PARP Inhibitors and Ovarian Cancer Gene Mutations
- PARP inhibitors, which are drugs that work by preventing ovarian cancer cells from repairing their own damaged DNA, often work best in women with BRCA gene mutations.
- All women with advanced stage ovarian cancer are eligible for PARP inhibitors at specific points in their cancer treatment. Genetic testing identifies the patients most likely to respond and derive the greatest benefit.
- All women with ovarian cancer should be offered genetic counseling to detect these important germline mutations that can confer family risk, and personal sensitivity to PARP inhibitors.
“Basically, PARP inhibitors are forcing cancer cells — instead of repairing their DNA and continuing to persist and kind of hobbling along and continue to help that tumor grow and develop– PARP inhibitors cause those cancer cells to die,” explains Sheryl Walker, a genetic counselor at Genome Medical in Dallas, Texas. “It forces them down the path towards self-destruction essentially.”
Read MorePARP 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 irrespective of whether the tumor is HRD. 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.
Important Guidelines
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.
“So if we can isolate and figure out which mutations are driving that tumor, pushing it forward, causing it to grow and develop, and we can target those specifically, that patient’s going to have a better response,” Walker explains. “They’re going to have a more effective treatment, and they’re hopefully going to have a better prognosis, which is very exciting.”
Learn more about SurvivorNet's rigorous medical review process.
