Truqap (capivasertib), a novel AKT inhibitor, has recently become available in Korea, marking a significant advancement in the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) locally advanced or metastatic breast cancer. This development offers new targeted therapy options for patients with PIK3CA, AKT1, and PTEN mutations, which account for approximately half of all patients with this type of breast cancer.
Unmet Needs in HR+/HER2- Breast Cancer Treatment
Professor Park Kyong-hwa of Korea University Anam Hospital highlighted the challenges in treating HR+/HER2- breast cancer. While endocrine therapy combined with CDK4/6 inhibitors is the standard first-line treatment, many patients experience disease progression and have limited effective options in subsequent lines of therapy. After the failure of CDK4/6 inhibitors, available treatments like fulvestrant monotherapy or everolimus + exemestane offer limited effectiveness, with fulvestrant showing a median progression-free survival (mPFS) of less than three months. This often leads to the use of cytotoxic anticancer drugs, which can significantly impact patients' quality of life.
Clinical Benefits of Truqap
Truqap is a targeted therapy that inhibits AKT, a key protein in the PI3K signaling pathway. It is approved for patients with mutations in PIK3CA, AKT1, and PTEN genes. These mutations are associated with poorer prognosis and resistance to CDK4/6 inhibitor therapy. The global phase 3 CAPItello-291 study demonstrated that Truqap, when combined with fulvestrant, significantly improved mPFS compared to fulvestrant alone (7.3 months vs. 3.1 months) in patients who had failed first-line endocrine therapy ± CDK4/6 inhibitors. The study also showed a 30% improvement in overall survival (OS), providing a crucial advantage in second-line treatment.
Truqap vs. Alpelisib
For patients with PIK3CA mutations, both alpelisib and Truqap are potential treatment options. However, Professor Park noted key differences in the clinical trials for these drugs. The SOLAR-1 study, which evaluated alpelisib, primarily included patients not previously treated with CDK4/6 inhibitors and excluded patients with high fasting blood glucose levels. In contrast, the Truqap study enrolled a significant proportion (approximately 70%) of patients previously treated with CDK4/6 inhibitors and allowed enrollment of patients with higher HbA1c levels. This makes the clinical data for Truqap more relevant to real-world scenarios where CDK4/6 inhibitors are commonly used as first-line therapy. While both drugs can cause hyperglycemia, diarrhea, and rash, Truqap has demonstrated a slightly better safety profile, particularly regarding its effect on blood sugar levels.
Genetic Testing and Treatment Strategies
Genetic analysis plays a crucial role in identifying patients who may benefit from targeted therapies like Truqap. While mutations in primary lesions are likely to persist in later relapses, secondary mutations can also occur due to treatment. Therefore, re-biopsy at the time of recurrence is recommended for genetic analysis. Liquid biopsy can be an alternative, though it has limitations in detecting certain mutations, such as PTEN deletions. NGS (Next Generation Sequencing) testing is generally recommended at the time of diagnosis of recurrence or metastasis to guide treatment decisions and prepare for subsequent therapies. Identifying ESR1 mutations, for example, can help determine which patients may benefit from fulvestrant monotherapy.
