PostMONARCH: Abemaciclib Combo Effective After CDK4/6i Failure

Abemaciclib plus fulvestrant showed a consistent benefit in patients with advanced breast cancer among multiple biomarker subgroups, according to additional research from the phase 3 postMONARCH clinical trial presented at the 2025 European Society for Medical Oncology (ESMO) Breast Cancer Annual Congress held in Munich, Germany.

A team of researchers, led by Seth Wander, MD, PhD, Massachusetts General Hospital, Boston, Massachusetts, investigated whether biomarkers detected through circulating tumor DNA (ctDNA) could help predict which patients who have hormone receptor (HR)-positive, HER2-negative advanced breast cancer would benefit more from abemaciclib plus fulvestrant versus fulvestrant alone after disease progression on CDK4/6 inhibitors (CDK4/6i).

The double-blind, randomized study enrolled patients (n=368) with disease progression on previous CDK4/6i plus aromatase inhibitor as initial therapy for advanced disease or recurrence on or after adjuvant CDK4/6i plus endocrine therapy.

Patients were randomly assigned 1:1 to abemaciclib plus fulvestrant or placebo plus fulvestrant. The study’s primary end point was investigator-assessed progression-free survival (PFS).

In the ctDNA evaluable cohort, 161 patients received the combination versus 159 patients who received fulvestrant alone. Wander and colleagues evaluated ESR1, PIK3CA, methylation, cell cycle genes, and MAPK/RAS and analyzed baseline plasma samples with the Guardant Infinity assay. Using the treatment arm and genomic subgroups, the researchers assessed associations between PFS and genomic subgroups with unstratified Cox proportional hazard.

The analysis showed a consistent treatment effect with abemaciclib in patients with multiple ESR1 or PIK3CA mutations. Furthermore, the researchers determined that methylation status, cell cycle, or MAPK pathway alterations were not associated with significant differences in treatment effect.

“These exploratory results are hypothesis-generating and offer further insight into the use of abemaciclib plus fulvestrant as a treatment option for HR-positive, HER2-negative advanced breast cancer after progression on CDK4/6i,” the researchers said.

Previous data published in the Journal of Clinical Oncology demonstrated a significantly improved PFS in patients with HR-positive, HER2-negative advanced breast cancer when treated with abemaciclib plus fulvestrant compared with fulvestrant alone. The combination therapy had a median PFS of 6 months versus 5.3 months with fulvestrant.

The findings of the ctDNA cohort analysis revealed that the combination of abemaciclib plus fulvestrant may be effective across a broad range of molecular profiles, including those with ESR1 and PI3K pathway mutations.

References:

Abstract 6MO. 2025 ESMO Breast Cancer Annual Congress. https://clin.larvol.com/abstract-detail/ESMO-BC%202025/75278625

Kalinsky K, et al. Clin Oncol. 2025 Mar 20;43(9):1101-1112. doi:10.1200/JCO-24-02086