Abemaciclib/Fulvestrant Improves PFS Across HR+/HER2– Advanced Breast Cancer Subgroups

The benefits achieved with abemaciclib (Verzenio) plus fulvestrant (Faslodex) over placebo plus fulvestrant in patients with hormone receptor–positive, HER2-negative advanced breast cancer following prior CDK4/6 inhibitor progression was consistent across multiple clinically relevant subgroups, according to findings from subgroup analyses of the phase 3 postMONARCH trial (NCT05169567).1

The data, which were presented at the 42nd Annual Miami Breast Cancer Conference, showed that among patients in the intent-to-treat (ITT) population who had liver metastases, the median progression-free survival (PFS) with abemaciclib plus fulvestrant (n = 68) was 4.1 months (95% CI, 3.7-5.7) vs 1.9 months (95% CI, 1.9-3.7) in those who received placebo plus fulvestrant (n = 71; HR, 0.63; 95% CI, 0.44-0.91). In those without liver metastases, the median PFS in these respective arms was 9.1 months (n = 114; 95% CI, 5.8-11.1) and 5.8 months (n = 115; 95% CI, 5.4-7.7; HR, 0.78 [95% CI, 0.56-1.09; P = .40]).

In patients in the ITT population with bone-only disease, the median PFS in the abemaciclib arm (n = 32) was 15.1 months (95% CI, 6.3-not reached [NR]) vs 6.2 months (95% CI, 5.4-9.9) in the placebo arm (n = 42; HR, 0.51; 95% CI, 0.28-0.95). In those without bone-only disease, these respective values were 5.6 months (n = 150; 95% CI, 4.0-7.1) and 3.9 months (n = 144; 95% CI, 3.6-5.4; HR, 0.78 [95% CI, 0.59-1.02; P = .23]).

In patients who had received CDK4/6 inhibition for less than 18 months, the median PFS with abemaciclib plus fulvestrant (n = 89) was 5.6 months (95% CI, 3.7-7.1) vs 3.6 months (95% CI, 1.9-5.4) in those who received placebo plus fulvestrant (n = 77; HR, 0.75; 95% CI, 0.53-1.07). In those who had received CDK4/6 inhibition for at least 18 months, the median PFS in these respective arms was 8.5 months (n = 93; 95% CI, 5.6-11.1) and 5.6 months (n = 104; 95% CI, 3.9-7.4; HR, 0.67 [95% CI, 0.47-0.95]).

Overall, PFS outcomes favored the abemaciclib arm in patients in the ITT population with visceral metastases (HR, 0.87; 95% CI, 0.64-1.17) and without visceral metastases (HR, 0.53; 95% CI, 0.34-0.83; P = .07).

“Consistent abemaciclib plus fulvestrant treatment effect was observed across key clinical subgroups in both biomarker-detected and non-detected populations, though some subgroups had small sample size, precluding definitive conclusions,” the study authors wrote in a poster presentation of the data.

Reflecting on the postMONARCH Trial Background and Design

CDK4/6 inhibitors in combination with endocrine therapy are the standard frontline treatment option for patients with hormone receptor­–positive, HER2-negative advanced breast cancer; however, the optimal treatment following disease progression has yet to be determined, the authors noted.

postMONARCH, which aimed to address this unmet need, enrolled men and pre- or post-menopausal women with hormone receptor–positive, HER2-negative advanced breast cancer who had progressed on a CDK4/6 inhibitor plus an aromatase inhibitor as initial therapy, or who had disease recurrence during or after treatment with a CDK4/6 inhibitor plus endocrine therapy in the adjuvant setting. Patients were not permitted to have received any other therapy for advanced breast cancer.

Between March 2022 and June 2023, 368 patients were enrolled across 96 centers in 16 countries. Patients were randomly assigned 1:1 to receive abemaciclib plus fulvestrant or placebo plus fulvestrant. Patients underwent scans every 8 weeks for the first 12 months, then every 12 weeks thereafter.

Investigator-assessed PFS served as the primary end point. Secondary end points included overall survival, PFS by blinded independent central review, overall response rate, clinical benefit rate, disease control rate, duration of response, safety, pharmacokinetics, and patient-reported outcomes. Patients were stratified by duration of prior CDK4/6 inhibition, the presence of visceral metastases, and geographic region.

