Olaparib

Ovarian, Fallopian Tube, and Peritoneal Cancers

Olaparib is used for the treatment and maintenance of advanced ovarian cancer, fallopian tube cancer, and primary peritoneal cancer. It is often prescribed in the following situations:

• Maintenance treatment: To help keep the cancer from returning after it has responded to platinum-based chemotherapy.
• Advanced cancer: For patients with a specific abnormal BRCA gene who have already received multiple rounds of chemotherapy.

Breast Cancer

This medication is used to treat certain types of metastatic breast cancer that have spread to other parts of the body. It is typically prescribed for patients with a BRCA gene mutation whose cancer is HER2-negative and who have previously been treated with chemotherapy.

Pancreatic Cancer

Olaparib is used as a maintenance treatment for metastatic pancreatic cancer in patients with a BRCA mutation. It is used when the cancer has not progressed after at least 16 weeks of a first-line platinum-based chemotherapy regimen.

Prostate Cancer

It is used to treat metastatic castration-resistant prostate cancer (mCRPC) in adults with specific genetic mutations, such as BRCA or other homologous recombination repair (HRR) genes. For certain types of prostate cancer, it may be used in combination with other medications, such as abiraterone and prednisone.

Mechanism of Action

Olaparib belongs to a class of medications called poly (ADP-ribose) polymerase (PARP) inhibitors. PARP is a natural enzyme found in cells that helps repair damaged DNA. In healthy cells, this repair process is essential for survival.

Cancer cells also use PARP to fix DNA damage. When olaparib blocks the PARP enzyme, it prevents the cancer cells from repairing certain types of DNA breaks. This leads to an accumulation of genetic damage within the cell.

Targeting Specific Mutations

Olaparib is particularly effective against cancer cells that have specific genetic mutations, such as BRCA1 or BRCA2. These mutations already limit the cell's ability to repair DNA through other pathways. By blocking the PARP pathway as well, olaparib leaves the cancer cell with no way to fix its DNA, eventually causing the cell to die.

This process helps to:

• Slow the growth of the tumor.
• Shrink existing tumors.
• Delay the progression of the disease.

Common Side Effects

• Nausea and vomiting
• Diarrhea or constipation
• Fatigue or weakness
• Loss of appetite
• Changes in taste
• Headache or dizziness
• Mouth sores
• Muscle or joint pain
• Cough or shortness of breath

Serious Side Effects

Olaparib may cause serious side effects that require immediate medical attention. These include:

• Low blood cell counts: This medication can lower red blood cells (anemia), white blood cells (neutropenia), and platelets (thrombocytopenia). Symptoms may include fever, chills, unusual bleeding or bruising, and extreme tiredness.
• Bone marrow problems: In rare cases, olaparib can lead to serious conditions like Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML).
• Lung problems: Inflammation of the lungs (pneumonitis) can occur. Seek help for new or worsening shortness of breath, cough, or wheezing.
• Blood clots: Symptoms may include pain or swelling in the legs, chest pain, or sudden shortness of breath.

Serious Blood Disorders

Olaparib may increase the risk of developing serious bone marrow or blood cancers, such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). These conditions can be life-threatening. Healthcare providers usually monitor blood cell counts before and during treatment to check for signs of these disorders. If blood counts do not recover within a certain timeframe, the medication may be paused or discontinued.

Lung Problems

Inflammation of the lungs, known as pneumonitis, has occurred in some people taking this medication. Symptoms to watch for include new or worsening shortness of breath, cough, wheezing, or fever. If these symptoms occur, treatment may need to be interrupted while the cause is investigated.

Blood Clots

There is an increased risk of blood clots in the veins (venous thromboembolism), including pulmonary embolism, particularly when olaparib is used in combination with certain other medications for prostate cancer. Signs of a blood clot may include swelling or pain in an arm or leg, chest pain, or sudden shortness of breath.

