Background: Delaying/overcoming resistance to ET in HR-positive HER2-negative BC patients (pts) is a major need to futhrt improve safe and efficacious treatment options. F is a selective estrogen receptor (ER) downregulator currently indicated for the treatment of HR-positive metastatic BC in postmenopausal women with disease progression following anti-estrogen therapy. In FIRST trial F 500mg improved median time to progression (TTP) over anastrozole (23.4 vs 13.1 months, respectively) in untreated metastatic BC. P is a selective reversible inhibitor of cyclin-dependent kinase 4/6. FDA granted its accelerated approval based on progression-free survival (PFS) in combination with letrozole for postmenopausal women with ER-positive and HER2-negative advanced BC as initial ET (PALOMA-1). In another study, after progression to ET, P in combination with F resulted in longer PFS than F alone (PALOMA-3).

The high median TTP achieved with F alone (FIRST) coupled with the significant benefit of adding P to F (PALOMA-3) suggest that F 500mg in combination with P in the first-line setting may significantly improve long-term disease control.

Trial Design:This is an international, randomized, double-blind, multicentre phase II study comparing F 500mg in combination with P vs F 500mg plus placebo as first line therapy in postmenopausal women with HR-positive, HER2-negative metastatic BC who have received ≥5 years of adjuvant ET for early disease and remained disease free for >12 months following its completion or have “de novo” metastatic disease. HR and HER2 status will be based on central testing on the most recent tumour biopsy. Patients will be randomized 1:1. The primary objective is to compare the efficacy of both treatment arms in terms of PFS at 1 year according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by investigator assessment. As secondary efficacy objectives,PFS, Objective Response Rate (ORR), Clinical Benefit Rate (CBR), Overall Survival (OS), and 1-year and 2-year survival probabilities, have been considered. Other secondary objectives include the comparison of safety, tolerability and health-related quality of life between the treatment arms. As exploratory objectives, the identification of promising biomarkers related with response to study therapy and primary/acquired drug resistance. Pts will be stratified by the site of disease (visceral vs non-visceral) and disease presentation at study entry (recurrent disease vs metastatic “de novo”). With a sample size of 190 pts, the analysis would have 80% power to detect a difference between both treatment arms, assuming PFS proportions of 0.545 and 0.695, respectively. This study is sponsored by GEICAM and Cancer Trials Ireland (formerly ICORG) is also participating. Recruitment started in February 2016 with 14 pts included. Analysis of the primary endpoint is planned for Q1 2018. ClinicalTrials.gov identifier:NCT02690480.

Citation Format: Moreno F, Martínez-Jañez N, Garau I, Guerra JA, Alarcón J, Bermejo B, Gonzalez-Cortijo L, Bueno C, Lao J, Bezares S, Rosell L, Blanch A, Caballero R, Carrasco E, Rojo F, Martín M, O'Connor M, Hernando A, Albanell J. A phase II study to compare fulvestrant (F) 500mg plus placebo versus (vs) F 500mg plus palbociclib (P) as first line treatment for postmenopausal women with hormone receptor (HR)-positive advanced breast cancer (BC) sensitive to endocrine therapy (ET). “The FLIPPER study” (GEICAM/2014-12) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-02-07.