Everolimus Plus Exemestane vs Everolimus or Capecitabine Monotherapy for Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer: The BOLERO-6 Randomized Clinical Trial

Abstract

Importance: Everolimus plus exemestane and capecitabine are approved second-line therapies for advanced breast cancer.

Objective: A postapproval commitment to health authorities to estimate the clinical benefit of everolimus plus exemestane vs everolimus or capecitabine monotherapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.

Design: Open-label, randomized, phase 2 trial of treatment effects in postmenopausal women with advanced breast cancer that had progressed during treatment with nonsteroidal aromatase inhibitors.

Interventions: Patients were randomized to 3 treatment regimens: (1) everolimus (10 mg/d) plus exemestane (25 mg/d); (2) everolimus alone (10 mg/d); and (3) capecitabine alone (1250 mg/m2 twice daily).

Main outcomes and measures: Estimated hazard ratios (HRs) of progression-free survival (PFS) for everolimus plus exemestane vs everolimus alone (primary objective) or capecitabine alone (key secondary objective). Safety was a secondary objective. No formal statistical comparisons were planned.

Results: A total of 309 postmenopausal women were enrolled, median age, 61 years (range, 32-88 years). Of these, 104 received everolimus plus exemestane; 103, everolimus alone; and 102, capecitabine alone. Median follow-up from randomization to the analysis cutoff (June 1, 2017) was 37.6 months. Estimated HR of PFS was 0.74 (90% CI, 0.57-0.97) for the primary objective of everolimus plus exemestane vs everolimus alone and 1.26 (90% CI, 0.96-1.66) for everolimus plus exemestane vs capecitabine alone. Between treatment arms, potential informative censoring was noted, and a stratified multivariate Cox regression model was used to account for imbalances in baseline characteristics; a consistent HR was observed for everolimus plus exemestane vs everolimus (0.73; 90% CI, 0.56-0.97), but the HR was closer to 1 for everolimus plus exemestane vs capecitabine (1.15; 90% CI, 0.86-1.52). Grade 3 to 4 adverse events were more frequent with capecitabine (74%; n = 75) vs everolimus plus exemestane (70%; n = 73) or everolimus alone (59%; n = 61). Serious adverse events were more frequent with everolimus plus exemestane (36%; n = 37) vs everolimus alone (29%; n = 30) or capecitabine (29%; n = 30).

Conclusions and relevance: These findings suggest that everolimus plus exemestane combination therapy offers a PFS benefit vs everolimus alone, and they support continued use of this therapy in this setting. A numerical PFS difference with capecitabine vs everolimus plus exemestane should be interpreted cautiously owing to imbalances among baseline characteristics and potential informative censoring.

Trial registration: ClinicalTrials.gov identifier: NCT01783444.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Jerusalem received research funding from Novartis Pharmaceuticals Corporation and Roche; received honoraria from Novartis Pharmaceuticals Corporation, Roche, Pfizer, Lilly, Celgene, Amgen, BMS, and Puma Technology; and received nonfinancial support from Novartis Pharmaceuticals Corporation, Roche, Pfizer, Lilly, Amgen, and BMS. Dr de Boer received research funding from Novartis Pharmaceuticals Corporation and Roche; and received honoraria from Novartis Pharmaceuticals Corporation, Roche, AstraZeneca, Eisai, and Amgen. Dr Hurvitz received research funding from Amgen, Bayer, BI Pharm, Genentech, GSK, Lilly, Novartis Pharmaceuticals Corporation, Pfizer, Roche, PUMA, Merrimack, Medivation, Dignatana, OBI Pharma, Biomarin, Cascadian, and Seattle Genetics; and received travel expenses from Lilly, Novartis Pharmaceuticals Corporation, OBI Pharma, and Bayer. Dr Yardley was an advisory board member and a speakers’ bureau member for Novartis Pharmaceuticals Corporation. Dr Ejlertsen received research funding from Novartis Pharmaceuticals Corporation, Roche and NanoString; and received expenses from AstraZeneca. Dr Blau was a consultant for BMS but did not receive compensation; and her husband (Tony Blau) is the owner of All4Cure and is employed at the University of Washington. Dr Özgüroğlu was an advisory board member for Janssen and Astellas. Drs Taran, Fan, Noel-Baron, and Ms Louveau are Novartis Pharmaceuticals Corporation employees. Dr Burris was a consultant for Mersana, AstraZeneca, Forma, Janssen, Novartis Pharmaceuticals Corporation, Roche/Genentech, TG Therapeutics, MedImmune, Bristol-Myers Squibb; and received research funding from Roche/Genentech, Bristol-Myers Squibb, Incyte, Tarveda Therapeutics, Mersana, AstraZeneca, MedImmune, Macrogenics, Novartis Pharmaceuticals Corporation, Boehringer Ingelheim, Lilly, Seattle Genetics, AbbVie, Bayer, Celldex, Merck, Celgene, Agios, Jounce Therapeutics, Moderna Therapeutics, CytomX Therapeutics, GlaxoSmithKline, Verastem, Tesaro, Immunocore, Takeda, Millennium, BioMed Valley Discoveries, Pfizer, PTC Therapeutics, Loxo, Vertex, eFFECTOR Therapeutics, Janssen, Gilead Sciences, Valent Technologies. No other disclosures are reported.

Figures

Figure 1.. Study Enrollment Flow Diagram

Discontinued intervention is defined as the primary reason for treatment discontinuation. AE indicates adverse event. aSome patients had multiple reasons for study exclusion.

Figure 2.. Kaplan-Meier Curves of Progression-free Survival for Everolimus Plus Exemestane vs Everolimus Alone and Capecitabine Alone

CAP indicates capecitabine; EVE, everolimus; EXE, exemestane; HR, hazard ratio.

Figure 3.. Kaplan-Meier Curves of Overall Survival for Everolimus Plus Exemestane vs Everolimus Alone and Capecitabine Alone

CAP indicates capecitabine; EVE, everolimus; EXE, exemestane; HR, hazard ratio.