Making Ovarian Cancer Treatment Decisions–Weighing the Benefits of PARP Inhibitors

PARP inhibitors have shown incredible promise as a treatment for ovarian cancer. Among the dozens of leading gynecologic oncologists SurvivorNet spoke to, there is clearly growing enthusiasm for the use of PARP Inhibitors because they extend life significantly for many women. There is also growing evidence that PARPS are effective as part of the first treatment for ovarian cancer, as well as in so-called maintenance treatment.

PARP inhibitors are available to almost all women, though women with BRCA gene mutations or who are HRD proficient may benefit the most from these drugs. However, the American Society of Clinical Oncology (ASCO) guidelines recommend 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.

But, as with any treatment decision, women should evaluate the benefits before proceeding, and oncologists stress that every patient is different.

Dr. Emese Zsiros, a gynecologic oncologist at the Roswell Park Comprehensive Cancer Center, says that “PARP inhibitors are wonderful medications, but you need to evaluate the patient on a case by case basis.” She suggests patients review several important factors before undergoing the treatment:

• There may be less of a benefit for women without the BRCA mutation – If women do not have a BRCA gene mutation, the benefits of a PARP inhibitor are less. However, in a really challenging cancer with few options for treatment, women who don’t have a BRCA mutation may still want to consider a PARP inhibitor because it can extend the time you live without cancer present.
• Side effects for some women – In some cases “women do not feel fine on PARP inhibitors,” says Zsiros. Women can experience nausea, vomiting, constipation, fatigue, and diarrhea which make it difficult to take these medications for long periods of time. But it should be noted that as a field, oncologists focused on ovarian cancer are getting better at managing these side effects.
• Financial burden – PARP inhibitors can cost as much as $10,000/month, and while insurance often covers these costs, it’s sometimes not full coverage. Manufacturers do offer “benevolent assistance” programs for some women, effectively gifting the drugs for people who meet certain financial requirements. The key here is to seek these programs out and ask for help.

Excellent Effectiveness As Part of First Treatment in BRCA Positive Women

There is one group of women that Dr. Zsiros feels should definitely consider taking PARP inhibitors: women with mutations in the BRCA gene. “Those patients would be offered to continue to take these oral medications or start taking these oral medications at the time that they finish chemotherapy,” she says. Along with most of her colleagues who treat ovarian cancer, she believes that these women should take PARP inhibitors after they finish their first chemotherapy treatment, as this group of women has been shown to be most receptive to the genetic pathway that PARPs use to fight cancer.

The important point is that although PARP inhibitors have shown promise as an effective treatment for ovarian cancer patients in a variety of stages and settings, they should not be universally prescribed. Each patient is different, with different physical and financial tolerances, so a comprehensive discussion with a doctor is key to making sure the proper patients receive PARP inhibitors. If you are considering expanding treatment to PARP inhibitors, experts like Dr. Zsiros agree that doctors communicate the costs and benefits of the treatment before moving forward.

How PARP Inhibitors Work

One of the key things to know about PARP inhibitors is that your genetic makeup and specific features of your cancer will have a significant impact on how effective these drugs may be. Experts tell SurvivorNet that every woman with ovarian cancer should get a genetic test to determine if they have a mutation called BRCA, because the mutation enables PARP inhibitors to function much more powerfully. Importantly, there is increasing data that even women without BRCA mutations can still derive some benefit from these drugs.

PARP inhibitors interrupt the process of single stranded DNA repair, an essential part of cell replication. Defects in DNA repair ultimately cause cell death. PARP inhibitors work best when there is a second error in DNA repair, such as that caused by a mutation in BRCA. 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. 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.

Newly-Diagnosed Epithelial ovarian cancer

The PARP inhibitor Zejula (niraparib) has been approved by the FDA for all women with newly-diagnosed ovarian cancer regardless of BRCA mutation/HRD status. The drug is used after successful treatment with a platinum-based chemotherapy, the mainstay chemotherapy for ovarian cancer.

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.

The PARP inhibitor Lynparza (olaparib) is approved for women newly diagnosed with ovarian cancer and with a germline or somatic mutation in BRCA1/2.

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.

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.

Learn more about the side effects of PARP inhibitors here.

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