Capivasertib, marketed as Truqap, is a targeted therapy drug that functions as an Akt inhibitor. This medication interferes with signals that tell cancer cells to grow and divide and is prescribed for certain forms of advanced or metastatic breast cancer. Capivasertib is administered orally in tablet form and is used in combination with other cancer therapies.
The Role of the Akt Pathway in Cancer
The Akt signaling pathway, also known as the PI3K/AKT pathway, regulates a cell’s growth, survival, and metabolism. This pathway is a chain of proteins that transmits signals from the cell surface to the nucleus. Under normal conditions, this system is tightly controlled to ensure cells only grow and divide when necessary.
In some cancers, this regulated system breaks down. Genetic mutations can cause the Akt pathway to become permanently switched on, leading to uncontrolled cell proliferation and the survival of malignant cells. These alterations are found in up to 50% of patients with the most common type of advanced breast cancer.
This persistent activation transforms the pathway into a driver of tumor growth and resistance to treatment. The overactive pathway contributes to the development and progression of the cancer. Interrupting this faulty signaling is a primary goal for drugs designed to treat these specific cancers.
Mechanism of Action
Capivasertib functions as a potent and competitive inhibitor that targets all three isoforms of the Akt protein: AKT1, AKT2, and AKT3. This type of inhibitor is called a “pan-Akt inhibitor” because of its comprehensive action. The drug works by binding to these proteins, physically blocking them from sending the downstream signals that promote cell growth and survival.
The drug is an adenosine triphosphate (ATP)-competitive inhibitor, meaning it competes with ATP to bind to the Akt enzyme. This action prevents the phosphorylation process, a chemical reaction that activates the downstream components of the pathway. This blockade hampers the signals that tell the cancer cell to proliferate, ultimately reducing the growth of tumor cells.
This mechanism is particularly effective when combined with other treatments that target different aspects of the cancer’s biology. Capivasertib is frequently administered with fulvestrant, an estrogen receptor (ER) degrader. This dual approach simultaneously shuts down the growth signals from the Akt pathway and the hormone-driven signals from the estrogen receptor.
Approved Uses and Clinical Efficacy
Capivasertib, in combination with fulvestrant, is approved for the treatment of adult patients with hormone receptor (HR)-positive, HER2-negative breast cancer. This approval is for cases where the cancer is locally advanced or has metastasized and contains one or more specific genetic alterations in the PIK3CA, AKT1, or PTEN genes. It is used after the disease has progressed on at least one prior endocrine-based therapy.
The approval was based on the results of the CAPItello-291 trial, a Phase III study that demonstrated the drug’s effectiveness. This randomized, double-blind trial evaluated the efficacy of adding capivasertib to fulvestrant compared to using fulvestrant with a placebo. The study enrolled patients with HR-positive, HER2-negative advanced breast cancer whose disease had progressed after hormonal therapies.
The trial’s primary measure of success was progression-free survival (PFS), the length of time a patient lives with the disease without it getting worse. In the subgroup of patients whose tumors had the relevant PIK3CA, AKT1, or PTEN alterations, the combination of capivasertib and fulvestrant showed a significant improvement in PFS compared to fulvestrant alone.
For pre- or perimenopausal women undergoing this treatment, it is also combined with a luteinising hormone-releasing hormone (LHRH) agonist. This additional medication works to lower the levels of hormones like estrogen that can fuel cancer growth. The targeted nature of capivasertib is guided by biomarker testing for specific gene alterations.
Side Effects and Patient Management
Treatment with capivasertib is associated with common side effects that require active monitoring and management by a healthcare team. The most frequently reported adverse events include diarrhea, cutaneous adverse reactions (skin toxicities), and changes in certain laboratory values. These side effects are manageable and an expected consequence of the drug’s mechanism.
Some side effects are directly linked to the biological role of the Akt pathway. For example, hyperglycemia, or high blood sugar, can occur because the Akt pathway is involved in the body’s insulin signaling and glucose metabolism. Skin rashes can develop as the pathway also plays a part in the normal growth and maintenance of skin cells.
Managing these side effects is a standard part of the treatment plan. Diarrhea is addressed with anti-diarrheal medications and dietary adjustments, while skin rashes are managed with topical corticosteroids and moisturizers. Patients are closely monitored through regular check-ups and blood tests to detect issues like hyperglycemia early. If side effects become severe, a doctor may recommend a dose reduction or a temporary pause in treatment.