Emulation of the MONALEESA-2 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 ribociclib; Drug: Initiation of letrozole

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 MONALEESA-2 trial. MONALEESA-2 was a Phase III, double-blind, randomized study assessing the efficacy and safety of ribociclib (600 mg orally once daily on days 1-21 of a 28-day cycle, followed by 7 days off) in combination with letrozole (2.5 mg orally once daily, continuously) versus letrozole alone in postmenopausal women with hormone receptor-positive [estrogen receptor (ER) and/or progesterone receptor (PR)], human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer who had not received prior systemic treatment for their advanced disease.

• Study Type: Observational
• Enrollment (Actual): 2495

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: No

• Sampling Method: Non-Probability Sample

Study Population

Postmenopausal women with hormone receptor (HR)-positive [estrogen receptor (ER) and/or progesterone receptor (PR)], human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer.

Description

Study Period:

ENCORE database 1 (EDB1): Patient identification period: 01/01/2011-04/30/2024 with follow-up information through data cut-off date on 04/30/2024 ENCORE database 3 (EDB3): Follow-up information through June 2023 (there is no specific time period restrictions for patient eligibility) ENCORE database 4 (EDB4): Patient identification period: 10/01/2018-09/30/2023 with follow-up information through data cut-off date on 09/30/2023.

Inclusion Criteria:

• Age ≥18 years through 2017 to 2023
• Metastatic breast cancer
• Hormone receptor positive (ER/PR+)
• Untreated with systemic anticancer therapy for advanced disease
• ECOG performance status of 0 or 1
• HER2-negative

Exclusion Criteria:

• Prior treatment with CDK4/6 inhibitor
• Locally advanced (unresectable) or inflammatory breast cancer
• Non-breast cancer malignancy other than basal/squamous cell skin cancer or carcinoma in situ of cervix
• Prior adjuvant therapy for breast cancer
• Systemic anticancer therapy other than ribociclib or letrozole

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Initiation of letrozole; Reference group	Drug: Initiation of ribociclib; Initiation of ribociclib plus letrozole described in electronic health records is used as the exposure; Drug: Initiation of letrozole; Initiation of letrozole described in electronic health records is used as the reference
Initiation of ribociclib plus letrozole; Exposure group	Drug: Initiation of ribociclib; Initiation of ribociclib plus letrozole described in electronic health records is used as the exposure

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to all-cause mortality/overall survival (OS)	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)

Collaborators and Investigators

• Sponsor: Shirley Vichy Wang
• 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): September 7, 2025
• Primary Completion (Actual): January 1, 2026
• Study Completion (Actual): January 1, 2026

Study Registration Dates

• First Submitted: November 20, 2025
• First Submitted That Met QC Criteria: November 27, 2025
• First Posted (Actual): December 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

• Other Study ID Numbers: 2022P002556-ENC-MONALEESA-2; 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