Abemaciclib Plus Fulvestrant in Advanced Breast Cancer Following Progression on CDK4/6 Inhibition: Results from the Phase III postMONARCH Trial.

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Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are the standard first-line treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC); however, disease progression occurs in almost all patients and additional treatment options are needed. Herein we report outcomes of the postMONARCH trial investigating a switch in ET with/without CDK4/6 inhibition with abemaciclib after disease progression on CDK4/6i. This double-blind, randomized Phase III study enrolled patients with disease progression on prior CDK4/6i plus aromatase inhibitor as initial therapy for advanced disease or recurrence on/after adjuvant CDK4/6i+ET. Patients were randomly assigned (1:1) to abemaciclib+fulvestrant or placebo+fulvestrant. The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included PFS by blinded independent central review (BICR), objective response rate (ORR), and safety. This study randomized 368 patients (abemaciclib+fulvestrant, n=182 placebo+fulvestrant, n=186). At the primary analysis (258 events), the hazard ratio (HR) was 0.73 (95% CI, 0.57-0.95; nominal P=0.017), with median PFS 6.0 (95% CI, 5.6-8.6) vs 5.3 (95% CI, 3.7-5.6) months and 6-month PFS rates of 50% and 37% in the abemaciclib+fulvestrant and placebo+fulvestrant arms, respectively. These results were supported by BICR-assessed PFS (HR, 0.55; 95% CI, 0.39-0.77; nominal P<0.001). A consistent treatment effect was seen across major clinical and genomic subgroups, including with/without ESR1 or PIK3CA mutations. Among patients with measurable disease, investigator-assessed ORR was improved with abemaciclib+fulvestrant versus placebo+fulvestrant (17% vs 7%; nominal P=0.015). No new safety signals were observed, with findings consistent with the known safety profile of abemaciclib. Abemaciclib+fulvestrant significantly improved PFS after disease progression on prior CDK4/6i+ET in patients with HR+, HER2- ABC, offering an additional targeted therapy option for these patients.