Martin, MZielinski, CRuiz-Borrego, MCarrasco, ETurner, NCiruelos, E MMuñoz, MBermejo, BMargeli, MAnton, AKahan, ZCsoszi, TCasas, M IMurillo, LMorales, SAlba, EGal-Yam, EGuerrero-Zotano, ACalvo, Lde-la-Haba-Rodriguez, JRamos, MAlvarez, IGarcia-Palomo, AHuang-Bartlett, CKoehler, MCaballero, RCorsaro, MHuang, XGarcia-Saenz, J AChacon, J ISwift, CThallinger, CGil-Gil, M2023-02-092023-02-092020-12-29Martin M, Zielinski C, Ruiz-Borrego M, Carrasco E, Turner N, Ciruelos EM, et al. 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. Ann Oncol. 2021 Apr;32(4):488-499http://hdl.handle.net/10668/16888Palbociclib 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. 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. 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). 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.enAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/HER2-negativeCapecitabineEndocrine therapyHormone receptor-positiveMetastatic breast cancerPalbociclibAntineoplastic Combined Chemotherapy ProtocolsAromatase InhibitorsBreast NeoplasmsCapecitabineEGF Family of ProteinsHumansPiperazinesPyridinesQuality of LifeReceptor, ErbB-2Receptors, Estrogenresearch article33385521open accessCalidad de vidaQuimioterapiaMutaciónPieNeutropeniaSensibilidad y especificidad10.1016/j.annonc.2020.12.0131569-8041http://www.annalsofoncology.org/article/S0923753420432211/pdf