Emulation of the PALOMA-2 Trial

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 initiative. EmulatioN of Comparative Oncology trials with Real-world Evidence (ENCORE) is the trial emulation discussed in this protocol 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 PALOMA-2 trial. PALOMA-2 was a Phase III, double-blind, randomized study assessing the efficacy and safety of palbociclib (125 mg orally, once daily for 21 days of a 28-day cycle) in combination with letrozole (2.5 mg orally, once daily, continuously) versus letrozole alone in postmenopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer who had not received prior systemic treatment for their advanced disease.

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
• Postmenopausal women with ER-positive, HER2-negative locally advanced or metastatic breast cancer who receive treatment without curative intent
• The line of therapy for patients in EDB1 and EDB3 is implicitly advanced/metastatic because the line of therapy classification starts after their advanced/metastatic diagnosis in the respective database
• In EDB4, patients must explicitly have any evidence of a metastasis prior initiating palbociclib plus letrozole or letrozole alone
• Adenocarcinoma histology
• No prior systemic treatment for advanced/metastatic disease
• ECOG performance status of 0 or 1

Exclusion criteria

• HER2+
• CNS metastases
• Prior treatment with CDK4/6 inhibitor
• Non-breast cancer malignancy other than basal/squamous cell skin cancer or carcinoma in situ of cervix
• Systemic anticancer therapy other than palbocicilib or letrozole
• Treatment with non-steroidal aromatase inhibitor (i.e.anastrozole, letrozole)