Capivasertib + Fulvestrant: the right choice after CDK4/6 inhibitor failure?

By Ana Espino | Published on october 17, 2025 | 3 min read



Metastatic HR+/HER2– breast cancer — the most common subtype in postmenopausal women — remains an incurable disease despite advances in endocrine therapy and CDK4/6 inhibitors. Most patients eventually develop secondary resistance, limiting therapeutic options. Alterations in the PI3K/AKT/PTEN pathway, frequently observed in this subtype, contribute to resistance and represent a promising therapeutic target.  

A major challenge in managing this disease lies in finding effective alternatives after failure of standard treatments. Integrating tumor biomarkers to guide therapeutic decisions is a promising strategy in the development of new targeted approaches. In this context, the development of AKT inhibitors such as capivasertib fits within the framework of precision medicine, aiming to restore endocrine sensitivity and delay tumor progression.    

A promising combination after CDK4/6 inhibitors?  

The FAKTION (Phase II) and CapItello-291 (Phase III) trials evaluated the efficacy of the capivasertib + fulvestrant combination in patients who had progressed on CDK4/6 inhibitors. In CapItello-291, progression-free survival (PFS) significantly increased from 3.6 to 7.2 months in the overall population and reached 7.3 months in patients with PI3K/AKT/PTEN pathway alterations (HR = 0.50; p < 0.001).

In the FAKTION study, the combination extended PFS to 12.8 months (vs. 4.6 months) and improved overall survival (OS) to 38.9 months (vs. 20.0 months) in the mutated subgroup. The safety profile was considered acceptable, with the most frequent adverse events being digestive (diarrhea, nausea) or metabolic (hyperglycemia) in nature — generally moderate and manageable.    

Toward a new standard line of therapy?  

Metastatic HR+/HER2– breast cancer, common yet incurable at this stage, becomes particularly challenging to treat after CDK4/6 inhibitor failure. In the face of this therapeutic impasse, the major challenges lie in identifying new targeted options, stratifying patients according to their molecular profile, and managing toxicities in real-world settings.  

The aim of this study was to evaluate the capivasertib + fulvestrant combination in pretreated patients, specifically targeting alterations in the PI3K/AKT/PTEN pathway.
Results from the CapItello-291 and FAKTION trials confirm the clinical efficacy of this approach, demonstrating a significant progression-free survival benefit, particularly in genetically altered subgroups.  

However, some limitations remain and warrant further research. Ongoing studies (such as CapItello-292) will need to clarify the exact place of capivasertib in treatment sequences, its potential in combination with other targeted agents, and its added value in the first-line setting. This targeted approach could therefore become a lasting part of the standard of care for metastatic HR+/HER2– breast cancer — provided it is introduced early and supported by broader access to precision medicine.

Read next: CDK4/6: The double-edged sword?

About the author – Ana Espino
As a scientific writer, Ana is passionate about bridging the gap between research and real-world impact. With expertise in immunology, virology, oncology, and clinical studies, she makes complex science clear and accessible. Her mission: to accelerate knowledge sharing and empower evidence-based decisions through impactful communication.