What to Know About Lynparza (Olaparib)

Lynparza (olaparib) is a medication for cancer that is classified as a poly adenosine diphosphate–ribose polymerase (PARP) inhibitor. Lynparza is currently approved by the Food and Drug Administration (FDA) for some people with metastatic ovarian cancer, as well as people with high-risk early-stage and metastatic breast cancer or metastatic pancreatic cancer who have BRCA mutations. It is an oral therapy that is taken twice daily, and when used appropriately may significantly improve progression-free survival.

The most common side effects include nausea, fatigue, and anemia. Since Lynparza is taken daily, management of these side effects is important, and sometimes a decrease in dose is needed. That said, studies suggest that the medication is well tolerated, and may still be very effective even when a reduced dose is needed.

Uses

Lynparza has different indications and criteria for ovarian cancer (including fallopian tube cancer and primary peritoneal cancer), breast cancer, and pancreatic cancer. The indications and effectiveness will be discussed separately for each cancer.

Unlike some medications that have similar effects, on average, among different people, the effectiveness of Lynparza can vary significantly from person to person depending on gene mutation status.

How It Works

PARP inhibitors work by interfering with the repair of damaged DNA in tumor cells. PARP enzymes play an important role in the cell by repairing damaged DNA. The body has several genes that function to make proteins that repair this ongoing damage. In cells that already have inadequate DNA repair (due to a BRCA or similar type of mutation), inhibiting PARP can prevent damaged cancer cells from repairing themselves, and subsequently lead to their death.

Many people find it confusing why these drugs work much better in people who have mutations such as BRCA mutations, so describing the mechanism can be helpful.

Genes such as BRCA genes are considered tumor suppressor genes. They provide the blueprint for proteins that repair damaged DNA, specifically, repair double-stranded breaks in DNA. While this dysfunction in gene repair accounts for the genetic predisposition to cancer in people who have BRCA mutations, this can also be exploited now to treat cancer.

Unlike the proteins produced by BRCA genes, PARP enzymes play a critical role in the repair of single-stranded DNA breaks. Ordinarily, if these PARP enzymes were inhibited, the cell could compensate. But when cells are also unable to repair double-stranded breaks, the cells may be damaged beyond repair. When tumor cells are subsequently not repaired, they are unable to reproduce, and the growth of the tumor is halted.

This explains why PARP inhibitors seem to be much more effective in people who carry a BRCA mutation; cancer cells with BRCA mutations rely more heavily on PARP proteins to repair their DNA than do cells that do not have the mutations.

There are other genes (such as some of the non-BRCA genes that raise breast cancer risk) that are also involved in DNA repair. Cells that carry these abnormal genes are said to have defects in homologous recombination repair. This explains why PARP inhibitors may be effective not only in people who have BRCA mutations associated with cancer, but non-BRCA mutations in genes that play a role in DNA repair.

Gene Mutations and Cancer

Since Lynparza carries indications for people who have specific gene mutations, it's helpful to briefly discuss these. There are two types of gene mutations that are often discussed with cancer.

• Germline (hereditary) mutations: These mutations are inherited from a parent and are present in every cell in the body.
• Somatic (acquired) mutations: These mutations are acquired after birth, usually in the process of a cell becoming a cancer cell. They are present only in the tumor, and not all the cells of the body. Genetic testing, for example, to determine if a targeted therapy would be indicated for lung cancer, looks for acquired gene mutations.

This distinction is important when discussing Lynparza. For example, the drug is currently approved for people with breast cancer who have a hereditary BRCA mutation. With ovarian cancer, however, the drug may be used both for those who have a hereditary BRCA mutation and those who have tumors that are positive for acquired BRCA mutations.

Breast Cancer

Lynparza has been approved to treat both high-risk early-stage and metastatic HER2 negative breast cancer in people who have a known or suspected germline (hereditary) BRCA mutation. It is indicated for people who have previously been treated with chemotherapy (either at the time of initial diagnosis or later). For people who have estrogen-receptor-positive tumors, endocrine therapy (such as an aromatase inhibitor or tamoxifen) should have previously been used if possible.

