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.
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Background Palbociclib plus endocrine therapy (ET) is the standard treatment for 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 inhibitors (AIs)-resistant MBC were included in two consecutive cohorts. In cohort 1 (C1), patients were randomised 1:1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about oestrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2 (C2), 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 C2 and in wild-type ESR1 patients (C1+C2). ESR1 hotspot mutations were analysed in baseline circulating tumour DNA.Results From March-2014 to July-2018, 296 and 305 patients were included in C1 and C2, respectively. Palbociclib plus ET was not superior to capecitabine in both C2 (median PFS: 7.5 vs. 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 vs. 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 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.
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Annals of oncology : official journal of the European Society for Medical Oncology, 2020