What is a PARP Inhibitor and How Does It Treat Ovarian Cancer?

Ovarian cancer is a complex and challenging disease, but recent advancements in targeted therapies like PARP inhibitors are providing new hope for patients. 

PARP inhibitors are an exciting class of drugs that have shown promising results in treating ovarian cancers, particularly those associated with BRCA gene mutations. In this article, we’ll dive into what PARP inhibitors are, how they work, and what ovarian cancer patients can expect from this innovative treatment option. While PARP inhibitors are also used to treat certain breast, prostate, and pancreatic cancers, our focus will be on their application in ovarian cancer.

What is a PARP Inhibitor?

To understand PARP inhibitors, let’s start with the basics. PARP, which stands for poly adenosine diphosphate-ribose polymerase, is a protein that helps cells repair damage to their DNA. DNA damage is a normal occurrence in cells, but when left unrepaired, it can lead to the development of cancer. In some types of cancer cells, including ovarian cancer cells, PARP plays a crucial role in repairing DNA damage through a process called homologous recombination repair (HRR).

PARP inhibitors block the activity of PARP enzymes, preventing them from repairing damaged DNA in cancer cells. By disrupting this repair mechanism, the inhibitors aim to cause the cancer cells to accumulate so much DNA damage that they ultimately die.

How Do PARP Inhibitors Work?

PARP inhibitors work particularly well against cancer cells that already have difficulty repairing their DNA due to gene mutations like BRCA1 or BRCA2. (You can learn more about these ovarian cancer mutations here.) This is because of a concept called “synthetic lethality.”

So, how do PARP inhibitors act on cancerous cells? Imagine a car with two sets of brakes: regular and emergency. If the regular brakes fail, the vehicle can still stop safely using the emergency brakes. But if both sets of brakes fail simultaneously, the car won’t be able to stop at all.

Similarly, cancer cells with BRCA1 or BRCA2 mutations have a faulty “set of brakes” for repairing their DNA. They rely on PARP, which acts as their “emergency brakes,” to fix DNA damage. When a PARP inhibitor is used, it disables the emergency brakes. The cancer cells are left unable to repair their DNA effectively, causing them to accumulate damage and eventually die.

So, the combination of two problems (the BRCA1 or BRCA2 mutation and the PARP inhibitor) makes the treatment effective. This is synthetic lethality: the cancer cells can survive with either problem alone, but when both issues occur together, it leads to their death.

In normal cells that don’t have BRCA1 or BRCA2 mutations, the “regular brakes” for DNA repair still work, even when PARP is inhibited. This means that PARP inhibitors are less likely to harm healthy cells, making them a targeted therapy for cancers with these specific mutations.

When are PARP Inhibitors Used to Treat Ovarian Cancer?

PARP inhibitors are typically used in the following situations for ovarian cancer treatment:

• Maintenance therapy after platinum-based chemotherapy: For patients with advanced ovarian cancer who have responded well to first-line platinum-based chemotherapy, PARP inhibitors can be used as a maintenance treatment to help delay cancer recurrence.
• Treatment for advanced ovarian cancer with BRCA mutations: PARP inhibitors can be used as a targeted treatment for patients with advanced ovarian cancer who have inherited BRCA1 or BRCA2 mutations. 
• Treatment for recurrent platinum-sensitive ovarian cancer: For patients whose ovarian cancer has recurred but still responds to platinum-based chemotherapy, PARP inhibitors can be used as a maintenance treatment to extend the time before the cancer progresses.

Types of PARP Inhibitors for Ovarian Cancer

There are currently three FDA-approved PARP inhibitors for treating ovarian cancer:

1. Olaparib (Lynparza): Olaparib was the first PARP inhibitor approved for ovarian cancer treatment. It is used as a maintenance therapy for patients with advanced ovarian cancer who have a BRCA mutation and have responded to first-line platinum-based chemotherapy. It is also approved for the treatment of advanced ovarian cancer in patients with BRCA mutations who have received three or more prior chemotherapy regimens.
2. Rucaparib (Rubraca): Rucaparib is approved as a maintenance treatment for patients with recurrent ovarian cancer who have responded to platinum-based chemotherapy, regardless of BRCA mutation status. It is also approved for the treatment of advanced ovarian cancer in patients with BRCA mutations who have received two or more prior chemotherapy regimens.
3. Niraparib (Zejula): Niraparib is approved as a maintenance treatment for patients with recurrent ovarian cancer who have responded to platinum-based chemotherapy, regardless of BRCA mutation status.