For people meeting these criteria, a 2017 study in the New England Journal of Medicine found that Lynparza provided a greater survival benefit than currently available approved treatments. The median progression-free survival was 2.8 months longer, and the risk of progression or death was 42% lower than with standard therapy.

Ovarian Cancer/Fallopian Tube/Primary Peritoneal Cancer

Lynparza has more than one recommendation for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer. These include:

• As maintenance therapy for adults with recurrent epithelial ovarian cancer (including fallopian tube and primary peritoneal cancer) who have had a partial or complete response to platinum-based chemotherapy. Platinum-based chemotherapy includes chemotherapy with drugs such as Platinol (cisplatin) or Paraplatin (carboplatin).
• For the treatment of adult patients who have a known or suspected germline or acquired BRCA mutation who have received three or more lines of chemotherapy (a line of chemotherapy is a course of treatment with a particular regimen and may include several infusions).

Unfortunately, for those who initially respond to chemotherapy (either a complete or partial response), recurrence is extremely common and often occurs relatively rapidly. The chance that an ovarian cancer will recur after cytoreductive surgery and chemotherapy is 70% over the next three years. When recurrent, the disease is no longer curable, and has traditionally been treated with repeated lines of chemotherapy for the remainder of a person's life. This risk of recurrence (or progression) may be greatly reduced with the use of Lynparza.

In a 2018 study in the New England Journal of Medicine, patients who were newly diagnosed and had completed primary treatment with surgery and chemotherapy were randomly assigned to receive either Lynparza or a placebo. After a median follow-up of 41 months, the risk of progression or death was 70% lower in the group taking Lynparza than in the group receiving the placebo.

It's important to note that, in clinical trials, people with non-BRCA-associated mutations (either hereditary or in their tumor alone) in genes involved with DNA repair also did much better on Lynparza than on standard therapy. The term used to describe these other genes involved in DNA repair is "homologous-recombination deficiency" (HRD) genes.

A 2019 study looked at the effect of adding Lynparza to bevacizumab as first-line maintenance therapy with ovarian cancer. In this study, it was found that Lynparza significantly improved progression-free survival in those who were BRCA negative but had other gene alterations classified as HRD. This is encouraging, and also reinforces the importance of testing for gene mutations other than BRCA in all patients with ovarian cancer.

Next-generation sequencing can now detect these other mutations in a tumor to help guide personalized therapy. If your oncologist—a physician who specializes in the diagnosis and treatment of cancer—is unfamiliar with this approach, consider getting a second opinion at one of the larger National Cancer Institute–designated cancer centers.

Pancreatic Cancer

In December 2019, Lynparza was approved for the maintenance treatment of adults with metastatic pancreatic cancer with a known or suspected germline BRCA mutation if their cancer has not progressed for at least 16 weeks on platinum-based chemotherapy. The presence of a BRCA mutation should be detected on an FDA-approved test.

A 2019 study in the New England Journal of Medicine found that among people with metastatic pancreatic cancer harboring a germline BRCA mutation, progression-free survival was longer in those treated with Lynparza than in those who were treated with a placebo.

(While many people are familiar with the link between BRCA genes and breast and ovarian cancer, BRCA2 gene mutations are associated with an increased risk of developing pancreatic cancer as well.)

Before Taking

Before taking Lynparza, it's important to discuss the goal of therapy and potential side effects carefully with your oncologist. Since the drug works better in some people than others, it's important to understand these differences when making a decision about your treatment.

Precautions and Contraindications

There are several issues to consider before taking Lynparza, as well as situations when the drug should not be used (contraindications).

Lynparza should not be used during pregnancy, as there is a significant risk of birth defects. Effective birth control should be used throughout treatment and for at least six months following the last dose.

The drug should not be used by people who are breastfeeding.

Any allergies should be discussed with your healthcare provider.

At the current time, it's not known how treatment with Lynparza may differ in patients who are elderly.

Drug Interactions

Lynparza should be avoided in people who are taking medications that are considered CYP3A inhibitors (these could increase the effect of Lynparza) or inducers (these could decrease the effect of Lynparza).

