According to the American Cancer Society, breast cancer is the most common cancer among women in the United States. HR-positive breast cancer (expressing estrogen or progesterone receptors, or both) is the most prevalent subtype, with more than 65% of tumors characterized as HR-positive and HER2-low or HER2-negative. Up to 50% of patients with advanced HR-positive breast cancer harbor mutations in PIK3CA and AKT1, as well as alterations in PTEN. However, patients with advanced HR-positive breast cancer often experience disease progression or develop resistance to widely used first-line endocrine therapies. Recently, the FDA approved a first-in-class combination regimen that provides a much-needed new treatment option for up to half of these patients. These specific biomarkers have the potential to delay disease progression and extend the duration of disease control.
On November 16, AstraZeneca announced that the U.S. Food and Drug Administration (FDA) has approved Truqap (capivasertib) in combination with Faslodex (fulvestrant) for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN mutations, as detected by an FDA-approved test. Patients must have progressed following at least one endocrine-based regimen in the metastatic setting, or relapsed within 12 months of completing adjuvant therapy.
Of note, fasting plasma glucose and HbA1c should be assessed prior to initiation of treatment.
Concurrently with the approval, the FDA also approved the FoundationOne CDx assay as a companion diagnostic to detect these relevant alterations (PIK3CA, AKT1, and PTEN).
Truqap is an oral, selective, ATP-competitive inhibitor that suppresses all three isoforms of the serine/threonine kinase AKT (AKT 1/2/3). The agent is designed to act by targeting AKT1 mutations, which drive tumor growth and proliferation. According to the pharmaceutical company, the drug is expected to be launched in mid-December 2023.
The FDA approval of Truqap was based on data from the Phase 3 CAPItello-291 trial (ClinicalTrials.gov Identifier: NCT04305496), which evaluated the efficacy of capivasertib plus fulvestrant (an estrogen receptor antagonist) versus placebo plus fulvestrant in 708 patients with locally advanced (unresectable) or metastatic HR+/HER2− breast cancer, including 289 patients whose tumors harbored PIK3CA/AKT1/PTEN mutations.
Study participants were randomized to receive capivasertib plus fulvestrant (n = 355) or placebo plus fulvestrant (n = 353). The primary efficacy outcome measure was progression-free survival (PFS) in the overall trial population and in the subgroup of patients with tumors harboring PIK3CA/AKT1/PTEN alterations (155 in the capivasertib arm and 134 in the placebo arm).
Results showed that among patients with PIK3CA/AKT1/PTEN-mutated tumors, median PFS was 7.3 months (95% CI, 5.5–9.0) in the capivasertib plus fulvestrant arm, compared with 3.1 months (95% CI, 2.0–3.7) in the placebo plus fulvestrant arm (hazard ratio [HR], 0.50; 95% CI, 0.38–0.65; P < .0001).
In an exploratory analysis of PFS among 313 patients with tumors without PIK3CA/AKT1/PTEN alterations, the HR was 0.79 (95% CI, 0.61–1.02), indicating that the difference in the overall population was driven by outcomes observed in patients with tumors harboring these genomic alterations.
Regarding safety, the most common adverse reactions reported in the trial were diarrhea, cutaneous adverse reactions, increased random glucose, lymphopenia, decreased hemoglobin, increased fasting glucose, nausea, fatigue, leukopenia, increased triglycerides, neutropenia, increased creatinine, vomiting, and stomatitis.
Regulatory applications for the combination of Truqap and fulvestrant are currently under review in China, the European Union, Japan, and several other countries.
Beyond HR-positive breast cancer, AstraZeneca stated that the Phase 3 CAPItello-290 trial is investigating Truqap as a first-line treatment for triple-negative breast cancer, with results expected in the first half of 2024.
