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. 2025 Sep 1;10(9):105570.
doi: 10.1016/j.esmoop.2025.105570. Online ahead of print.

Real-world progression-free survival of CDK4/6 inhibitors plus an aromatase inhibitor in HR-positive/HER2-negative metastatic breast cancer in United States routine clinical practice

H S Rugo  1 , R M Layman  2 , F Lynce  3 , X Liu  4 , B Li  4 , L McRoy  4 , A B Cohen  5 , M Estevez  6 , G Curigliano  7 , A Brufsky  8
Affiliations

Real-world progression-free survival of CDK4/6 inhibitors plus an aromatase inhibitor in HR-positive/HER2-negative metastatic breast cancer in United States routine clinical practice

H S Rugo et al. ESMO Open. .

Abstract

Background: All three cyclin-dependent kinase 4/6 inhibitors (CDK4/6i; palbociclib, ribociclib, and abemaciclib) plus aromatase inhibitor (AI) significantly prolonged progression-free survival (PFS) versus placebo plus AI and achieved a similar reduction in risk of disease progression in randomized controlled trials (RCTs) evaluating first-line (1L) treatment of hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC). To date, there have been no head-to-head RCT data comparing CDK4/6i, and most real-world comparative effectiveness studies were limited by small sample sizes and/or short follow-up. In this analysis, we compared real-world PFS (rwPFS) in patients with HR-positive/HER2-negative mBC receiving 1L CDK4/6i plus AI in United States routine clinical practice.

Patients and methods: P-VERIFY was a retrospective comparative effectiveness study using a US nationwide deidentified electronic health record-derived longitudinal database. Patients had HR-positive/HER2-negative mBC, were ≥18 years of age, and started 1L CDK4/6i plus AI between February 2015 and November 2023. rwPFS was defined as months from CDK4/6i plus AI initiation to disease progression or death from any cause. Stabilized inverse probability of treatment weighting (sIPTW) as primary analysis was used to balance baseline characteristics. Multivariable Cox proportional hazards model was carried out as a sensitivity analysis.

Results: Of 9146 eligible patients, 6831, 1279, and 1036 received palbociclib, ribociclib, and abemaciclib, respectively, plus AI. Baseline characteristics were generally balanced between treatment groups after sIPTW. Median [95% confidence interval (CI)] rwPFS after sIPTW was 22.7 (21.6-23.8), 22.9 (21.0-25.6), and 22.9 (20.2-26.5) months in the palbociclib, ribociclib, and abemaciclib groups, respectively. After sIPTW, there were no significant rwPFS differences (all P > 0.05) between ribociclib versus palbociclib (adjusted hazard ratio 0.97, 95% CI 0.88-1.07), abemaciclib versus palbociclib (0.96, 0.86-1.06), and abemaciclib versus ribociclib (0.98, 0.86-1.12). Findings were generally consistent across subgroups and sensitivity analyses.

Conclusions: Our study, the largest real-world CDK4/6i comparative effectiveness study to date, demonstrated no significant rwPFS differences between 1L palbociclib, ribociclib, and abemaciclib, plus AI, in patients with HR-positive/HER2-negative mBC.

Keywords: abemaciclib; comparative effectiveness; cyclin-dependent kinase 4/6 inhibitor; palbociclib; ribociclib.

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Figures

None
Graphical abstract
Figure 1
Figure 1
Kaplan-Meier plot of rwPFS before and after sIPTW. rwPFS in the (A) unadjusted analysis and (B) after sIPTW among the three CDK4/6 inhibitors.ABE, abemaciclib; AI, aromatase inhibitor; CDK4/6, cyclin-dependent kinase 4/6; CI, confidence interval; PAL, palbociclib; rwPFS, real-world progression-free survival; RIB, ribociclib; sIPTW, stabilized inverse probability of treatment weighting.
Figure 2
Figure 2
Forest plot of rwPFS by subgroup after sIPTW. (A) Abemaciclib + AI versus palbociclib + AI, (B) ribociclib + AI versus palbociclib + AI, and (C) abemaciclib + AI versus ribociclib + AI. ABE, abemaciclib; AI, aromatase inhibitor; DFI, disease-free interval; Dx, diagnosis; ECOG PS, Eastern Cooperative Oncology Group performance status; ND, not determined; PAL, palbociclib; RIB, ribociclib; rwPFS, real-world progression-free survival; sIPTW, stabilized inverse probability of treatment weighting.
Figure 3
Figure 3
Kaplan-Meier plot of rwPFS before and after sIPTW. rwPFS in the (A) unadjusted analysis and (B) after sIPTW among the three CDK4/6 inhibitors.ABE, abemaciclib; AI, aromatase inhibitor; CDK4/6, cyclin-dependent kinase 4/6; CI, confidence interval; PAL, palbociclib; rwPFS, real-world progression-free survival; RIB, ribociclib; sIPTW, stabilized inverse probability of treatment weighting.
Figure 4
Figure 4
Forest plot of rwPFS by subgroup after sIPTW in patients who started index treatment from 2017. (A) Abemaciclib + AI versus palbociclib + AI, (B) ribociclib + AI versus palbociclib + AI, and (C) abemaciclib + AI versus ribociclib + AI. ABE, abemaciclib; AI, aromatase inhibitor; DFI, disease-free interval; Dx, diagnosis; ECOG PS, Eastern Cooperative Oncology Group performance status; ND, not determined; PAL, palbociclib; RIB, ribociclib; rwPFS, real-world progression-free survival; sIPTW, stabilized inverse probability of treatment weighting.
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