Vepdegestrant

Vepdegestrant (Veppanu) is an oral hormonal therapy approved by the Food and Drug Administration (FDA) to treat certain people with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer that has an ESR1 mutation.

Vepdegestrant is the first proteolysis-targeting chimera (PROTAC) approved to treat breast cancer. PROTACs are a newer type of medicine that targets estrogen receptors that help some breast cancers grow.

Vepdegestrant works differently from other hormonal therapies used to treat hormone receptor-positive breast cancer, including selective estrogen receptor degraders (SERDs) such as fulvestrant (Faslodex), elacestrant (Orserdu), and imlunestrant (Inluriyo).

How vepdegestrant works

Some breast cancers use estrogen receptors to receive signals that help cancer cells grow and divide.

When advanced hormone receptor-positive breast cancer stops responding to hormonal therapy, such as aromatase inhibitors, it can sometimes be because the cancer has developed a mutation in the ESR1 gene. This mutation can cause estrogen receptors to stay active and continue signaling cancer cells to grow, even when estrogen is not directly activating the receptors.

SERDs are designed to attach to estrogen receptors and help break them down. By reducing the number of estrogen receptors available, these medicines can help slow or stop cancer growth.

Vepdegestrant is part of a newer class of medicines called PROTACs. It attaches to estrogen receptors and helps mark them for destruction. The cell’s natural waste-disposal system then recognizes those receptors and breaks them down.

Unlike other hormonal therapies that simply block estrogen receptors, vepdegestrant helps remove the receptors themselves. After helping target one receptor for destruction, the medicine can move on to help target others.

Researchers believe this approach may be especially useful in cancers that have developed ESR1 mutations. These mutations can make some hormonal therapies less effective. By actively targeting estrogen receptors for removal, vepdegestrant may help overcome some forms of treatment resistance.

Although vepdegestrant has shown promising results, researchers are still studying how it compares with oral SERDs and how best to use it alongside other treatments.

What the research shows

The FDA approved vepdegestrant based on results from a clinical trial called VERITAC-2.

The study enrolled 624 adults with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer whose cancer had stopped responding to hormonal therapy.

Participants received either vepdegestrant, taken by mouth once daily, or fulvestrant injections. Among people whose cancers had ESR1 mutations, people remained on vepdegestrant treatment for a median of 5.1 months, compared with 2.8 months for those who received fulvestrant.

Researchers found that vepdegestrant worked better than fulvestrant for people whose cancers had an ESR1 mutation. People who took vepdegestrant lived longer without their cancer growing or spreading than people who received fulvestrant.

These results led the FDA to approve vepdegestrant for people with ESR1-mutated, hormone receptor-positive, HER2-negative advanced or metastatic breast cancer.

Who gets vepdegestrant

Vepdegestrant is approved for adults with:

• Hormone receptor-positive, HER2-negative advanced or metastatic breast cancer
• An ESR1 mutation
• Disease that has progressed after at least one line of hormonal therapy

Your healthcare team may order testing to determine whether your cancer has an ESR1 mutation and whether vepdegestrant may be an appropriate treatment option.

ESR1 mutation testing

Hormonal therapies work by blocking estrogen’s ability to help breast cancer grow. Over time, however, some hormone receptor-positive breast cancers develop mutations in the ESR1 gene that allow estrogen receptors to remain active despite treatment.

ESR1 mutations can become more common after treatment with aromatase inhibitors and other hormonal therapies. Because of this, your healthcare team may recommend ESR1 mutation testing if your cancer progresses during or after treatment.

Having an ESR1 mutation does not mean there are no treatment options. Several therapies are now available that specifically target cancers with ESR1 mutations.

ESR1 mutations can be identified through a blood test that looks for circulating tumor DNA (ctDNA) or through testing performed on tumor tissue. When the FDA approved vepdegestrant, it also approved the Guardant360 CDx blood test to detect ESR1 mutations. The test can confirm whether a person is eligible to take vepdegestrant. Other tests can also be used to find ESR1 mutations. Learn more about ESR1 mutation testing.

