What comes after CDK4/6 inhibitors? SERDs, combinations and the future of HR+ advanced breast cancer
The post-CDK4/6 inhibitor setting in HR-positive, HER2-negative advanced breast cancer is one of the most pressing unmet needs in oncology. CDK4/6 inhibitors with endocrine therapy are the established first-line standard, but disease progression on this backbone remains nearly universal, driven by varied resistance mechanisms: ESR1 mutations, PI3K/AKT/mTOR pathway alterations and RB1 loss. That diversity shows the limits of one-size-fits-all approaches.
Next-generation oral SERDs, such as elacestrant, camizestrant and imlunestrant, are reshaping the field. They degrade the estrogen receptor more completely than fulvestrant, are active in ESR1-mutant disease, and are being actively evaluated in combination strategies with CDK4/6 and targeted therapies. Together, they are helping shift the post-CDK4/6 setting toward a more dynamic, biomarker-informed treatment paradigm.
