Fulvestrant-Palbociclib vs Letrozole-Palbociclib as Initial Therapy for Endocrine-Sensitive, Hormone Receptor–Positive, <i>ERBB2</i>-Negative Advanced Breast Cancer
Authors: Antonio Llombart-Cussac, José Manuel Pérez-García, Meritxell Bellet, Florence Dalenc, Miguel Gil-Gil, Manuel Ruíz-Borrego, Joaquín Gavilá, Miguel Sampayo-Cordero, Elena Aguirre, Peter Schmid, Frederik Marmé, Serena Di Cosimo, Joseph Gligorov, Andreas Schneeweiss, Joan Albanell, Pilar Zamora, Duncan Wheatley, Eduardo Martínez-de Dueñas, Kepa Amillano, Andrea Malfettone, Javier Cortés, Antonio Antón, Vladimir Moiseyenko, Paul Cottu, Gemma Viñas, Thierry Petit, Petra Tesarova, Vladimir Vladimirov, Juan Cueva Bañuelos, Marco Colleoni, Gianfilippo Bertelli, Purificación Martínez, Raquel Andres, Tatiana Barannikova, Sonia Servitja, Jacques Medioni, Saverio Cinieri, Juan Bayo, Santiago González, Bohuslav Melichar, Vicente Caranyana, Francesco Atzori, Mark Beresford, Steven Chan, Maria Luque-Cabal, Juan de la Haba, Joachim Bischoff, Guzel Mukhametsina, Maria Cazzaniga, Daniele Generali, Andrew Wardley, Laura Cortesi, Luigi Cavanna, Mario Airoldi
Journal: JAMA Oncology (2021)

The cyclin-dependent kinase 4 and 6 inhibitor palbociclib in combination with letrozole has become a standard first-line treatment for patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer. Meanwhile, the antiestrogen fulvestrant was shown to be superior to anastrozole in the absence of cyclin-dependent kinase 4 and 6 inhibition for this patient population.To assess whether fulvestrant is superior to letrozole when combined with palbociclib in the first-line scenario.In this international, randomized, open-label, phase 2 clinical study conducted from July 30, 2015, to January 8, 2018, patients with hormone receptor-positive, ERBB2-negative advanced breast cancer with no prior therapy in the metastatic setting and endocrine-sensitive criteria were recruited from 47 centers in 7 countries. Data were analyzed from February 11 to May 15, 2020.Patients were randomly assigned (1:1 ratio) to receive palbociclib with either fulvestrant or letrozole. Stratification factors were type of disease presentation (de novo vs recurrent) and the presence of visceral involvement (yes vs no).The primary end point was investigator-assessed progression-free survival determined by Response Evaluation Criteria in Solid Tumors, version 1.1.A total of 486 women (median age, 63 years [range, 25-90 years]; 3 Asian women [0.6%]; 4 Black women [0.8%]; 461 White women [94.9%]; 18 women of unknown race [3.7%]) were randomized (243 to fulvestrant-palbociclib and 243 to letrozole-palbociclib). Median investigator-assessed progression-free survival was 27.9 months (95% CI, 24.2-33.1 months) in the fulvestrant-palbociclib group vs 32.8 months (95% CI, 25.8-35.9 months) in the letrozole-palbociclib group (hazard ratio, 1.13; 95% CI, 0.89-1.45; P = .32). This result was consistent across the stratification factors. No significant differences were observed in objective response rate (46.5% vs 50.2%) and 3-year overall survival rate (79.4% vs 77.1%) for fulvestrant-palbociclib and letrozole-palbociclib, respectively. Grade 3-4 adverse events were comparable among treatment groups, and no new safety signals were identified. No treatment-related deaths were reported.Although fulvestrant-palbociclib demonstrated significant antitumor activity, this randomized clinical trial failed to identify an improvement in progression-free survival with this regimen over letrozole-palbociclib in patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer.ClinicalTrials.gov Identifier: NCT02491983.