On November 16, 2023, the FDA approved capivasertib (Truqap; AstraZeneca Pharmaceuticals), in combination with fulvestrant, for the treatment of hormone receptor (HR)-positive, HER2-negative, locally advanced or metastatic breast cancer in patients with ≥1 PIK3CA, AKT1, or PTEN genetic mutations, as detected by an FDA-approved test. Eligible patients should have disease progression after receiving ≥1 endocrine-based regimens in the metastatic setting or have had disease recurrence directly after or within 12 months of completing adjuvant therapy. The FDA granted this approval priority review.
On the same day, the FDA also approved the FoundationOne CDx assay as a companion diagnostic test to identify patients with breast cancer who are eligible for treatment with capivasertib plus fulvestrant.
Capivasertib is a first-in-class, potent adenosine triphosphate-competitive inhibitor of all 3 AKT isoforms (AKT1-3).
The approval of capivasertib plus fulvestrant was based on the results of CAPItello-291 (NCT04305496), a randomized, double-blind, placebo-controlled, multicenter, phase 3 trial in 708 patients with locally advanced HR–positive, HER2-negative breast cancer, of which 289 patients had tumors with AKT pathway alterations. All patients were required to have disease progression after receiving an aromatase inhibitor, with or without a CDK4/6 inhibitor. The patients were allowed to have received ≤2 previous lines of endocrine therapy and 1 previous line of chemotherapy for locally advanced or metastatic disease. The patients were randomized in a 1:1 ratio to capivasertib 400 mg or to placebo orally twice daily for 4 days, followed by 3 days off treatment each week of a 28-day treatment cycle. Both patient cohorts received fulvestrant 500 mg intramuscularly on cycle-1 days 1 and 15, and then every 28 days thereafter. Treatment continued until disease progression or unacceptable adverse events.
The dual primary end point of the study was investigator-assessed progression-free survival (PFS) in the overall population and in the patients whose tumors had qualifying alterations in the PI3K/AKT pathway according to RECIST V1.1. In the 289 patients with PIK3CA/AKT1/PTEN alterations, the median PFS was 7.3 months in the capivasertib plus fulvestrant group versus 3.1 months in the placebo plus fulvestrant group (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.38-0.65; P<.001). An exploratory analysis of PFS in the 313 (44%) patients whose tumors did not have PIK3CA/AKT1/PTEN alterations showed an HR of 0.79 (95% CI, 0.61-1.02).
The most common (≥20%) adverse events with capivasertib plus fulvestrant, including laboratory abnormalities, were diarrhea, cutaneous adverse reactions, increased random glucose, decreased lymphocytes, decreased hemoglobin, increased fasting glucose, nausea, fatigue, decreased leukocytes, increased triglycerides, decreased neutrophils, increased creatinine, vomiting, and stomatitis.
“Patients with advanced HR-positive breast cancer typically experience tumour progression or resistance with widely used first-line endocrine therapies and there is an urgent need to extend the effectiveness of these approaches,” said Komal Jhaveri, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, in a press release. “The combination of capivasertib and fulvestrant, a first-of-its-kind combination, provides a much-needed new treatment option for up to half of patients in this setting with these specific biomarkers, offering the potential to delay disease progression and provide more time with their disease under control,” she added.
The recommended dose of capivasertib, in combination with fulvestrant, is 400 mg orally twice daily (approximately 12 hours apart) with or without food for 4 days followed by 3 days off treatment. Capivasertib is contraindicated in patients who have a severe hypersensitivity to capivasertib or any of its components.
Capivasertib is being evaluated in phase 3 trials for the treatment of multiple subtypes of breast cancer and in other tumor types as monotherapy and in combination with established treatments.