Olaparib, rucaparib, and niraparib are all PARP inhibitors, meaning they work by blocking the PARP enzyme. Each drug has a unique chemical structure, which means it might be processed differently by the body.

Because of these differences in chemical structure, the body might handle each drug differently in terms of how quickly it is absorbed, distributed, and removed from the system.

Despite these small variations, all three PARP inhibitors are effective at treating ovarian cancer by blocking the PARP enzyme. Your ovarian cancer doctor will help determine which PARP inhibitor is best for your individual situation, considering factors like your specific cancer type, overall health, and any potential side effects or interactions with other medications.

How to Prepare for Treatment with PARP Inhibitors

Before starting treatment with a PARP inhibitor, your doctor will likely recommend genetic testing to determine if you have a BRCA mutation. This information helps guide treatment decisions and determine if a PARP inhibitor is a suitable option for you.

Your gynecologic oncologist and healthcare team will also discuss the potential side effects of inhibitors and how to manage them. You must report any side effects you experience during treatment to your doctor so they can help you manage them effectively.

PARP inhibitors are administered orally in pill form, meaning you can take them at home. Your doctor will provide specific instructions on taking the medication, such as the dosage, frequency, and any special considerations (e.g., taking with or without food).

Potential Side Effects of PARP Inhibitors

Like all cancer treatments, PARP inhibitors can cause side effects. Some of the most common side effects include: 

• Fatigue
• Nausea and vomiting
• Anemia (low red blood cell count)
• Thrombocytopenia (low platelet count)
• Neutropenia (low white blood cell count)
• Decreased appetite
• Diarrhea or constipation
• Headache
• Dizziness
• Insomnia

Most side effects are manageable with supportive care or by adjusting the dose of the PARP inhibitor. However, in rare cases, PARP inhibitors can cause more serious side effects, such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). These conditions affect the blood and bone marrow and can be life-threatening. It’s crucial to report any unusual symptoms to your healthcare team promptly.

Why Do PARP Inhibitors Stop Working Sometimes?

While PARP inhibitors have shown remarkable success, they are not effective for everyone, and some patients diagnosed with ovarian cancer may develop resistance to these drugs over time. Researchers are actively investigating the mechanisms behind inhibitor resistance to develop strategies to overcome it.

One of the main reasons PARP inhibitors stop working is the development of secondary mutations in the BRCA genes or other genes involved in DNA repair. These mutations can restore the cancer cell’s ability to repair DNA damage, making PARP inhibitors less effective. 

Other potential mechanisms of resistance include increased drug efflux (pumping the drug out of the cell), altered drug metabolism, and changes in the tumor microenvironment.

Ongoing research is exploring ways to overcome PARP inhibitor resistance, such as combining PARP inhibitors with other targeted therapies or chemotherapy agents, developing new PARP inhibitors that can bypass resistance mechanisms, and identifying ovarian cancer biomarkers that can predict which patients are more likely to develop resistance.

PARP Inhibitors and the Path to Better Outcomes for Ovarian Cancer Patients

PARP inhibitors have revolutionized the treatment landscape for ovarian cancer, offering a targeted approach that exploits the unique vulnerabilities of cancer cells with DNA repair defects. By blocking the PARP enzyme’s ability to repair DNA damage, these drugs cause an accumulation of DNA damage that ultimately leads to cancer cell death. PARP inhibitors have shown particularly promising results in treating ovarian cancers with BRCA mutations, improving progression-free survival and quality of life for many patients.

As research continues to unravel the complexities of inhibitor resistance and explore new strategies to enhance their effectiveness, the future of ovarian cancer treatment looks increasingly hopeful. Combining PARP inhibitors with other targeted therapies, immunotherapies, or chemotherapy agents may help overcome resistance and improve outcomes for more patients.

Ovarian cancer patients must work closely with their healthcare team to determine if PARP inhibitors are a suitable treatment option. Genetic testing for BRCA mutations, discussing potential side effects, and understanding the treatment process are all crucial steps in making informed decisions about their care.

At Not These Ovaries, we understand the importance of advancing ovarian cancer research and bringing new, effective treatments to patients as quickly as possible. Our non-profit organization is dedicated to growing our ovarian cancer research fund and funding clinical trials to improve outcomes and quality of life for those affected by this disease. 

If you or a loved one has been diagnosed with ovarian cancer, know that you are not alone. With the rapid advancements in targeted therapies like PARP inhibitors, there is reason to be optimistic about the future of ovarian cancer treatment. Don’t hesitate to contact your healthcare team, support organizations, or the Not These Ovaries team for information, support, and guidance on your journey.