Capivasertib – Potent Selective Akt Kinase Inhibitor Targeted Therapy
Capivasertib is an oral, first-in-class, highly selective small-molecule targeted inhibitor of all three isoforms of the serine-threonine protein kinase Akt (Akt1, Akt2, and Akt3). The drug is engineered for the precision oncology treatment of advanced hormone-receptor positive malignancies. The mechanism of action of capivasertib involves highly specific binding to the ATP-binding domain of the Akt kinase, preventing the phosphorylation of its numerous downstream substrates. The PI3K/Akt/mTOR pathway is a central regulatory cascade controlling cell survival, proliferation, and metabolism. In tumor cells, this pathway is frequently constitutively hyperactivated due to somatic mutations in PIK3CA or AKT1 genes, or through the loss-of-function alterations in the PTEN tumor suppressor. Akt blockade by capivasertib effectively disrupts oncogenic signaling, restores apoptotic mechanisms, and suppresses the growth of tumor clones exhibiting resistance to standard endocrine therapies.
The clinical uniqueness of capivasertib lies in its ability to overcome acquired endocrine resistance in patients with HR-positive, HER2-negative breast cancer harboring specific alterations within the PI3K/Akt/PTEN pathway, particularly when combined with selective estrogen receptor degraders (such as fulvestrant). The drug displays high oral bioavailability. Steady-state plasma concentrations are achieved within the first week of administration utilizing an intermittent dosing schedule designed to minimize systemic liabilities. Capivasertib is primarily metabolized in the liver via the CYP3A4 isoenzyme and is excreted as metabolites and unchanged drug predominantly through the intestines in the feces and partially via the kidneys in the urine.
The drug is administered orally. Prior to initiating targeted treatment, documentation of genetic alterations in PIK3CA, AKT1 genes, or PTEN deficiency using a validated molecular-genetic NGS or PCR assay is mandatory. Strict clinical monitoring of plasma glucose levels and cutaneous integrity is required throughout therapy.
Indications
Capivasertib is indicated as a precision targeted combination therapy for adult patients with the following malignant oncological condition:
- Hormone-Resistant Breast Cancer: treatment of adult patients with locally advanced or metastatic hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer harboring one or more genetic alterations (PIK3CA mutations, AKT1 mutations, or PTEN alterations), following progression on or after endocrine-based regimens, in combination with fulvestrant.
Dosage and administration
The dosing regimen of capivasertib is intermittent, specifically structured to reduce the severity of systemic metabolic and gastrointestinal toxic liabilities.
- Standard Dose: the recommended therapeutic dose is 400 mg (two 200 mg tablets) taken orally twice daily (morning and evening, approximately 12 hours apart).
- Schedule and Duration: the drug is taken on an intermittent schedule: 4 consecutive days of treatment followed by 3 days of mandatory rest each week. Treatment should be maintained until disease progression or unacceptable systemic toxicity occurs.
- Administration Method: tablets must be swallowed whole with a glass of water and can be taken with or without food. Tablets must not be broken, crushed, or chewed during handling.
- Missed Dose: if a scheduled dose is missed by more than 4 hours, it should be skipped. The patient must take the next dose at the regular scheduled time. A double dose must never be taken.
- Dose Modification for Toxicity: if severe skin rash, uncontrolled diarrhea, or severe hyperglycemia develops, therapy must be temporarily withheld. Upon resolution, treatment is resumed with step-down reductions (first step down to 320 mg twice daily, and second step down to 200 mg twice daily following the same 4/3 schedule).
