Capivasertib: Redefining the Fight Against Breast Cancer

What Is Capivasertib?

For the treatment of breast cancer, a drug called "Capivasertib" is used. It is used explicitly for a specific type of breast cancer. To be precise, those breast cancers with human epidermal growth factor receptor 2 (HER2)-negative, hormone receptor-positive breast cancer that has spread locally or metastasised can be considered.

Capivasertib was granted FDA approval by the United States Food and Drug Administration (USFDA) on November 16th, 2023. It is a common practice to combine Capivasertib with Fulvestrant, which is another drug for breast cancer.

Drug Group:

Capivasertib belongs to the class of drugs known as kinase inhibitors. This group of drugs specifically targets enzymes involved in cell division and proliferation.

Capivasertib acts as a treatment for advanced breast cancer by blocking abnormal proteins that are essential in triggering the growth of cancer cells. Capivasertib can slow down or prevent the spread of cancer cells by interfering with this signaling system.

Because of this mechanism, Capivasertib is considered a valuable tool in the management of advanced breast cancer, especially when the cancer has progressed to other body parts. The medication functions as a precision medicine in treating this particular type of cancer because of its targeted action on particular cellular processes.

What Is Capivasertib Used For?

Capivasertib breast cancer treatment is approved for individuals with a certain kind of metastatic or advanced breast cancer. It is often advised to be given in combination with Fulvestrant.

This treatment is meant for people whose breast cancer is

• Is hormone-receptor positive (HR-positive).

• Is HER2-negative.

• Has certain genetic modifications known as PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), AKT1 (AKT serine or threonine kinase 1), or PTEN (phosphatase and tensin homolog).

An FDA-approved test is required to verify these changes. Then, only this treatment will be started. Patients whose cancer has returned within a year of finishing adjuvant therapy or whose cancer has progressed after trying at least one hormonal therapy in the advanced stage are also advised to pursue this treatment.

Contraindications:

Capivasertib should not be used in patients with a strong allergic reaction (severe hypersensitivity) to Capivasertib.

Dosage Forms and Available Strengths

Capivasertib comes in two strengths:

• 160 mg (Milligram) Tablets: These are round, beige-colored, and film-coated. They have 'CAV' above '160' engraved on one side, while the other side is plain.

• 200 mg Tablets: These are capsule-shaped, beige-colored, and have a film coating. On one side, they are marked 'CAV 200'; on the other, they are plain.

For Patients

What Is Capivasertib?

Capivasertib is basically a medicine that is used for the treatment of a particular type of breast cancer. Certain advanced and metastatic breast cancer patients can benefit from this medicine, as it is best suited for them. It selectively blocks a protein called "AKT" (Ak strain transforming).

The AKT protein helps certain cancer cells survive and grow. So, once Capivasertib blocks that protein, it becomes difficult for those cancer cells to multiply and spread. However, it can be effective for cancers that depend on this particular protein. That is the reason why Capivasertib doesn’t work for all cancers.

How Does Capivasertib Work?

There is a signaling pathway inside our cells called the PI3K (phosphatidylinositol 3-kinase) AKT pathway. This pathway has strong control over our cell growth and survival, like a control switch. This pathway shows overactivity in certain cancers due to the presence of specific mutated genes involved in it.

Capivasertib blocks or reduces AKT activity. As AKT activity reduces, the signal for cancer cell division also reduces. That is how this super-powerful medicine helps slow down cancer and its progression.

This medicine is particularly useful if you are someone with breast cancer having any of these gene changes, like PIK3CA, AKT1, or PTEN. These genetic changes make the cancer cell more dependent on the PI3K AKT pathway.

Why Is Capivasertib Prescribed?

Once your breast cancer stops responding to the conventional hormone treatment, your doctor may suggest Capivasertib to you. It is prescribed for those whose cancer has progressed and spread to other areas despite them being on hormone treatment.

It is also used if your breast cancer returns within 12 months after your adjuvant treatment. In both these cases, doctors may consider Capivasertib. However, certain criteria must be met before prescribing them. The breast cancer must be HR-positive, HER2-negative, and locally advanced.

In addition, Capivasertib is used in conjunction with Fulvestrant. It inhibits the abnormal protein that helps cancer cells grow, thereby slowing or stopping their ability to spread.

How Should I Use Capivasertib?

