US Food and Drug Administration Approval Summary: Capivasertib With Fulvestrant for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced or Metastatic Breast Cancer With PIK3CA/AKT1/PTEN Alterations.

Purpose: The US Food and Drug Administration (FDA) approved capivasertib in combination with fulvestrant for adult patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced, or metastatic breast cancer (MBC) who have received at least one previous endocrine therapy and whose tumors harbor one or more phosphatidylinositol 3-kinase (PIK3CA)/AKT Serine/Threonine Kinase 1 (AKT1)/phosphatase and tensin homolog (PTEN) alterations, as detected by an FDA-approved test.

Patients and methods: Approval was based on CAPItello-291, a randomized, double-blind, multicenter trial of 708 patients with hormone receptor-positive, HER2-negative advanced or MBC, including 289 patients with PIK3CA/AKT1/PTEN tumor alterations. Patients were randomly assigned 1:1 to receive capivasertib 400 mg twice daily for 4 days per week with fulvestrant versus placebo with fulvestrant. Random assignment was stratified by presence of liver metastases, previous treatment with CDK4/6i, cyclin-dependent kinase four and six (CDK4/6) inhibitors, and geographical region.

Results: A statistically significant progression-free survival (PFS) benefit was demonstrated in the overall population (hazard ratio [HR], 0.6 [95% CI, 0.51 to 0.71]); this result was driven by 289 patients in the biomarker-positive population (HR, 0.5 [95% CI, 0.37 to 0.68]). An exploratory analysis of investigator-assessed PFS in the 313 (44%) patients in the biomarker-negative population showed uncertain benefit (HR, 0.78 [95% CI, 0.60 to 1.01]). With capivasertib, more patients had Grade ≥3 toxicities. Key concerns included hyperglycemia (18% all-grade, 2.8% Grade ≥3), cutaneous toxicity (58% all-grade, 17% Grade ≥3), and diarrhea (72% all-grade, 9% Grade ≥3).

Conclusion: Capivasertib with fulvestrant was approved for patients whose tumors harbored PIK3CA/AKT1/PTEN alterations. Benefit-risk assessment in this subgroup was favorable based on a statistically significant and clinically meaningful improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in overall survival. By contrast, the benefit-risk was unfavorable in the biomarker-negative population.