Emulation of the MONARCH-3 Trial Using Specialty Oncology Electronic Health Records Databases

Investigators are building an empirical evidence base for real world data through large-scale emulation of randomized controlled trials. The investigators' goal is to understand for what types of clinical questions real world data analyses can be conducted with confidence and how to implement such studies.

Study Overview

• Status: Completed
• Conditions: Advanced Breast Cancer
• Intervention / Treatment: Drug: Initiation of abemaciclib plus letrozole/anastrozole; Drug: Initiation of letrozole/anastrozole

Detailed Description

Randomized controlled trials (RCTs) are generally regarded as the gold-standard of evidence for establishing efficacy of medical products. However, real-world data (RWD) are increasingly used to complement evidence from RCTs. Yet, to have confidence in the accuracy of non-interventional studies medical products and their outcomes in oncology, investigators need to know what questions can be validly answered, with which non-interventional study designs, and which analysis methods are appropriate, given the data that is available. Building on a process from the RCT DUPLICATE initiative1-4 EmulatioN of Comparative Oncology trials with Real-world Evidence (ENCORE) is part of the expansion project specific to oncology and aims to emulate 12 randomized oncology RCTs using multiple EHR data sources.

The purpose of this protocol is to describe the emulation of the MONARCH-3 trial. MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole/anastrozole, daily.

• Study Type: Observational
• Enrollment (Actual): 3883

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02120
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Postmenopausal women with ER/PR-positive, HER2-negative locally advanced or metastatic breast cancer who receive treatment without curative intent

Description

Inclusion Criteria:

• Female aged ≥18 years at treatment initiation from 2017 - 2023
• Evidence of metastatic breast cancer (MBC)
• Documentation of Estrogen/Progesterone receptor-positive (ER/PR+)
• Documentation of Human Epidermal Growth Factor Receptor Negative (HER2-)
• ECOG performance status of 0 or 1 within 90 days of index date

Exclusion Criteria:

• CNS metastases
• Prior treatment with CKD4/6 inhibitor
• Prior or current treatment with chemotherapy or endocrine therapy other than letrozole/anastrozole for systemic anticancer therapy for MBC.
• Prior (neo-)adjuvant endocrine therapy
• Systemic anticancer therapy other than abemaciclib or letrozole/anastrozole
• Non-breast cancer malignancy other than basal/squamous cell skin cancer or carcinoma in situ of cervix

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Initiation of abemaciclib plus letrozole/anastrozole; Any doses and frequency observed in clinical practice will be allowed	Drug: Initiation of abemaciclib plus letrozole/anastrozole; Any doses and frequency observed in clinical practice will be allowed
Initiation of letrozole/anastrozole; Any doses and frequency observed in clinical practice will be allowed	Drug: Initiation of letrozole/anastrozole; Any doses and frequency observed in clinical practice will be allowed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to all-cause mortality (overall survival)	Hazard ratio (95% CI)	From time of initiation of therapy through the earliest of death from any cause (the primary outcome of interest) or end of data availability (depending on specialty oncology registry data provider, end of data ranges from June 2023 to April 2024)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to next treatment (TTNT)	Hazard ratio (95% CI)	From time of initiation of therapy through the earliest of TTNT, death from any cause, or end of data availability (depending on specialty oncology registry data provider, end of data ranges from June 2023 to April 2024)

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Food and Drug Administration (FDA)
• Investigators: Principal Investigator: Shirley Wang, PhD, ScM, Brigham and Women's Hospital; Principal Investigator: Denys Shay, MD, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2025
• Primary Completion (Actual): January 31, 2026
• Study Completion (Actual): January 31, 2026

Study Registration Dates

• First Submitted: November 5, 2025
• First Submitted That Met QC Criteria: November 6, 2025
• First Posted (Actual): November 10, 2025

Study Record Updates

• Last Update Posted (Actual): May 12, 2026
• Last Update Submitted That Met QC Criteria: May 8, 2026
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Nitriles; Triazoles; Letrozole; Anastrozole
• Other Study ID Numbers: 2022P002556-ENC-MONARCH-3; 75F40122C00181 (Other Grant/Funding Number: Food and Drug Administration)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No