When Are Niraparib, Olaparib, and Rubraca Used for Ovarian Cancer Treatment?

The drug blocks the body’s natural DNA repair mechanisms so cancerous cells are unable to divide and thrive. PARP inhibitors stop rapidly-dividing cancer cells from repairing their own genetic damage, preventing them from replicating.

1. PARP inhibitors work best when there is a second error in DNA repair, such as that caused by a mutation in BRCA.
2. BRCA is a critical player in homologous recombination, a highly effective double stranded DNA repair process. BRCA is not the only important part of homologous recombination, other genes are involved.
3. The label homologous recombination deficient (HRD) indicates a tumor which has one of many possible errors in the double stranded DNA repair process of homologous recombination.

PARPs For Newly Diagnosed Ovarian Cancer

1. The PARP inhibitor Zejula (niraparib) has been approved by the FDA for all women with newly-diagnosed ovarian cancer irrespective of whether the tumor is HRD+ (or has advantageous issues associated with DNA replication). The drug is used after successful treatment with a platinum-based chemotherapy, the mainstay chemotherapy for ovarian cancer. The niraparib approval is not limited to women with a BRCA mutation, which means a woman’s genetics and her tumor's biology are a not a restriction from receiving this treatment.
2. Due to limited benefit in progression free survival seen in the absence of HRD, gynecologic oncologists differ on whether PARP inhibitors should be universally recommended in the "upfront maintenance setting." Each patient should be made aware of risks and benefits to PARP inhibitor maintenance and decide with their oncologist what is the best treatment plan for them.
3. The PARP inhibitor Lynparza (olaparib) is approved for women newly diagnosed with ovarian cancer and with a germline or somatic mutation in BRCA1/2.
4. Lynparza is also approved in combination with Avastin (bevacizumab) for women with HRD.  Avastin is a blood vessel growth inhibitor, which works by starving the tumor of vital nutrients needed to grow.

Most recently, the American Society of Clinical Oncology (ASCO) released new guidelines recommending PARP inhibitors be offered to women, with or without genetic mutations, who are newly diagnosed with stage III or IV ovarian cancer and have improved with chemotherapy.

This doesn't mean that all women will get the same benefit from a PARP inhibitor.  In addition to patients with a BRCA mutation, patients with homologous recombination deficiency (HRD) have far better responses than those without them. “Patients who have this tumor characteristic are able to use niraparib even as third- or fourth-line therapy,” Dr. Chan says.

Using PARPs to Treat Recurrence

Unfortunately, too often, ovarian cancer comes back.

For women with ovarian cancer who have had a recurrence and responded to platinum-based chemotherapy, Lynparza, Zejula and another PARP inhibitor called Rubraca (rucaparib) are FDA approved for use as a maintenance therapy, regardless of whether a woman has a BRCA mutation or HRD.

For some women who have had prior chemotherapy treatments, Rubraca, Zejula or Lynparza may also be options. These uses are based on factors such as number of prior therapies and BRCA mutation or HRD.

Homologous Recombination Deficiency Explained

Historically, PARP inhibitors have been most effective for patients who have hereditary risk of developing ovarian cancer, such as a BRCA-1 or -2 mutation, but emerging research suggests these drugs are also effective for patients who have HRD.

What is homologous recombination? It’s the ability of two pairs of DNA to swap chromosomes to feed the cancer. “It’s kind of like having two cars,” says Dr. Chan. “If you have two cars in your household, and one car has a deficient front tire that’s going bald. You can take the other car’s front tire and switch over the tire so that you can keep one car driving.”

With homologous recombination, there’s a switch in DNA that allows the cancer cell to continue to divide. PARP inhibitors like niraparib can hobble that ability.

“When you have a deficiency in the homologous recombination, that makes it so that the cancer cell can’t repair itself,” Dr. Chan says. In recent trials, a BRCA mutation or HRD deficiency indicated a much stronger response to niraparib.

PARP Inhibitor Side Effects

Unfortunately, like all cancer therapies, niraparib comes with side effects. Whether or not you’ll experience significant side effects depends on several factors, including what dose you’re ingesting, and whether you’re using it alone or in combination with other therapies.

The common side effects of niraparib, like all PARP inhibitors, include:

• Nausea
• Vomiting
• Stomach upset
• Fatigue

No matter which PARP inhibitor protocol you’ve embarked on, doctors can modify your treatment schedule to reduce side effects. A few possibilities:

• Discontinue treatment for a brief time period
• Reduce the dose
• Transition to another PARP inhibitor to see if there’s any improvement

Dr. Amanika Kumar of the Mayo Clinic who spoke to SurvivorNet, cautioned that women still need to speak with their doctor to evaluate the benefit of taking a PARP inhibitor to extend life, because there are very real side effects due to the toxicity of the drug.

"Patients with HRD (homologous recombination deficiency) have a far better response than those without and those with BRCA mutations even more so. It is on us as clinicians to help patients understand the risks and benefits of treatment. Patients that have no mutation or HRD may choose not to go on maintenance (in fact I recommend they don't) because there is real toxicity to these meds."

Your doctor, patient education, and counseling can help you make decisions about cancer treatment, including PARP inhibitors like niraparib. Learning more about the drug can help you understand your individual risks and benefits, given your own genetic profile and the disease you’re dealing with.

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