In recent years and across multiple lines of therapy, the combination of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors with hormonal therapy has become a standard of care for patients with advanced, hormone-receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative breast cancer. As previously reported, in the PALOMA-3 trial (N = 521) the combination of the CDK4/6 inhibitor palbociclib and fulvestrant resulted in an almost 5-month improvement in progression-free survival (PFS), compared to fulvestrant plus placebo (9.5 months vs 4.6 months; HR 0.46, P<.0001) in pretreated patients with advanced HR-positive, HER2-negative breast cancer. During the Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress, Massimo Cristofanilli, MD (Northwester University, Chicago, Illinois, United States), presented final results from this study, including mature overall survival (OS) data. These results were simultaneously published in The New England Journal of Medicine.
At a median 44.8-month follow-up, the PFS palbociclib remained consistent, with a 6.6-month improvement in median PFS with palbociclib and fulvestrant compared to placebo and fulvestrant (11.2 months vs 4.6 months; HR 0.497, P<.000001). The addition of palbociclib to fulvestrant also resulted in a 6.9-month improvement in median OS compared to fulvestrant plus placebo, though this was not statistically significant (34.9 months vs 28.0 months; stratified HR 0.814, P = .0429). However, among 410 patients with sensitivity to prior endocrine therapy, the benefit of palbociclib was more pronounced, resulting in a statistically significant 10-month improvement in OS (39.7 months vs 29.7 months; HR 0.721, P = .0081). Interestingly, the median OS among the 108 premenopausal or perimenopausal patients was 38 months in both the palbociclib/fulvestrant and the fulvestrant/placebo groups. Of note, in patients who were not sensitive to prior endocrine therapy, OS favored fulvestrant/placebo, though the difference was not significant (20.2 months vs 26.2 months; HR 1.137, P = .2969).
Dr Cristofanilli concluded that these results confirm the use of combination palbociclib/fulvestrant as a standard of care in previously treated patients with HR-positive, HER2-negative advanced breast cancer. The discussant for this abstract, Fatima Cardoso, MD (Champalimaud Clinical Center, Lisbon, Portugal), agreed that palbociclib is now a preferred treatment option for patients who have progressed on endocrine therapy. However, she cautioned that the improvement in survival was not significant, and she called to ‘’stop accepting PFS benefit alone as the main goal of the trials and to include OS at least as co-primary endpoint.’’ Furthermore, she raised several unanswered questions, including how to identify patients that will benefit from addition of CDK4/6 inhibitors to endocrine therapy, in which line of therapy these agents should be used in patients with advanced disease, the role for treatment beyond progression, and how endocrine therapy and CDK 4/6 inhibitors compare with other treatment options for patients with advanced luminal-like breast cancer.