In recent years, inhibitors of the cyclin dependent kinases 4 and 6 emerged as real gamechangers in the treatment of hormone-receptor positive (HR+) breast cancer. Across seven large, pivotal phase III trials the addition of a CDK4/6 inhibitor to endocrine therapy (ET) consistently resulted in a statistically significant and clinically relevant delay in the occurrence of disease progression. Importantly, this benefit was seen in the first- and second-line setting, irrespective of the type of ET that was used and regardless of the menopausal status and hormone sensitivity of patients.
Following the highly positive results of these studies in terms of progression-free survival (PFS), the scientific community was eager to see whether this delayed disease progression would also translate into a significant prolongation in overall survival (OS). By now, four of the seven pivotal phase III trials evaluating a CDK4/6 inhibitor in this setting have released OS data. The results of MONARCH-2 and MONALEESA-3 and -7 convincingly show that adding a CDK4/6 inhibitor to ET in patients with HR+/HER2- advanced breast cancer results in a statistically significant and clinically relevant prolongation of the OS. In PALOMA-3, on the other hand, no significant OS benefit was observed with the addition of palbociclib.
There may be several reasons why the overall survival data with the different CDK4/6 inhibitors in metastatic disease are not identical, in contrast to the largely similar PFS data. In fact, differences in study populations, differences in the post-study use of CDK4/6 inhibition, or statistical chance, may partly explain these effects. At present, it is unclear whether these differences in OS outcomes reflect a different antitumor activity of the 3 approved CDK4/6 inhibitors, or if they might be linked to the continuous vs. Discontinuous dosing schedule of the different CDK4/6 inhibitors.
Combined with the previously reported consistent PFS benefit obtained with this therapeutic strategy and the fact that CDK4/6 inhibitors do not have a detrimental effect on the quality of life of patients, these findings strongly support these agents as the undisputed standard of care in this setting. The convincing nature of these findings is further illustrated by the fact that this statement was almost unanimously (97.4%) endorsed by breast cancer specialists attending the most recent International Consensus Conference for Advanced Breast Cancer (ABC5).
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PP-AL-BE-0153 April 2021