Capivasertib is given orally as pills twice a day, about 12 hours apart, with or without food. The course of Capivasertib therapy is quite unique. You will have to take the medicine only for the first four days of a seven-day cycle.

You don’t need to take it during the last 3 days of the same seven-day cycle; those three days are off days. The cycle repeats like this every week. For the first 4 days, you will be on medication, and for the last 3 days, you won't take any. The doctor will determine how long to repeat the cycle.

It is recommended that the tablets be consumed whole, with water, without being divided, chewed, or crushed. Capivasertib should not be taken if vomiting occurs; the usual dosing regimen should be continued the next day.

The doctor may adjust the dosage or course of treatment for Capivasertib based on the individual's response and any Capivasertib side effects they experience. Even if one feels better, it is crucial to keep taking Capivasertib. In fact, you should only stop taking it after talking to your doctor.

When treating breast cancer, patients who have not gone through menopause or who are in the early stages may also be prescribed Goserelin or Leuprolide in addition to Capivasertib and Fulvestrant.

If you have any confusion regarding its dosing regimen, reach out to our Oncologist.

What Is the Prescribed Dosage and Method of Administration for Capivasertib?

• Choosing a Patient: Patients with advanced or metastatic breast cancer who are HR-positive, HER2-negative, and have specific genetic alterations (PIK3CA, AKT1, or PTEN) can only be considered for Capivasertib treatment.

• Assessment Suggested Before Beginning Capivasertib: Your glycated hemoglobin (HbA1C) and fasting blood glucose (FG) levels should be checked before beginning Capivasertib. This evaluation aims to identify potential problems, and it should be performed both before and during treatment.

• Suggested Dosage and Administration: 400 mg twice daily for four days, followed by three days off, is the recommended Capivasertib dose when taken with Fulvestrant. This cycle continues until the disease worsens or its adverse effects become intolerable. Capivasertib tablets should be swallowed whole; do not break or crush them.

• Adjustments to Dosage for Severe and Mild CYP3A Inhibitors: Strong CYP3A (cytochrome P450 3A) inhibitors should not be taken with Capivasertib. The doctor will reduce the dosage of Capivasertib if avoidance is not possible.

Moderate CYP3A inhibitors should have their doses adjusted appropriately. Once these inhibitors are stopped, return to the Capivasertib dosage given before starting the inhibitor after three to five half-lives of the inhibitor.

What Are the Side Effects of Capivasertib?

Capivasertib is a cancer medicine, so yes, it does have some sort of side effects, like every other cancer medicine.

Contact the doctor if you experience any of the following symptoms, especially if they are severe or continue:

• Throwing up.

• Reduced appetite.

• Weakness.

• Headache.

• Dysentery (an intestinal infection that results in bloody diarrhea).

• Oral lesions.

Some adverse effects may be dangerous. The following symptoms should be noticed immediately. Stop taking the drug, call the doctor, or get emergency care if you notice any of these:

• Fever and symptoms similar to the flu.

• Frequent, loose, or watery stools; stomach cramping.

• Weakness, reduced urine, dry mouth, and ankle or leg swelling.

• Rash, blistering (lips, eyes, or mouth), peeling, dry, or reddish skin.

Furthermore, Capivasertib may have other adverse effects, too. If you experience any odd issues while taking this drug, you should get in touch with your doctor.

What Capivasertib Precautions Should I Follow?

• Allergies: If you have had any allergies to Capivasertib, other drugs, or the chemicals in the Capivasertib tablet form, keep your doctor informed. If you are unsure of the ingredient, ask the pharmacist for an ingredient list; they can help.

• Drug Interaction: Inform your doctor about all prescription and over-the-counter medications, vitamins, supplements, and herbal remedies you take. Dosage modifications or monitoring for adverse effects might be required in such cases.

• Medical Conditions: If you have any medical conditions, be open and tell your doctor beforehand.

• Pregnancy: Tell your doctor if you are pregnant, intend to become pregnant, or are thinking about becoming a father. Pregnancy testing could be necessary before starting therapy. You should use reliable birth control both during and after therapy for quite some time to minimize the risk of getting pregnant. Pregnancy while on this medicine can be harmful to the baby.

• Breastfeeding: The patient should avoid nursing while using Capivasertib.

• Monitoring Blood Glucose: Remember that Capivasertib may raise blood glucose levels. Therefore, you should check blood sugar levels if you have diabetes, as instructed by your physician. If you have symptoms such as intense thirst, frequent urination, hunger, dizziness, disorientation, or weakness, you should contact your doctor.

