A final protocol-defined analysis of the global phase III Palbociclib CoLlaborative Adjuvant Study (PALLAS) does not show significant improvements in survival endpoints for the addition of palbociclib to adjuvant endocrine therapy over endocrine therapy alone in patients with early hormone receptor-positive, HER-2 negative breast cancer. In addition, 44.9% of patients did not complete two years of palbociclib treatment, mainly because of neutropenia. The results are published by Prof. Michael Gnant of the Medical University of Vienna, Comprehensive Cancer Center and the Austrian Breast and Colorectal Cancer Study Group (ABCGS) in Vienna, Austria and colleagues on 7 December 2021 in the Journal of Clinical Oncology.
The authors wrote in the study background that addition of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to endocrine therapy has improved outcomes for patients with metastatic hormone receptor-positive, HER2-negative breast cancer. Large clinical studies are conducted to assess the usefulness of CDK4/6 inhibitors in the curative early disease setting.
PALLAS investigated the efficacy and safety of the addition of two years of adjuvant palbociclib to endocrine therapy in patients with hormone receptor-positive, HER2-negative early breast cancer. The addition of palbociclib to endocrine therapy has been proven to be clinically safe in studies in metastatic setting, which is a precondition for using a drug in the early, curative breast cancer setting. Typically, reversible neutropenia without associated infection is the most common side effect.
In the prospective, randomised, phase III PALLAS study, patients with hormone receptor-positive, HER2-negative early breast cancer were randomly assigned to receive 2 years of palbociclib 125 mg orally once daily on days 1-21 of a 28-day cycle with adjuvant endocrine therapy or adjuvant endocrine therapy alone for at least 5 years. The primary endpoint of the study was invasive disease-free survival (iDFS). Secondary endpoints were invasive breast cancer–free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival.
Among 5,796 patients enrolled at 406 centres in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups: iDFS at 4 years was 84.2% versus 84.5% with hazard ratio 0.96 (confidence interval 0.81 to 1.14, p = 0.65).
No significant differences were observed for secondary time-to-event endpoints, and subgroup analyses did not show any differences by subgroup.
There were no new safety signals for palbociclib in this study.
The authors commented that the lack of adjuvant palbociclib efficacy does not preclude further integration of CDK4/6 inhibitors into the breast cancer treatment algorithm. In addition to new combinations being currently investigated in various breast cancer subtypes, translational science will help to better understand unique tissue and/or serum biomarkers that may predict individual benefit or resistance for each of the approved CDK4/6 inhibitors to guide optimal patient selection and treatment combinations. The sizable trans-PALLAS biorepository containing both tumour tissue and serial plasma specimens together with the planned clinical long-term follow-up of patients will serve as an excellent resource to support such important research.
The study was presented in part at San Antonio Breast Cancer Symposium (SABCS) 2021, December 7-10. Preliminary data were presented in part at ESMO 2020 Congress and at SABCS 2020.
The academic PALLAS study was legally cosponsored by the ABCSG and the Alliance Foundation, in collaboration with the Eastern Cooperative Oncology Group, the NSABP Foundation, Inc, the German Breast Group, and the Breast International Group. The study was funded by Pfizer that provided the study drug and financial support.
Gnant M, Dueck AC, Frantal S, et al. Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03). JCO; Published online 7 December 2021. DOI: 10.1200/JCO.21.02554