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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., Competing Interests: 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., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The randomised phase III TANIA trial demonstrated that continuing bevacizumab with second-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC) after progression on first-line bevacizumab-containing therapy significantly improved progression-free survival (PFS) compared with chemotherapy alone [hazard ratio (HR) = 0.75, 95% confidence interval (CI) 0.61-0.93]. We report final results from the TANIA trial, including overall survival (OS) and health-related quality of life (HRQoL)., Patients and Methods: Patients with HER2-negative LR/mBC that had progressed on or after first-line bevacizumab plus chemotherapy were randomised to receive standard second-line chemotherapy either alone or with bevacizumab. At second progression, patients initially randomised to bevacizumab continued bevacizumab with their third-line chemotherapy, but those randomised to chemotherapy alone were not allowed to cross over to receive third-line bevacizumab. The primary end point was second-line PFS; secondary end points included third-line PFS, combined second- and third-line PFS, OS, HRQoL and safety., Results: Of the 494 patients randomised, 483 received second-line therapy; 234 patients (47% of the randomised population) continued to third-line study treatment. The median duration of follow-up at the final analysis was 32.1 months in the chemotherapy-alone arm and 30.9 months in the bevacizumab plus chemotherapy arm. There was no statistically significant difference between treatment arms in third-line PFS (HR = 0.79, 95% CI 0.59-1.06), combined second- and third-line PFS (HR = 0.85, 95% CI 0.68-1.05) or OS (HR = 0.96, 95% CI 0.76-1.21). Third-line safety results showed increased incidences of proteinuria and hypertension with bevacizumab, consistent with safety results for the second-line treatment phase. No differences in HRQoL were detected., Conclusions: In this trial, continuing bevacizumab beyond first and second progression of LR/mBC improved second-line PFS, but no improvement in longer term efficacy was observed. The second-line PFS benefit appears to be achieved without detrimentally affecting quality of life., Clinicaltrialsgov: NCT01250379., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)