Unveiling the Potential of Cyclin-Dependent Kinases 4 and 6 Inhibitors Beyond Progression in Hormone Receptor Positive/Human Epidermal Growth Factor Negative Advanced Breast Cancer – A Clinical Review

Opinion Statement Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) have revolutionized the management of hormone receptor-positive (HR +) breast cancer. However, resistance to CDK4/6i remains an unavoidable challenge, with limited evidence to guide the choice of subsequent treatments. Continuation of CDK4/6 inhibition raises as a compelling treatment option and is currently an active area of research. This approach encompasses multifaceted strategies regarding CDK4/6i sequence (same or switched agent), endocrine therapy (ET) partner and potential combination with a third drug. Continuing CDK4/6 inhibition while targeting ET resistance in tumours still dependent on ER activity (i.e., ESR1 mutation) through a ctDNA-guided approach has the potential of becoming practice-changing, pending the results of ongoing phase III studies. Conversely, the efficacy of this strategy in cases of radiological progression in a biomarker-unselected population appears to be rather unsatisfactory. While some benefit, albeit modest, has been observed from switching to a different CDK4/6i after progression (e.g. ribociclib after palbociclib in the MAINTAIN trial and abemaciclib after both palbociclib and ribociclib in the postMONARCH trial), the current evidence (mainly with palbociclib) clearly argues against maintaining the same CDK4/6i. Biomarker analyses to optimally identify patients suitable for this approach yielded inconsistent findings that do not apply to daily clinical decision making. Attractive preliminary efficacy has recently emerged from combining a third agent (immunotherapy, AKT/ PIK3CA/mTOR inhibitor, new ET agents, CDK2 inhibitors) to CDK4/6i and ET, but further validation in larger ongoing trials is required to also determine the optimal timing for incorporating these agents into the therapeutic timeline. To date, CDK4/6i after CDK4/6i progression is far from being a standard of care. However, selected patients with indolent disease, prolonged exposure to previous CDK4/6i treatment (especially palbociclib) and without actionable molecular alterations, may be suitable for suchmaintenance strategy beyond progression. In this challenging and rapidly evolving treatment landscape, ongoing studies can refine the optimal approach and identify clinical and molecular factors to select the best treatment for the right patient.