The phase 3 postMONARCH study (NCT05169567) has revealed that abemaciclib (Verzenio) combined with fulvestrant (Faslodex) significantly improves progression-free survival (PFS) in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer who have progressed on prior CDK4/6 inhibitor therapy. These findings, presented at the 2024 ASCO Annual Meeting, offer a potential new treatment strategy for this patient population. The study addresses previous inconsistencies in phase 2 trial results regarding the continuation of CDK4/6 inhibitors and switching hormonal therapy after progression.
Study Design and Patient Population
The postMONARCH trial was a randomized, placebo-controlled study involving 368 patients. Participants had previously been treated with an aromatase inhibitor and a CDK4/6 inhibitor. Patients were randomly assigned to receive either fulvestrant monotherapy or fulvestrant in combination with abemaciclib. The primary endpoint was progression-free survival.
Efficacy Outcomes
The results demonstrated a significant improvement in PFS with the combination of abemaciclib and fulvestrant compared to fulvestrant alone. According to Kevin Kalinsky, MD, MS, professor in the Department of Hematology and Medical Oncology, Emory University School of Medicine, the greatest benefit was observed in patients with prior palbociclib use and those with non-visceral, bone-only disease.
Impact of Genetic Mutations
An important aspect of the postMONARCH study was the independence of the treatment effect from specific genetic mutations. "One thing that’s worth noting about [the efficacy outcomes with abemaciclib plus fulvestrant] is [they were] not dependent on mutations that patients had; there was benefit [with the regimen vs placebo plus fulvestrant], regardless of whether patients had ESR1 mutations or mutations in the PI3K/AKT pathway," Kalinsky noted. This suggests that the abemaciclib and fulvestrant combination could be a broadly applicable treatment option for patients with HR-positive, HER2-negative advanced breast cancer, irrespective of their mutation status.
Clinical Significance
The postMONARCH study provides clarity in a field where previous phase 2 studies have yielded conflicting results. While two studies with palbociclib in this population had negative outcomes, a trial with ribociclib showed a positive effect. The robust phase 3 design of postMONARCH, evaluating abemaciclib plus fulvestrant, offers a more definitive answer, supporting the use of this combination in patients progressing on prior hormonal therapy and CDK4/6 inhibitors.
