Mafalda Oliveira, MD, highlighted pivotal advancements in managing hormone receptor (HR)-positive/HER2-negative advanced breast cancer, particularly after progression on CDK4/6 inhibitors. Data shows that switching both endocrine therapy (ET) and the CDK4/6 inhibitor in the second-line setting yields better outcomes compared with rechallenging with the same CDK4/6 agent following progression, a trend consistently supported by pooled trial analyses. However, certain patients with molecular alterations, such as RB1 or FAT1 mutations, may not respond well to a CDK4/6 rechallenge, emphasizing the need for tailored approaches, particularly ones that are based on mutational alterations.
Dr Oliveira briefly discussed that the EVoPAR trial is currently evaluating the efficacy of the selective PARP1 inhibitor saruparib plus camizestrant in patients with BRCA1/2 mutations. Currently approved PI3K/AKT pathway inhibitors, including alpelisib, capivasertib, everolimus, and inavolisib, offer additional options for treating patients with actionable alterations, such as PIK3CA mutations. These inhibitors have demonstrated significant improvements in progression-free survival, though each was studied in distinct patient populations. Their use is associated with distinct side effect profiles, including hyperglycemia and diarrhea.
When selecting an agent for a patient with an alteration in the PI3K/AKT pathway, clinicians must consider both disease-related aspects, such as tumor burden and previous treatment duration, and patient-related factors, including comorbidities, preferences, and tolerability of previous therapies. Ongoing studies are investigating combinations of PI3K/AKT inhibitors with ET and CDK4/6 inhibitors, as well as exploring next-generation targeted agents.
These advancements highlight the importance of precision medicine in navigating the complex post–CDK4/6 inhibitor landscape, offering new hope for improved outcomes in advanced breast cancer management.
Source: Oliveira M. Treatment strategies after CDK4/6 inhibitor progression. Presented at: San Antonio Breast Cancer Symposium 2025. December 9, 2025; San Antonio, TX. Presentation ED1-01.