Examples of CYP3A inhibitors include:

• Antifungals such as Nizoral, Extina, or Xolegel (ketoconazole), Diflucan (fluconazole), Onmel or Sporanox (itraconazole), Noxafil (posaconazole), and Vfend (voriconazole)
• Some antibiotics, such as Biaxin (clarithromycin), E.E.S. and others (erythromycin), and Cipro (ciprofloxacin)
• Some antinausea medications, such as Emend (aprepitant) and Akynzeo (netupitant)
• Some heart/blood pressure medications, such as Cardizem or Tiazac (diltiazem), Verelan (verapamil), and Cordarone (amiodarone)
• Prilosec (omeprazole)
• Some HIV medications and medications used to treat hepatitis C, including Reyataz, Evotaz (atazanavir), Prezista (darunavir), Sustiva, Atripla (efavirenz), Intelence (etravirine), Lexviva (fosamprenavir), Crixivan (indinavir), Viracept (nelfinavir), Kaletra (ritonavir/lopinavir), Invirase (saquinavir)
• Some nutritional supplements, such as goldenseal
• Grapefruit

Examples of CYP3A inducers include:

• Rifamate (rifampin)
• Some seizure medications, such as phenobarbital, Dilantin (phenytoin), and Tegretol (carbamazepine)
• Corticosteroids
• Provigil (modafinil)
• Some dietary supplements, for example, St. John's wort
• Chronic alcohol use can function as an inducer

It's important to note that there are different degrees of CYP3A inhibition (for example, potent, strong, moderate, and weak inhibitors), so it's critical to talk to your healthcare provider about any medication you are taking. For example, two moderate inhibitors might add up to be a potent inhibitor.

Other PARP Inhibitors

In addition to Lynparza, other FDA-approved PARP inhibitors include:

• Rubraca (rucaparib): Rubraca is approved for ovarian cancer following two rounds of chemotherapy or as a maintenance therapy.
• Zejula (niraparib): This drug is approved only for maintenance therapy in people with ovarian cancer that is sensitive to platinum chemotherapy.
• Talzena (talazoparib): Talzena is approved for metastatic or locally advanced HER2-negative BRCA-positive breast cancer.

Dosage

According to the manufacturer, Lynparza is taken orally (by mouth) at 300 milligrams (mg) twice daily, with the doses taken 12 hours apart.

It is available as both tablets and capsules of either 150 mg or 100 mg. Check your prescription and talk to your healthcare provider to make sure you are taking the correct dose for your particular situation.

The tablets should be swallowed whole, and not chewed, crushed, or divided.

Lynparza may be taken with or without food.

Grapefruit, grapefruit juice, Seville oranges (bitter orange), and Seville orange juice must be avoided while taking Lynparza.

If you miss a dose of your medication, you should take your next dose at the scheduled time (do not take an extra dose). If you take too much of your medication, call your oncologist.

Modifications

For people with moderate kidney disease (renal disease), the dosage of Lynparza may need to be reduced. For those who have a creatinine clearance of 31 to 50 milliliters per minute (mL/min), the dosage should be reduced to 200 mg twice daily. With liver test abnormalities, the medication may need to be held if:

• Transaminases (SGOT or ALT, etc.) are more than five times the upper limit of normal
• Bilirubin is three times the upper limit of normal
• Alkaline phosphatase is more than two times the upper limit of normal

With some medications, for example, if a medication classified as a CYP3A4 inhibitor is needed, dosage adjustments may be needed.

Dose reductions are often needed due to side effects such as nausea, fatigue, and anemia. A 2019 study looking at half-dose Lynparza in patients with ovarian cancer found that the lower doses were both safe and effective. Due to the frequency of side effects (and since this is a medication that must be taken daily as long as it is effective), the researchers advised that treatment guidelines for Lynparza should make note of this effectiveness even when lower doses are needed.

How to Take and Store

Lynparza should be stored at room temperature (between 68 and 77 degrees Fahrenheit), and kept in the original bottle to reduce moisture. Avoid keeping your medication in a humid environment, such as the bathroom.

