Abstract GS2-07: Results from PEARL study (GEICAM/2013-02_CECOG/BC.1.3.006): A phase 3 trial of Palbociclib (PAL) in combination with endocrine therapy (ET) versus Capecitabine (CAPE) in hormonal receptor (HR)-positive/human epidermal growth factor receptor (HER) 2-negative metastatic breast cancer (MBC) patients (pts) whose disease progressed on aromatase inhibitors (AIs)
Authors: Martín Miguel , Zielinski Christoph , Ruíz-Borrego Manuel , Carrasco Eva , Ciruelos Eva , Muñoz Montserrat , Bermejo Begoña , Margeli Mireia , Turner Nicholas , Casas Maribel , Antón Antonio , Csöszi Tibor , Corsaro Massimo , Murillo Laura , Morales Serafín , Alba Emilio , Bartlett Cynthia H , Koehler Maria , Guerrero Angel , Kahan Zsuzsanna , Gil-Gil Miguel 
Published: March 2020

Abstract
Background: PAL is approved for use in combination with ET in HR-positive, HER2-negative MBC pts in first and later lines. However, the relative value of PAL plus ET versus (vs) chemotherapy (CT) in pretreated pts is not established yet. PEARL is a multinational, open label, controlled, randomized phase 3 trial comparing the efficacy and safety of PAL in combination with ET (exemestane [EXE] or fulvestrant [FUL]) vs CAPE in postmenopausal women with HR-positive/HER2-negative MBC whose disease progressed on AIs.
Methods: The study had two successive cohorts. In cohort 1 (C1) patients were randomized 1:1 to EXE+PAL vs CAPE. In 2016, after data showing that ESR1 mutations may induce resistance to AIs but not to FUL, cohort 2 (C2), with FUL+PAL vs CAPE, was added to the trial. Stratification criteria were site of disease (visceral vs non-visceral), prior sensitivity to ET (yes vs no), prior CT for MBC (yes vs no) and country. The study has two co-primary objectives: to demonstrate 1) the superiority of PAL+FUL over CAPE in progression-free survival (PFS) and 2) the superiority of PAL+ET (EXE or FUL) over CAPE in PFS in pts with ESR1 wild type (wt) tumors, measured in ctDNA, at study entry. In order to have an 80% power to detect a difference in median PFS between CAPE (6 months) and either PAL+FUL or PAL+ET ESR1 wt (9 months), for a hazard ratio (HR) of 0.667 and a significance level of 5%, a sample size of 300 pts and 193 events were required for each analysis. An exploratory analysis of intrinsic BC subtypes determined by an algorithm derived from the HTG EdgeSeq Oncology Biomarker Panel was also performed.
Results: From March 2014 to July 2018, 601 pts were recruited (296 in C1 and 305 in C2) in 4 countries. Median age was 60 (C1) and 61 (C2) years; 26.4% (C1) and 28.2% (C2) had ESR1 mutations; 66.6% (C1) and 65.2% (C2) had visceral disease; 71.3% (C1) and 79.0% (C2) had prior sensitivity to hormonal treatment; 30.1% (C1) and 26.9% (C2) received one prior chemotherapy for MBC; 19.6% (C1) and 26.6% (C2) had not received any prior line for MBC.C2 results: with a median follow-up of 13.5 m (range 0.0 to 30.7), the median PFS was 7.5 m in PAL+FUL vs 10 m in CAPE (adjusted HR [HRa] [confidence interval (CI) 95%]: 1.09 [0.83, 1.44]; p=0.537). The Objective Response Rate (ORR) was 26.7% for PAL+FUL vs 33.3% for CAPE. The analysis of BC subtypes was performed for 74.4% of pts, 89.1% (PAL+ET) and 91.5% (CAPE) had luminal tumors. For luminal pts median PFS was 7.5 m in PAL+FUL vs 10 m in CAPE (HR [CI 95%]: 1.07 [0.77, 1.50]; p=0.684); for non-luminal pts it was 4.4 m in PAL+FUL vs 14.8 m in CAPE (HR [CI 95%]: 2.39 [0.81, 7.08]; p=0.116).ESR1 wt (C1 + C2) results: with a median follow-up of 19.0 m (range 0.0 to 56.3), the median PFS was 8.0 m in PAL+ET vs 10.6 m in CAPE (HRa [CI 95%]: 1.08 [0.85-1.36]; p=0.526). The ORR was 27.8% for PAL+ET vs 36.9% for CAPE.The analysis of BC subtypes was performed for 79.6% of pts, 89.2% (PAL+ET) and 91.8% (CAPE) had luminal tumors. For luminal pts median PFS was 9.3 m in PAL+ET vs 11.0 m in CAPE (HR [CI 95%]: 1.02 [0.77, 1.34]; p=0.913); for non-luminal pts it was 2.7 m in PAL+ET vs 13.7 m in CAPE (HR [CI 95%]: 3.19 [1.28, 7.95]; p=0.013). Most frequent grade 3-4 toxicities with EXE+PAL, FUL+PAL and CAPE respectively were neutropenia (57.4%, 55.7% and 5.5%) with febrile neutropenia (1.3%, 0.7% and 1.4%), hand/foot syndrome (0%, 0% and 23.5%) and diarrhea (1.3%, 1.3% and 7.6%).
Conclusions: The PEARL study did not show a statistically superiority in PFS for PAL+ET vs CAPE in MBC pts progressing to AIs. No superiority of PAL+ET was observed in the luminal subgroup either. Treatment with PAL+ET was generally better tolerated than CAPE.
Citation Format: Miguel Martín, Christoph Zielinski, Manuel Ruíz-Borrego, Eva Carrasco, Eva Ciruelos, Montserrat Muñoz, Begoña Bermejo, Mireia Margeli, Nicholas Turner, Maribel Casas, Antonio Antón, Tibor Csöszi, Massimo Corsaro, Laura Murillo, Serafín Morales, Emilio Alba, Cynthia H Bartlett, Maria Koehler, Angel Guerrero, Zsuzsanna Kahan, Miguel Gil-Gil. Results from PEARL study (GEICAM/2013-02_CECOG/BC.1.3.006): A phase 3 trial of Palbociclib (PAL) in combination with endocrine therapy (ET) versus Capecitabine (CAPE) in hormonal receptor (HR)-positive/human epidermal growth factor receptor (HER) 2-negative metastatic breast cancer (MBC) patients (pts) whose disease progressed on aromatase inhibitors (AIs) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS2-07.