Notably, postMONARCH was the first phase 3 randomized, placebo-controlled trial to demonstrate the benefit of continuing CDK4/6 inhibition with abemaciclib in combination with fulvestrant in patients in this population who had progressed on a prior CDK4/6 inhibitor and endocrine therapy. In the primary analysis of this trial, which was conducted after 258 PFS events, at a median follow-up of 13 months (IQR, 10-17 months), the median PFS with abemaciclib plus fulvestrant (n = 182) was statistically significantly improved compared with placebo plus fulvestrant (n = 186), at 6.0 months (95% CI, 5.6-8.6) vs 5.3 months (95% CI, 3.7-5.6), respectively (HR, 0.73; 95% CI, 0.57-0.95; nominal P = .017).2

Diving Further Into Subgroup Data

In the current subgroup analyses, among all patients with circulating tumor DNA–evaluable disease, PFS outcomes consistently favored the abemaciclib arm (HR, 0.74; 95% CI, 0.57-0.97), including in patients with (HR, 0.86; 95% CI, 0.63-1.17) and without (HR, 0.54; 95% CI, 0.34-0.88) visceral metastases (P = .12); those with (HR, 0.71; 95% CI, 0.49-1.05) and without (HR, 0.78; 95% CI, 0.55-1.11) liver metastases (P = .75); and those with (HR, 0.63; 95% CI, 0.33-1.23) and without (HR, 0.75; 95% CI, 0.56-0.10) bone-only disease (P = .65).1

When patients were stratified by biomarker status, PFS outcomes generally favored the abemaciclib arm regardless of ESR1 mutation status (detected: HR, 0.79 [95% CI, 0.54-1.15]; non-detected: HR, 0.79 [95% CI, 0.55-1.13]). Outcomes among patients with detected ESR1 mutations favored the abemaciclib arm regardless of the presence of visceral metastases (yes: HR, 0.80 [95% CI, 0.51-1.26]; no: HR, 0.32 [95% CI, 0.12-0.82]; P = .09), liver metastases (yes: HR, 0.57 [95% CI, 0.33-0.97]; no: HR, 0.69 [95% CI, 0.38-1.23]; P = .64), and bone-only disease (yes: HR, 0.43 [95% CI, 0.13-1.44]; no: HR, 0.72 [95% CI, 0.47-1.10]; P = .43).

Outcomes among patients with no detected ESR1 mutations favored the abemaciclib arm in all populations except for those with bone-only disease (HR, 1.02; 95% CI, 0.37-2.81). In contrast, among patients without bone-only disease, the HR was 0.77 (95% CI, 0.53-1.14). The HRs were 0.89 (95% CI, 0.58-1.37) and 0.79 (95% CI, 0.40-1.53; P = .75) in favor of the abemaciclib arm for patients with and without visceral metastases, respectively; and 0.90 (95% CI, 0.51-1.58) and 0.91 (95% CI, 0.56-1.46; P = .98) in favor of the abemaciclib arm for patients with and without liver metastases, respectively.

PFS outcomes also favored the abemaciclib arm across all clinically relevant subgroups regardless of PIK3CA/PTEN/AKT1 mutation status (detected, HR, 0.86 [95% CI, 0.60-1.23]; non-detected, HR, 0.73 [95% CI, 0.51-1.06]), including in those with visceral metastases (detected: HR, 0.90 [95% CI, 0.58-1.41]; non-detected: HR, 0.83 [95% CI, 0.54-1.29]), those without visceral metastases (detected: HR, 0.70 [95% CI, 0.37-1.33]; non-detected: HR, 0.46 [95% CI, 0.22-0.96]), those with liver metastases (detected: HR, 0.64 [95% CI, 0.37-1.11]; non-detected: HR, 0.74 [95% CI, 0.43-1.26]), those without liver metastases (detected: HR, 0.93 [95% CI, 0.57-1.50]; non-detected: HR, 0.75 [95% CI, 0.45-1.26]), those with bone-only disease (detected: HR, 0.92 [95% CI, 0.41-2.08]; non-detected: HR, 0.42 [95% CI, 0.13-1.32]), and those without bone-only disease (detected: HR, 0.80 [95% CI, 0.53-1.20]; non-detected; HR, 0.73 [95% CI, 0.49-1.09]).

“Abemaciclib plus fulvestrant offers a targeted therapy option after disease progression on a CDK4/6 inhibitor for patients with hormone receptor­–positive, HER2-negative advanced breast cancer not selected for biomarker status,” the authors concluded.

References

1. Rosca A, Bianchini G, Martin M, et al. Abemaciclib plus fulvestrant for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: subgroup analysis from the phase 2 postMONARCH trial. Presented at: 42nd Annual Miami Breast Cancer Conference. March 6-9, 2025; Miami, Florida. Poster 85.
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. Published online December 18, 2024. doi:10.1200/JCO-24-02086