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

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.

• Initiation of abemaciclib plus letrozole/anastrozole (Drug): Any doses and frequency observed in clinical practice will be allowed
• Initiation of letrozole/anastrozole (Drug): Any doses and frequency observed in clinical practice will be allowed

Primary outcomes

• Time to all-cause mortality (overall survival) [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)]: Hazard ratio (95% CI)

Secondary outcomes

• Time to next treatment (TTNT) [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)]: Hazard ratio (95% CI)

Sex: Female, ages: 18 Years to any

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 Protocol and Statistical Analysis Plan (PDF, 2026-02-09)

• Shirley Wang, PhD, ScM, Principal investigator, Brigham and Women's Hospital
• Denys Shay, MD, Principal investigator, Brigham and Women's Hospital