How vepdegestrant is given

Vepdegestrant is a pill taken by mouth once a day with food. Try to take it at about the same time each day.

Your doctor will tell you how many tablets to take. Do not change your dose or stop taking vepdegestrant unless your doctor tells you to.

Premenopausal and perimenopausal women and men who take vepdegestrant may also receive a gonadotropin-releasing hormone (GnRH) agonist, a medicine that lowers the amount of estrogen or testosterone made by the body.

Talk with your care team about what to do if you miss a dose, vomit after taking vepdegestrant, or have trouble taking the medicine as prescribed.

Side effects and things to remember

Vepdegestrant can cause side effects. Some side effects are mild, while others may be more serious.

Common side effects include:

• Nausea and vomiting
• Fatigue
• Decreased appetite
• Diarrhea
• Constipation
• Menopausal symptoms like hot flashes
• Joint pain
• Muscle pain
• Headache

Your care team can help you manage side effects. Tell them about any new symptoms, symptoms that get worse, or symptoms that make it hard to take vepdegestrant as prescribed.

Vepdegestrant can also affect the heart’s electrical rhythm. This is called QTc interval prolongation. Before starting vepdegestrant, your doctor may order an electrocardiogram, also called an ECG or EKG, to check your heart rhythm. Your doctor may also check your heart rhythm again during treatment.

Vepdegestrant can harm an unborn baby. Tell your doctor if you are pregnant, planning to become pregnant, or could become pregnant. Your doctor can talk with you about birth control options during treatment.

Taking other medicines and supplements with vepdegestrant

Some medicines and supplements can interact with vepdegestrant. These interactions can change how much vepdegestrant is in your body, make side effects more likely, or make vepdegestrant less effective.

Before starting vepdegestrant, tell your care team about all prescription medicines, over-the-counter medicines, vitamins, and supplements you take. Do not start, stop, or change any medicine or supplement without talking with your care team.

If you take any of the medicines or supplements below and need to keep taking them, ask your doctor about your options. These are examples and not complete lists.

Medicines that slow down how quickly the body processes vepdegestrant

Some medicines and supplements can slow down how quickly the body processes vepdegestrant. This can increase the amount of vepdegestrant in the body and may increase the risk of side effects.

Examples include:

• Antifungal medicines, such as itraconazole (Sporanox, Tolsura, Onmel) and ketoconazole
• Antibiotics, such as clarithromycin (Biaxin)
• Certain HIV medicines, such as atazanavir (Reyataz)
• Certain antidepressants, such as nefazodone
• Grapefruit or grapefruit juice
• Goldenseal, an herbal supplement sometimes used for colds, digestive symptoms, or other health concerns

Medicines that speed up how quickly the body processes vepdegestrant

Some medicines and supplements can speed up how quickly the body processes vepdegestrant. This can lower the amount of vepdegestrant in the body and may make it less effective.

Examples include:

• Seizure medicines used to treat epilepsy and other seizure disorders, such as:
• Carbamazepine (Tegretol, Carbatrol)
• Phenytoin (Dilantin)
• Rifampin (Rifadin, Rimactane), an antibiotic used to treat tuberculosis and other infections
• St. John’s wort, an herbal supplement sometimes used for depression

Other medicines that interact with vepdegestrant

There are other medicines that may interact with vepdegestrant because vepdegestrant can increase the amount of those medicines in the body. This can increase the risk of serious side effects from those medicines.

Examples include:

• Some medicines used after organ transplant, such as cyclosporine
• Some heart medicines, such as digoxin
• Some cholesterol medicines, including certain statins
• Some anesthesia medicines, such as propofol
• Some pain medicines, such as acetaminophen

Vepdegestrant can also interact with medicines that affect the heart’s electrical rhythm. These are sometimes called medicines that prolong the QTc interval. If you take one of these medicines, your doctor may recommend additional heart monitoring or a different treatment plan.