Pregnancy and Breastfeeding

Olaparib can cause harm to a developing fetus. It is important to use effective birth control during treatment and for a specific period after the last dose. Male patients with pregnant partners or partners who can become pregnant should also use effective contraception. Breastfeeding is generally not recommended during treatment and for one month following the final dose.

Monitoring

Regular laboratory tests are necessary to monitor for side effects, including:

• Complete blood counts (CBC) to check for anemia, low white blood cells, or low platelets.
• Kidney function tests, as the dose may need adjustment for those with kidney impairment.

Pregnancy

Olaparib may cause serious harm to a developing fetus. Healthcare providers typically require a pregnancy test before starting this medication to ensure the patient is not pregnant. It is important to discuss reproductive health and potential risks with a doctor before beginning treatment.

Effective contraception is necessary for both men and women during and after treatment:

• Females: Use effective birth control during treatment and for at least 6 months after the final dose.
• Males: Use effective contraception, such as condoms, during treatment and for at least 3 months after the final dose if a partner is pregnant or could become pregnant. Males should also avoid donating sperm during this time.

Breastfeeding

It is currently unknown whether olaparib passes into human breast milk. Because of the risk of serious adverse reactions in a nursing child, breastfeeding is not recommended during treatment and for at least 1 month after the last dose. Patients should talk to their healthcare provider about the safest way to feed their infant while taking this medication.

Available Forms

Olaparib is supplied for oral administration in the following forms:

• Tablets
• Capsules

It is important to note that olaparib tablets and capsules are not interchangeable. These two forms have different bioavailability and are not substituted for one another on a direct basis. Patients should only use the specific form prescribed by their healthcare provider and should not switch between tablets and capsules unless specifically instructed to do so.

FDA Approval and Indications

Olaparib was first approved by the FDA as a PARP inhibitor. It is currently approved for the treatment of several specific types of cancer, often depending on the presence of certain genetic biomarkers such as BRCA mutations.

Approved indications include:

• Ovarian Cancer: Used for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. It is also approved for first-line maintenance in BRCA-mutated advanced ovarian cancer.
• Breast Cancer: Approved for patients with germline BRCA-mutated, HER2-negative metastatic breast cancer who have previously received chemotherapy.
• Prostate Cancer: Approved for certain patients with metastatic castration-resistant prostate cancer (mCRPC), including those with HRR gene mutations or in combination with abiraterone for BRCA-mutated cases.
• Pancreatic Cancer: Used as a maintenance treatment for patients with germline BRCA-mutated metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.

Biomarker Testing

The FDA labeling for olaparib includes information regarding pharmacogenomic biomarkers. Treatment eligibility is often determined by FDA-approved companion diagnostic tests that identify BRCA1, BRCA2, or other homologous recombination repair (HRR) gene mutations.

Regulatory Requirements

Olaparib is a prescription-only medication. While it does not currently have a Boxed Warning, the FDA requires monitoring for serious potential risks such as myelodysplastic syndrome or acute myeloid leukemia, which have been reported in clinical trials.

Indications for Breast Cancer

Olaparib is used to treat adults with a specific type of inherited (germline) BRCA-mutated, HER2-negative metastatic breast cancer. It is typically prescribed for patients who have already received chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. If the cancer is hormone receptor (HR)-positive, patients should have also received endocrine therapy or be considered inappropriate candidates for it.

Additionally, olaparib is approved as an adjuvant treatment for patients with germline BRCA-mutated, HER2-negative high-risk early breast cancer who have previously been treated with chemotherapy before or after surgery.

Mechanism of Action

As a PARP inhibitor, olaparib blocks an enzyme called poly (ADP-ribose) polymerase (PARP) that helps repair DNA. Because BRCA-mutated cancer cells already have a limited ability to repair DNA, blocking the PARP enzyme causes DNA damage to accumulate to a point where the cancer cells can no longer survive.

Required Testing

Treatment with olaparib requires confirmation of a germline BRCA mutation. Healthcare providers use specific FDA-approved companion diagnostic tests to determine if a patient's genetic profile makes them a candidate for this therapy.