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.

Martin, M; Zielinski, C; Ruiz-Borrego, M; Carrasco, E; Turner, N; Ciruelos, E M; Muñoz, M; Bermejo, B; Margeli, M; Anton, A; Kahan, Z; Csöszi, T; Casas, M I; Murillo, L; Morales, S; Alba, E; Gal-Yam, E; Guerrero-Zotano, A; Calvo, L; Haba-Rodriguez, J de la; Ramos, M; Alvarez, I; Garcia-Palomo, A; Bartlett, C Huang; Koehler, M; Caballero, R; Corsaro, M; Huang, X; Garcia-Sáenz, J A; Chacón, J I; Swift, C; Thallinger, C; Gil-Gil, M

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.