• Dietary Considerations: Avoid eating grapefruit or drinking grapefruit juice while taking this medication.

Storage: Make sure the container is securely closed, and keep the medication in the same container it arrived in. Room temperature is ideal for its storage, away from sources of heat or moisture, and most importantly, not in the restroom. It is essential to keep the medication out of children's reach because they can readily open their containers.

Disposal: Once the drug Capivasertib has served its purpose, dispose of it in a manner that poses no risk to children, pets, or others. Capivasertib should not be flushed down the toilet. The best course of action is to implement a medication take-back program. Speak with the pharmacist or contact the recycling or trash department. They can help you more with drug take-back initiatives.

Missed Dose: You should take the missed dose as soon as you remember. On the other hand, skip the missed dose and continue with the regular dosing plan if more than 4 hours have elapsed since the scheduled time. Avoid taking two doses to make up for a missed dose.

Overdose: If you take too much of this medicine, call the poison control helpline. You may collapse, have a seizure, struggle to breathe, or be unable to be woken up. So dial emergency services right away.

For Doctors

Pharmacodynamics:

Relationships Between Exposure and Response: The exact relationship between the body's Capivasertib level, its effectiveness, and the time to show results is unknown. However, researchers noted that at doses between 80 and 800 mg, or 0.2 to 2 times the average recommended dosage, adverse effects such as diarrhea, dermatitis, and elevated blood sugar levels were more likely to occur.

Electrophysiology of the Heart: The QTc interval, which measures how long it takes the heart to recharge between beats, did not significantly increase at the normal dose of Capivasertib in terms of the heart's electrical activity.

Mechanism of Action: Capivasertib inhibits the AKT protein, which is involved in cancer cell development. The mechanism of action of Capivasertib specifically inhibits all three AKT isoforms (AKT1, AKT2, and AKT3). Activation of AKT in cancers is typically caused by mutations in AKT itself, modifications to associated proteins such as PIK3CA, or loss of the PTEN protein.

Capivasertib showed the ability to inhibit the growth of breast cancer cells in vitro, particularly those with specific mutations in “AKT1, PIK3CA, or PTEN”. In in vivo experiments, Capivasertib, either alone or in combination with Fulvestrant, effectively inhibited tumor growth in mice. This comprises models of breast cancer with alterations in AKT1, PTEN, and PIK3CA.

Pharmacokinetics: Unless otherwise noted, the mean [% coefficient of variation (% (CV) represents the Capivasertib pharmacokinetic characteristics. The Cmax (the highest concentration of a drug in the blood) is 1,371 ng/mL (nanograms per milliliter) (30 percent), and the steady-state AUC is 8,069 h·ng/mL (37 percent).

Beginning in week two, concentrations normalize on the third and fourth dosage days of every week. On days without dosage, plasma concentrations range from 0.5 percent to 15 percent of the steady-state Cmax. Within the range of 80 to 800 mg (0.2 to 2 times the recommended dosage), AUC and Cmax are dose-related.

Absorption: Tmax (peak time of drug concentration) is roughly one to two hours, and 29 percent of the drug has absolute bioavailability.

Impact of Food: Following treatment with either a low-fat meal (about 400 kcal (kilocalories); fat 26 percent) or a high-fat meal (roughly 1,000 kcal; fat 60 percent), no clinically significant variations in Capivasertib pharmacokinetics were detected.

Distribution: The oral volume of distribution in a steady state is 1,847 L-liter (36 percent). The ratio of plasma to blood is 0.71, and the plasma protein binding is 22 percent.

Elimination: Renal clearance accounts for 21 percent of total clearance; the half-life is 8.3 hours; and steady-state oral clearance is 50 L/h (37 percent CV).

Metabolism: The capivasertib drug molecule is metabolized by CYP3A4 and UGT2B7 (UDP-glucuronosyltransferase 2 Family, Polypeptide B7).

Excretion: The drug molecule is excreted mainly through feces. The mean total recovery after a single 400 mg radiolabeled oral dose was 50 percent in feces and 45 percent in urine.

Drug Interactions:

• Strong Inhibitors of CYP3A: Capivasertib may be exposed to higher levels when taken with potent CYP3A inhibitors. This increased exposure increases the chance of Capivasertib side effects. To mitigate this risk, it is strongly advised to avoid coadministration of Capivasertib with potent CYP3A inhibitors. If avoidance is not an option, it is advisable to reduce the dose of Capivasertib while closely monitoring patients for potential adverse effects.

