Adding abemaciclib to adjuvant endocrine therapy may lead to better outcomes in hormone receptor-positive, HER2-negative, high-risk, early breast cancer. In a phase III trial, the combination improved invasive disease-free survival and distant relapse-free survival compared with endocrine therapy alone. However, a trial of another CDK4/6 inhibitor came to the opposite conclusion.

Adding abemaciclib (Verzenio; Eli Lilly) to adjuvant endocrine therapy may stave off disease recurrence and relapse in hormone receptor (HR)–positive, HER2-negative, high-risk, early breast cancer. In the phase III monarchE trial, the combination improved invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) compared with endocrine therapy alone. Results, which were presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 September 20 and simultaneously published in the Journal of Clinical Oncology, contradict findings of the phase III PALLAS trial, also presented at the conference.

Patients with this subtype of breast cancer typically receive adjuvant endocrine therapy for 5 to 10 years after treatment. However, up to 20% of these patients develop recurrent disease, which is even more likely among those with high-risk disease.

“Novel treatments are needed to overcome resistance and prevent these early recurrences and distant metastases,” said Stephen Johnston, PhD, of The Royal Marsden NHS Foundation Trust in London, UK, who presented the findings.

A CDK4/6 inhibitor, abemaciclib was FDA approved in combination with endocrine therapy as a first-line therapy for patients with HR-positive, HER2-negative, advanced or metastatic breast cancer based on the phase III MONARCH III trial. The agent's success as a first-line treatment led Johnston and his colleagues to design the monarchE trial to investigate its potential as an adjuvant therapy.

The trial enrolled 5,637 previously treated patients with HR-positive, HER2-negative early breast cancer considered to be at high risk for recurrence based on the extent of their disease. Half the patients received 2 years of abemaciclib plus 5 to 10 years of endocrine therapy, and half received 5 to 10 years of endocrine therapy alone.

Patients treated with the combination had a 2-year IDFS rate of 92.2% and a 2-year DRFS rate of 93.6%, compared with 88.7% and 90.3%, respectively, in those who received endocrine therapy alone. Due to side effects, 16.6% of patients taking abemaciclib discontinued the treatment, compared with 0.8% on endocrine therapy alone. The most common side effects associated with abemaciclib were diarrhea, neutropenia, and fatigue.

“This establishes for the first time a proof of concept for CDK4/6 inhibition in the adjuvant setting,” said George Sledge, MD, of Stanford University School of Medicine in California, who provided commentary on the trial. “This is the first improvement seen over aromatase inhibitor therapy in the adjuvant setting for ER-positive early-stage breast cancer.”

However, Sledge added that “this is a very early presentation of data, and indeed some might argue premature.” Longer follow-up is needed to fully understand the side effects, as well as to determine whether improvements in IDFS and DRFS translate into overall survival and whether the combination can prevent recurrence after 5 years. Questions also remain about the optimal duration of treatment, why some patients don't benefit, how to overcome resistance, and whether the CDK4/6 inhibitor ribociclib (Kisqali; Novartis), under investigation in the phase III NATALEE trial, may be similarly effective.

Notably, the monarchE findings run counter to results of the PALLAS trial. After 2 years of follow-up in PALLAS, adjuvant therapy with the CDK4/6 inhibitor palbociclib (Ibrance; Pfizer) plus endocrine therapy did not lower recurrence rates in patients with HR-positive, HER2-negative early breast cancer compared with endocrine therapy alone. Sledge offered several potential explanations: monarchE focused on patients more likely to have their disease recur early; the agents vary in relative potency against CDK4 and CDK6; abemaciclib was given continuously whereas palbociclib was given intermittently; and patients taking palbociclib were more likely to discontinue therapy than those taking abemaciclib, 42.2% vs. 16.6%, respectively. More recently, Pfizer announced that in the phase III PENELOPE-B trial, palbociclib plus endocrine therapy also failed to improve IDFS in patients with residual disease after neoadjuvant chemotherapy.

“The decision to use adjuvant CDK4/6 inhibitor therapy is more complex than a simple perusal of disease-free survival or distant relapse-free survival data and will need to be weighed against evolving measures of benefit,” Sledge concluded. –Catherine Caruso