer who were treatment-naıve or had received up to one line of prior endocrine therapy in the advanced setting.

This international study randomly assigned 484 postmenopausal women to ribociclib plus fulvestrant, and 242 to placebo plus fulvestrant. Median progression-free survival (PFS), the study’s primary endpoint, was significantly improved with ribociclib plus fulvestrant versus placebo plus fulvestrant: 20.5 months versus 12.8 months.

Treatment effects were observed in patients who were treatment-naive in the advanced setting as well as in patients who had received up to one line of prior endocrine therapy for advanced disease. Among patients with measurable disease, the overall response rate was 41% for ribociclib plus fulvestrant and 29% for placebo plus fulvestrant.

Grade 3 adverse events reported by at least 10% of patients in either arm included neutropenia (46.6% ribociclib vs 0% placebo) and leukopenia (13.5% ribociclib vs 0% placebo); the only grade 4 event reported by at least 5% of patients was neutropenia (6.8% ribociclib vs 0% placebo).

The investigators concluded that ribociclib plus fulvestrant is a new and effective regimen for treatment of first- or second-line HR+/HER2- advanced breast cancer.


The MONALEESA-3 study demonstrated that ribociclib plus fulvestrant significantly improves PFS compared with fulvestrant alone in postmenopausal women with HR+/HER2-advanced breast cancer, resulting in a 41% reduction in the risk for progression. This is the first study to demonstrate that a combination of a CDK4/6 inhibitor and fulvestrant is effective and tolerable as first- or second-line therapy for patients with metastatic breast cancer. Additional analyses from the study may help to elucidate mechanisms of resistance to endocrine therapy and the role of CDK4/6 inhibitors in overcoming resistance to antiestrogen therapies.

Previously, MONALEESA-2 showed that ribociclib plus letrozole led to improved outcomes in patients who had received no prior therapy in the advanced setting, with a PFS hazard ratio of 0.57 compared with single-agent letrozole.[1]

Although it is too early to know how these improvements in PFS will affect overall survival and quality of life, this marks an important step forward by expanding the options for endocrine therapy in the advanced setting. With time we will learn about other effective combinations. We'll understand which patients benefit most from combination therapies and which ones may do well with monotherapies consisting of an estrogen degrader or blocker or an aromatase inhibitor.



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