postMONARCH ctDNA Analysis Underscores Benefit of Abemaciclib Plus Fulvestrant in HR+ Advanced Breast Cancer

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Findings from an exploratory circulating tumor DNA (ctDNA) analysis from the phase 3 postMONARCH trial (NCT05169567) demonstrated that the benefit of abemaciclib (Verzenio) plus fulvestrant (Faslodex) was consistent across multiple biomarker subgroups of patients with hormone receptor–positive, HER2-negative advanced breast cancer treated during the study.1

Data presented at the 2025 ESMO Breast Cancer Congress showed that a consistent treatment effect was observed regardless of circulating tumor fraction. Among evaluable patients from both arms of the trial (n = 306), a higher proportion of progression-free survival (PFS) events were reported in the placebo plus fulvestrant arm (n = 120/152) compared with the abemaciclib plus fulvestrant arm (n = 106/154; HR, 0.73; 95% CI, 0.56-0.95). In patients without circulating tumor fractions detected (n = 16), PFS events were similar between the abemaciclib arm (n = 2/7) and the placebo arm (n = 3/9; HR, 1.19; 95% CI, 0.20-7.11).

Additionally, a higher proportion of events were recorded in the placebo arm among patients who had a high tumor fraction with a methylation score of more than 3.98% (n = 74/90) compared with the abemaciclib arm (n = 54/70; HR, 0.84; 95% CI, 0.59-1.19). A higher proportion of events was seen in the abemaciclib arm (n = 54/90) vs the placebo arm (n = 49/71) for those without high tumor fractions (HR, 0.80; 95% CI, 0.55-1.18).

Subgroup analyses also showed that treatment effect trends favoring the abemaciclib regimen were observed in patients with PIK3CA mutations (HR, 0.78; 95% CI, 0.52-1.19), those without PIK3CA mutations (HR, 0.79; 95% CI, 0.57-1.10), patients with multiple PIK3CA mutations (HR, 0.66; 95% CI, 0.21-2.02), those harboring ESR1 mutations (HR, 0.82; 95% CI, 0.56-1.19), and patients without ESR1 mutations (HR, 0.78; 95% CI, 0.54-1.11).

“[These results give us] further insight into the use of the combination of fulvestrant with abemaciclib as an important treatment option for patients with hormone receptor–positive advanced [breast cancer]—at this moment—regardless of biomarker status,” lead study author Seth Wander, MD, PhD, said in a presentation of the data.

Wander is a medical oncologist at the Massachusetts General Hospital and an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts.

postMONARCH Background

The double-blind, randomized, placebo-controlled trial enrolled patients with hormone receptor–positive, HER2-negative advanced breast cancer who experienced disease progression on previous CDK4/6 inhibitor plus and aromatase inhibitor as initial therapy for advanced disease, or those who had a recurrence during or after an adjuvant CDK4/6 inhibitor with endocrine therapy.2

Patients were randomly assigned in a 1:1 fashion to receive abemaciclib plus fulvestrant or placebo plus fulvestrant. Investigator-assessed PFS served as the trial’s primary end points. Secondary end points included PFS per blinded independent central review, objective response rate, and safety.

Findings from the primary analysis showed that patients treated with abemaciclib plus fulvestrant (n = 182) achieved an investigator-assessed median PFS of 6.0 months (95% CI, 5.6-8.6) compared with 5.3 months (95% CI, 3.7-5.6) for those given placebo plus fulvestrant (n = 186; HR, 0.73; 95% CI, 0.57-0.95; nominal P = .017). The 6-month PFS rates were 50% and 37%, respectively.

During the study, baseline plasma sample were analyzed using the Guardant Infinity assay.1 To conduct the ctDNA analysis, associations between investigator-assessed PFS and genomic subgroups were evaluated using an unstratified Cox proportional hazard model.

Among all randomly assigned patients in the abemaciclib arm (n = 182), 88% (n = 161) were included in the ctDNA analysis. Reasons for exclusion included lack of a ctDNA sample (n = 20) and failed quality control (n = 1). In the placebo arm (n = 186), 87% (n = 161) were included in the ctDNA analysis, with the remainder (n = 25) excluded due to lack of samples.

Additional ctDNA Subgroup Findings

Although trends favoring the abemaciclib regimen were seen across most genomic subgroups, these benefits were not seen in patients with AKT1 mutations (ctDNA-evaluable patients in both arms, n = 14; HR, 1.06; 95% CI, 0.27-4.14), patients with PTEN alterations (n = 35; HR, 1.46; 95% CI, 0.71-3.01), patients with RB1 mutations (n = 36; HR, 1.12; 95% CI, 0.54-2.33), and those with KMT2C rearrangements (n = 34; HR, 0.98; 95% CI, 0.45-2.14).

“We begin to see some trends with genes like RB1 and TP53 [n = 115; HR, 0.90; 95% CI, 0.59-1.37], but we’re significantly limited by sample size, and none of these [trends] reached statistical significance,” Wander said.

Another analysis looking at treatment effects based on most oncogenic pathways and CDK resistance signatures, the effects were consistent between the 2 arms, with most subgroups trending in favor of abemaciclib. However, a trend favoring the placebo arm was seen in patients with RAS MAPK alterations (HR, 1.10; 95% CI, 0.63-1.93).

Oncoprint results from patients with RAS MAPK alterations showed that the most common mutated genes were NF1 (n = 24), MAP3K1 (n = 18), KRAS (n = 9), MAP2K4 (n = 8), HRAS (n = 7), BRAF (n = 6), MAPK1 (n = 2), and RAF1 (n = 1).

Disclosures: Wander reported serving in a consulting or advisory board role with Foundation Medicine, Veracyte, Hologic, Eli Lilly, Biovica, Pfizer/Arvinas, Puma Biotechnology, Novartis, AstraZeneca, Genentech, Regor Therapeutics, Menarini, and Gilead; serving in education/speaking roles with Eli Lilly, Guardant Health, and 2ndMD; and receiving institutional research support from Genentech, Eli Lilly, Pfizer/Arvinas, Nuvation Bio, Regor Therapeutics, and Sermonix.

References

1. Wander SA, Hamilton E, Bianchini G, et al. Baseline ctDNA and methylation status as predictors of treatment benefit in the phase III post MONARCH trial of abemaciclib + fulvestrant in advanced breast cancer patients. Presented at: 2025 ESMO Breast Cancer Congress; May 14-17, 2025; Munich, Germany. Abstract 6MO.
2. Kalinsky K, Bianchini G, Hamilton E, et al. Abemaciclib plus fulvestrant in advanced breast cancer after progression on CDK4/6 inhibition: results from the phase III postMONARCH trial. J Clin Oncol. 2025;43(9):1101-1112. doi:10.1200/JCO-24-02086