CARE Initiative: Real-world Emulation of the PALOMA-2 Trial

The goal of this non-interventional study is to emulate the PALOMA-2 randomized controlled trial of palbociclib as first-line therapy in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer using real-world, electronic health record data. The main questions this study aims to answer are:

1. Do patients with metastatic ER+/HER2- breast cancer treated with palbociclib and letrozole have improved real-world progression-free survival (rwPFS) compared with patients treated with letrozole alone?
2. How do the results of this non-interventional study compare to those of the PALOMA-2 randomized controlled trial?

The Coalition to Advance Real-World Evidence through Randomized Controlled Trial Emulation (CARE) Initiative is a program designed to build an empirical evidence base for the use of real-world data (RWD) in clinical and regulatory decision-making. Using randomized controlled trials (RCT) as a benchmark for causal effect estimates, a series of RCT emulations will be conducted across varying trials, real world data sources, and study design elements to better understand under what conditions non-interventional studies, using data generated during routine clinical care, can provide reliable conclusions about drug effectiveness.

In this study, real-world electronic health record (EHR) data will be used to emulate the Palbociclib: Ongoing Trials in the Management of Breast Cancer (PALOMA-2) efficacy trial of palbociclib as first-line therapy in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer.2 Similarly to the PALOMA-2 trial, this study will compare real-world progression-free survival (rwPFS) between patients who initiate palbociclib and letrozole and those initiating letrozole alone.

Eligibility Criteria:
Inclusion Criteria:

* Breast cancer diagnosis
* Histology not indicative of non-adenocarcinoma histologies
* Metastatic disease
* Estrogen-receptor positive (ER+)
* No prior systemic treatment for metastatic breast cancer
* Post-menopausal
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2 or missing or Karnofsky performance status \&gt;=50 or missing
* No lab results indicating inadequate organ function, as defined in the PALOMA-2 RCT protocol

Exclusion Criteria:

* Human epidermal growth factor receptor 2 (HER2) positive tumor
* Diagnosis of brain, central nervous system, and/or spinal cord metastases
* Neoadjuvant or adjuvant treatment with anastrozole or letrozole ≤12 months before metastatic diagnosis
* Prior treatment with treatment with ribociclib, abemaciclib, or palbociclib
* Treatment with a CYP3A4 inhibitor or inducer or drugs known to prolong the QT interval, as specified in the PALOMA-2 trial protocol, in the 7 days prior to study treatment initiation
* Anti-cancer therapy or major cancer-related surgery within 2 weeks before study treatment initiation
* Diagnosis of a second primary malignancy within 3 years prior to study treatment initiation
* Diagnosis of long or short QT syndrome, Brugada syndrome, QTc prolongation, or Torsade de Pointes
* Diagnosis of hypocalcemia, hypokalemia, or hypomagnesemia
* Diagnosis of myocardial infarction, angina, ongoing cardiac dysrhythmias, atrial fibrillation, congestive heart failure, cerebral infarction, transient ischemic attack, or pulmonary embolism in the 6 months prior to study treatment initiation
* Diagnosis of inflammatory bowel disease chronic diarrhea, or short bowel syndrome
* Diagnosis of human immunodeficiency virus infection