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Clinical Trial
. 2021 Apr;32(4):488-499.
doi: 10.1016/j.annonc.2020.12.013. Epub 2020 Dec 29.

Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL

M Martin  1 , C Zielinski  2 , M Ruiz-Borrego  3 , E Carrasco  4 , N Turner  5 , E M Ciruelos  6 , M Muñoz  7 , B Bermejo  8 , M Margeli  9 , A Anton  10 , Z Kahan  11 , T Csöszi  12 , M I Casas  4 , L Murillo  13 , S Morales  14 , E Alba  15 , E Gal-Yam  16 , A Guerrero-Zotano  17 , L Calvo  18 , J de la Haba-Rodriguez  19 , M Ramos  20 , I Alvarez  21 , A Garcia-Palomo  22 , C Huang Bartlett  23 , M Koehler  24 , R Caballero  4 , M Corsaro  25 , X Huang  23 , J A Garcia-Sáenz  26 , J I Chacón  27 , C Swift  28 , C Thallinger  29 , M Gil-Gil  30
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Free article
Clinical Trial

Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL

M Martin et al. Ann Oncol. 2021 Apr.
Free article

Abstract

Background: Palbociclib plus endocrine therapy (ET) is the standard treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC). However, its efficacy has not been compared with that of chemotherapy in a phase III trial.

Patients and methods: PEARL is a multicentre, phase III randomised study in which patients with aromatase inhibitor (AI)-resistant MBC were included in two consecutive cohorts. In cohort 1, patients were randomised 1 : 1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about estrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2, in which patients were randomised 1 : 1 between palbociclib plus fulvestrant and capecitabine. The stratification criteria were disease site, prior sensitivity to ET, prior chemotherapy for MBC, and country of origin. Co-primary endpoints were progression-free survival (PFS) in cohort 2 and in wild-type ESR1 patients (cohort 1 + cohort 2). ESR1 hotspot mutations were analysed in baseline circulating tumour DNA.

Results: From March 2014 to July 2018, 296 and 305 patients were included in cohort 1 and cohort 2, respectively. Palbociclib plus ET was not superior to capecitabine in both cohort 2 [median PFS: 7.5 versus 10.0 months; adjusted hazard ratio (aHR): 1.13; 95% confidence interval (CI): 0.85-1.50] and wild-type ESR1 patients (median PFS: 8.0 versus 10.6 months; aHR: 1.11; 95% CI: 0.87-1.41). The most frequent grade 3-4 toxicities with palbociclib plus exemestane, palbociclib plus fulvestrant and capecitabine, respectively, were neutropenia (57.4%, 55.7% and 5.5%), hand/foot syndrome (0%, 0% and 23.5%), and diarrhoea (1.3%, 1.3% and 7.6%). Palbociclib plus ET offered better quality of life (aHR for time to deterioration of global health status: 0.67; 95% CI: 0.53-0.85).

Conclusions: There was no statistical superiority of palbociclib plus ET over capecitabine with respect to PFS in MBC patients resistant to AIs. Palbociclib plus ET showed a better safety profile and improved quality of life.

Keywords: HER2-negative; capecitabine; endocrine therapy; hormone receptor-positive; metastatic breast cancer; palbociclib.

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Conflict of interest statement

Disclosure MM has received consulting fees from AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly, PUMA, Taiho Oncology, and Pfizer; speakers' honoraria from AstraZeneca, Amgen, Roche/Genentech, Novartis, Daiichi-Sankyo, and Pfizer; contracted research fees from Roche, Novartis, and PUMA. CZ has received consulting fees and speaker’s honoraria from Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Imugene, Ariad, Pfizer, Merrimack, Merck KGaA, Fibrogen, AstraZeneca, Tesaro, Gilead, Servier, Shire, Eli Lilly, and Athenex. His institution, Central European Cancer Center, Wiener Privatklinik Hospital, has received fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, AstraZeneca, and Merck KGaA. MRB has received speaker fees and advisory grants from Pfizer, Novartis, and Lilly. EC, who has a stock and other ownership interests from Lilly, has received travel and accommodation support from Roche, and her husband who has participated in consulting and advisory board activities with Bristol-Myers Squibb, Novartis, Celgene, Roche Pharma, Janssen, Amgen, Incyte, Abbvie, and Pfizer, has received travel and accommodation support from Celgene, Novartis, and Bristol-Myers Squibb. His institution has received research funding from Celgene, Janssen, Bristol-Myers Squibb, Novartis, Celgene, Roche/Genentech, Amgen, Pfizer, and Abbvie. GEICAM has received research funding from Roche/Genentech, Bristol-Myers Squibb, Novartis, Pfizer, Celgene, AstraZeneca, Merck Sharp & Dohme, Pierre Fabre, and Takeda. NT has received advisory board honoraria from AstraZeneca, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Bicycle Therapeutics, Taiho, Zeno Pharmaceuticals, and Repare Therapeutics and research funding from AstraZeneca, Bio-Rad, Pfizer, Roche/Genentech, Clovis, Merck Sharp & Dohme, and Guardant Health. MM has received travel and congress assistance support from Roche, Novartis, Pfizer, and Eisai. BB has received advisory board honoraria from Genentech, Novartis, Merck Sharpe and Dohme, speakers’ honoraria from Genentech, Eisai and she has received travel and congress assistance support from Pfizer. MM has received advisory board fees from Roche, Novartis, Pfizer, and Eisai. Her institution, Hospital Universitari Germans Trias i Pujol, Badalona, has received funding research from Roche, Pfizer, Novartis, Lilly, AstraZeneca, Eisai, and Kern. AA has received advisory board fees from Bayer, Spain. EA has received advisory board fees from Roche, Novartis, Pfizer, Lilly, Bristol-Myers Squibb, Genomic Health, and Nanostring. He has received travel support from Celgene. His institution, Hospitales Regional y Virgen de la Victoria, Málaga, has received funding research from Roche, Pfizer, Sysmex, Merck Sharp & Dohme, and Nanostring. EG-Y has received honoraria, travel support, and has participated in advisory boards for Pfizer, Roche, Novartis, and Eli Lilly. ÁG-Z has received investigational fees and travel support from Pfizer. JdelaH has received honoraria from AstrazZeneca, Pfizer, Novartis, Roche, and Agendia. MR has received honoraria from Novartis, Roche, and Pfizer. IÁ has received consulting or advisory board honoraria from AstraZeneca, Pfizer, Novartis, and Roche; speakers’ honoraria from AstraZeneca, Pfizer, Novartis, Roche, and Eisai; travel and congress assistance support from AstraZeneca, Pfizer, Roche, and Eisai. CH has a stock from Pfizer and AstraZeneca, she was an employee of Pfizer during the study, and is an employee of AstraZeneca currently, where she holds a stock. MK has Pfizer stock and was an employee of Pfizer during the study. MC is employed by Pfizer and has the company’s stock options. XH is employed by Pfizer and has the company’s stock options. JAG-S has consultancy/speaker fees from Novartis, Celgene, Eli Lilly, Eisai, and AstraZeneca. He received travel support from Novartis, Roche, and Pfizer. His institution, Hospital Clínico Universitario San Carlos, received research funding from AstraZeneca. MG-G has received honoraria from Pfizer and Eisai and has participated in advisory boards of Genentech and Daiichi-Sankyo. He has received travel support from Pfizer, Novartis, Daiichi-Sankyo, Roche, and Kern. All remaining authors have declared no conflicts of interest. A complete list of the PEARL trial collaborators is provided in the Supplementary Appendix.

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