• Moderate Inhibitors of CYP3A: When used with Capivasertib, moderate CYP3A inhibitors have the same potential to increase Capivasertib exposure as potent inhibitors. Capivasertib is more likely to cause adverse reactions as a result of this higher exposure. To manage this, it is recommended to lower the dose of Capivasertib when co-administered with a moderate CYP3A inhibitor. Patients receiving this combination should be continuously monitored for potential adverse effects.

• Potent and Mild CYP3A Inducers: Conversely, exposure to Capivasertib is reduced by strong or moderate CYP3A inducers. This decrease in exposure may jeopardize the effectiveness of Capivasertib. To alleviate this worry, it is advised against taking Capivasertib in conjunction with strong or moderate CYP3A inducers. The goal is to preserve Capivasertib's therapeutic efficacy in treating the intended illnesses.

Clinical Studies: The efficacy of Capivasertib in combination with Fulvestrant was investigated in a trial comprising 708 adult patients with HER2-negative, HR-positive, locally progressed, or metastatic breast cancer. Progression-free survival (PFS) was significantly improved by the trial, both in the general population and in patients with PIK3CA, AKT1, or PTEN abnormalities.

Major outcomes included PFS, overall survival, objective response rate, and response durability. Patients received either Capivasertib or a placebo. Patients with PIK3CA, AKT1, or PTEN changes benefited significantly from the trial, indicating that Capivasertib is helpful in this particular group. The research provided important insights into the effectiveness of Capivasertib by considering several variables, including age, race, and prior treatments.

Warnings and Precautions:

• Hyperglycemia: The medicine Capivasertib may cause hyperglycemia or elevated blood sugar. Some patients experienced severe instances, particularly those who required insulin or had type 1 diabetes.

It is essential to regularly check blood sugar levels, and patients should call their doctor if they experience symptoms like increased thirst or urination. It may be necessary to modify the course of treatment, and a lifestyle change is advised.

• Diarrhea: Capivasertib can induce diarrhea, and in severe cases, dehydration may result. It is crucial to watch for symptoms; people who experience diarrhea should start taking antidiarrhoeal medication as soon as it appears. Depending on the severity, dose modifications or cessation can be required.

• Cutaneous Adverse Reactions: When using Capivasertib, patients may have skin reactions such as palmar-plantar erythrodysesthesia (redness and pain on palms and soles due to chemotherapy) or erythema multiforme (target-like lesions caused by drugs or illnesses).

It is essential to monitor skin reactions, and seeing a dermatologist as soon as possible is advisable. Depending on the severity, changes to the treatment may be necessary.

• Embryo-Fetal Toxicity: Animal studies indicate that Capivasertib may be harmful to a developing fetus. Effective contraception should be used both during and after therapy for persons who are pregnant or who may become pregnant in the future. Male patients should utilize contraception if they have female partners who are capable of having children. The drug is used in conjunction with Fulvestrant.

Use in Specific Populations:

• Pregnancy: If Capivasertib is used with Fulvestrant, the growing fetus may suffer harm. Pregnant women or those who may become pregnant should be informed of the hazards, as animal studies have demonstrated negative consequences. Since there is no information about Capivasertib use during human pregnancy, caution is advised.

• Lactation: It is unclear how Capivasertib will affect nursing. There is a lack of information regarding Capivasertib’s presence in human milk, and it is advisable to use caution as the possibility for harm to a breastfeeding infant is not ruled out.

• Reproductive Potential: Pregnancy testing is advised before beginning treatment since Capivasertib can be harmful to a fetus. It is recommended that women use effective contraception during and for one month following treatment and that men who have female partners use contraception for four months following the final dose.

• Pediatric Use: There is no evidence of safety or efficacy of Capivasertib in children.

• Geriatric Use: Compared with younger patients, patients over 65 had higher rates of severe adverse events, dose modifications, interruptions, and permanent discontinuations, but there were no appreciable differences in Capivasertib's effectiveness.

• Renal Impairment: Mild-to-severe renal impairment does not require dose modification. There are no data on severe renal impairment.

• Hepatic Impairment: It is not advisable to change the dosage in cases of minor hepatic impairment. Caution is suggested, as moderate impairment may enhance exposure to Capivasertib. There is no data available on severe liver impairment.