Capivasertib inhibits a key pathway in metastatic breast cancer
Mené au Royaume-Uni sur 140 patientes atteintes d'un cancer du sein inopérable ER+ HER2- de stade métastatique ou localement avancé, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'ajout du capivasertib au fulvestrant, après l'échec d'un traitement par inhibiteur de l'aromatase
In the pursuit of improved therapies for metastatic breast cancer, a succession of drugs have been approved that target a range of mechanisms. However, resistance to these therapies is inevitably encountered. This resistance underscores the emergence and perhaps persistence of compensatory pathways that allow cancer cells to survive. Hormone-directed strategies are integral in the management of hormone receptor-positive breast cancer, because they effectively target the oestrogen receptor signalling pathway. Ongoing research aims to explore the synergistic effects of additive therapies in this space. Notable examples include the CDK4/6 inhibitors, such as palbociclib, abemaciclib, and ribociclib, several of which have been reported to confer a survival advantage upon addition to the selective oestrogen receptor degrader fulvestrant. Capivasertib is a potent pan-AKT inhibitor with notable anti-proliferative activity in preclinical models. The PI3K/AKT/mTOR axis specifically has a central position in several pathways with key functions in promoting cell survival, growth, and proliferation. Substantial cross-talk between these pathways and mediators of oestrogen receptor signalling are well appreciated, and thus these mediators are logical targets in hormone-sensitive disease. Previous attempts at inhibition of these downstream kinases are highlighted by the BOLERO-2 trial, which evaluated the addition of everolimus, a selective mTOR inhibitor, to the aromatase inhibitor exemestane, and reported an improvement in progression-free survival but not in overall survival. Inhibition of PI3K, although particularly effective in patients with tumours with PIK3CA mutations, has proved challenging owing to the toxicity profile of PI3K inhibitors.
The Lancet Oncology , commentaire en libre accès, 2019