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

Abstract

Purpose: 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.

Methods: This double-blind, randomized phase III study enrolled patients with disease progression on previous 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, objective response rate (ORR), and safety.

Results: This study randomly assigned 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 to 0.95; nominal P = .017), with median PFS 6.0 (95% CI, 5.6 to 8.6) versus 5.3 (95% CI, 3.7 to 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 to 0.77]; nominal P < .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% v 7%; nominal P = .015). No new safety signals were observed, with findings consistent with the known safety profile of abemaciclib.

Conclusion: Abemaciclib + fulvestrant significantly improved PFS after disease progression on previous CDK4/6i + ET in patients with HR+, HER2- ABC, offering an additional targeted therapy option for these patients.

Trial registration: ClinicalTrials.gov NCT05169567.

FIG 1.

CONSORT diagram. ^aIncludes four deaths due to AE and one death due to study disease. ^bDeath due to study disease. AE, adverse event.

FIG 2.

Primary analysis of (A) investigator-assessed and (B) BICR-assessed PFS. BICR, blinded independent central review; HR, hazard ratio; NR, not reached; PFS, progression-free survival.

FIG 3.

(A) Investigator-assessed and (B) BICR-assessed PFS in clinically relevant subgroups. ABC, advanced breast cancer; BICR, blinded independent central review; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor(s); HR, hazard ratio; PFS, progression-free survival; PR, progesterone receptor.

FIG 4.

Exploratory biomarker analysis in biomarker-evaluable population. (A) Frequency of gene alterations in ESR1 and the PI3K pathway. (B) Investigator-assessed PFS. ctDNA, circulating tumor DNA; HR, hazard ratio; PFS, progression-free survival.

FIG A1.

Interim analysis of investigator-assessed PFS. HR, hazard ratio; PFS, progression-free survival.

FIG A2.

Investigator-assessed PFS for clinically relevant subgroups: (A) patients with visceral metastasis; (B) patients without visceral metastasis; (C) patients with liver metastasis; (D) patients without liver metastasis; (E) patients with bone-only disease; (F) patients without bone-only disease; (G) patients who received previous CDK4/6i for <12 months; and (H) patients who received previous CDK4/6i for ≥12 months. CDK4/6i, cyclin-dependent kinase 4/6 inhibitor(s); HR, hazard ratio; NR, not reached; PFS, progression-free survival.