Side Effects

As with most cancer drugs, there are both common and sometimes serious side effects associated with the use of Lynparza.

Common

The most common side effects, occurring in 10% or more of people, include:

• Nausea: Nausea is the most common side effect of Lynparza, with roughly 70% of people experiencing some degree of it (usually mild). It's important to avoid antinausea medications that are listed above under drug interactions, such as Emend. For medications that have a moderate to high "emetic risk," or risk of nausea, such as Lynparza, the National Comprehensive Cancer Network (NCNN) recommends a serotonin (5-HT3) receptor antagonist, such as the medication Zofran (ondansetron), 8 mg to 16 mg daily, roughly 30 minutes before taking a PARP inhibitor. Since Lynparza is taken twice daily, this may need to be taken twice daily. The NCCN also has several alternative recommendations for those who do not tolerate or respond to this regimen.
• Fatigue
• Anemia: Most often anemia is mild, but in some cases may require a transfusion.
• Vomiting
• Abdominal pain
• Diarrhea
• Dizziness
• Neutropenia
• Joint and/or muscle pain
• Headache
• Taste changes
• Decreased appetite
• Constipation
• Mouth sores
• Thrombocytopenia

Severe

There is the potential for a few less common but serious adverse reactions related to Lynparza, including:

Myelodysplastic syndrome (MDS): Myelodysplastic syndrome occurs in less than 1.5% of people taking the medication. Blood tests (including a complete blood count) are done at baseline and then every month to monitor any changes.

Acute myeloid leukemia (AML): Acute myeloid leukemia is a potential adverse reaction with Lynparza as with chemotherapy. It is thought to be uncommon, occurring in roughly 1% of people.

Pneumonitis: Pneumonitis, or inflammation of the lungs, has been seen uncommonly with Lynparza (less than 1% of the time).

Payment Assistance

Lynparza, like most newer cancer drugs, is expensive. If you are struggling with the cost, there are options that can be explored.

The drug company AstraZeneca has two programs that may be helpful:

• AstraZeneca AZ&Me Prescription Savings Program
• AstraZeneca Access 360 program

Talking with a social worker or pharmacist at your cancer center can also be very helpful. They could help you look into assistance through your cancer center, through one of the nonprofit organizations supporting your cancer, and more.

Often overlooked is that many of these expenses are tax-deductible, and it's surprising how quickly medical deductions for cancer add up to a significant refund.

Resistance

As with many types of cancer treatment, Lynparza may stop working in time. How soon this occurs overall is uncertain due to the newness of the drug. As with other forms of resistance, it's thought that tumors mutate in a way that allows them to bypass the actions of the drugs. For example, with ovarian cancer, some cells have actually reversed their BRCA mutations.

A Word From Verywell

Lynparza now offers an additional therapy for some people with metastatic breast, ovarian, or pancreatic cancer that appears to reduce the risk of disease progression or death beyond standard therapies available to date. Unfortunately, every treatment brings side effects, and with a medication that must be taken twice a day indefinitely, this can be challenging.

It is important to bring a list of all other medicines and supplements you are taking to your oncologist and pharmacist. Other medicines and supplements can interfere with each other and cause a drug interaction. As a tip, having all your prescriptions filled at the same pharmacy will help avoid possible interactions.

If you are experiencing side effects that are interfering with your quality of life, talk to your healthcare provider. Unlike some medications that are much less effective when used at a lower dose, reducing the dose of Lynparza instead of eliminating the medication entirely may help you obtain the benefit of treatment while maximizing your quality of life.

When coping with side effects, it can also be helpful to compare not only the side effects you would have with or without the drug, but also what you might be experiencing without the drug. Certainly, there are many symptoms associated with a cancer that is growing and spreading, and if a drug such as Lynparza can slow this growth and spread, it may reduce the chance of symptoms you would otherwise be experiencing.

Understanding your treatment plan and asking a lot of questions is more important than ever, as oncology is changing so rapidly. Being your own advocate in your care can not only help you feel more in control during this challenging time, but may possibly even affect your outcome.