AstraZeneca's Phase Ib/III CAPItello-292 trial is actively enrolling participants to assess whether adding the AKT inhibitor capivasertib to CDK4/6 inhibitor plus fulvestrant backbone therapy improves outcomes in locally advanced or metastatic HR+/HER2- breast cancer. The randomized, open-label design tests capivasertib in combination with palbociclib, ribociclib, or abemaciclib against CDK4/6 inhibitor–fulvestrant doublet therapy alone.

AstraZeneca is currently recruiting participants for CAPItello-292 (NCT04862663), a Phase Ib/III open-label, randomized trial investigating the addition of capivasertib—a selective pan-AKT inhibitor—to standard CDK4/6 inhibitor and fulvestrant therapy in adults with hormone receptor-positive, HER2-negative locally advanced unresectable or metastatic breast cancer.

The trial compares the triplet regimen of capivasertib plus a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) and fulvestrant against the CDK4/6 inhibitor–fulvestrant doublet. This design reflects the clinical rationale that PI3K/AKT/mTOR pathway activation is a well-characterized mechanism of endocrine and CDK4/6 inhibitor resistance in HR+ breast cancer, and that upstream AKT blockade may restore or enhance sensitivity to these agents.

Capivasertib previously demonstrated efficacy in the CAPItello-291 trial, where it improved progression-free survival in combination with fulvestrant in PIK3CA/AKT1/PTEN-altered HR+/HER2- metastatic breast cancer, leading to FDA approval in that setting. CAPItello-292 extends this strategy by interrogating whether AKT inhibition can augment the CDK4/6 inhibitor–fulvestrant combination, potentially addressing a broader or earlier-line population.

The Phase Ib component will inform dosing and safety of the triplet combinations before the Phase III efficacy readout. Key unknowns include the relative benefit across individual CDK4/6 inhibitor partners, biomarker-defined subgroup performance, and the tolerability profile of the three-drug regimen at scale.

Key points

  • CAPItello-292 is a Phase Ib/III randomized trial evaluating capivasertib added to CDK4/6 inhibitor plus fulvestrant versus CDK4/6 inhibitor plus fulvestrant alone in HR+/HER2- advanced breast cancer.
  • Eligible CDK4/6 inhibitor partners include palbociclib, ribociclib, and abemaciclib, allowing broad applicability across standard-of-care backbones.
  • The mechanistic rationale centers on AKT pathway inhibition as a strategy to overcome or prevent resistance to CDK4/6 inhibitor–endocrine therapy combinations.
  • Capivasertib is already FDA-approved in combination with fulvestrant for PIK3CA/AKT1/PTEN-altered HR+/HER2- metastatic breast cancer based on CAPItello-291 data.
  • The trial is currently recruiting; Phase Ib safety and dosing data will precede the Phase III efficacy analysis.

Why it matters

If the triplet regimen demonstrates superior efficacy, CAPItello-292 could redefine first- or second-line treatment architecture for HR+/HER2- metastatic breast cancer by integrating AKT inhibition into the CDK4/6 inhibitor–endocrine therapy standard. The trial also provides an opportunity to characterize whether AKT pathway alteration status further stratifies benefit in this combination context.

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