Novel Agents, Genetic Testing Propel Personalized Care in Ovarian Cancer

Angeles Alvarez Secord, MD

Treatment for patients with ovarian cancer has evolved considerably over the last few years, in part due to the implementation of genetic testing.

According to Angeles Alvarez Secord, MD, once a patient is diagnosed with ovarian, fallopian tube, or peritoneal cancer, the conversation about genetic testing begins. She added that it is important to include a genetic counselor in these conversations if possible, as they can guide the patient on the importance of testing, as well as the different tests available and the implications of their results.

For example, if a test reveals that a patient has a BRCA1/2 mutation, PARP inhibitors have shown to be beneficial. Genetic testing can also reveal whether a patient has a predisposition for other cancers, such as those of the breast and pancreas, and steps can then be taken to address that risk.

“It is incredibly important to understand that it is not a one-size-fits-all paradigm anymore,” said Secord.

OncLive: Reflecting on the different presentations tonight, what does this signify about the progress being made in this disease?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Ovarian Cancer, Secord, a gynecologic cancers specialist at Duke Cancer Center, discussed recent updates in ovarian cancer, with an emphasis on the clinical significance of genetic testing.Secord: We have made incredible progress in ovarian cancer. Some of this program provided basics in terms of the landscape and the treatment of women with newly diagnosed disease, as well as surgical management of ovarian cancer. The first half of the meeting dealt with how to treat someone with advanced, newly diagnosed ovarian, fallopian tube, and peritoneal cancer. We covered the chemotherapy options, as well as the surgical management. Importantly, we also discussed genetic testing. This part of the program provided a hint of what is to come. That is personalized medicine—individualized care for women who have these types of cancers.

Dr Wendel Naumann of Atrium Health discussed the surgical management of this disease. Surgery is certainly a cornerstone of management, but we need to decide in which patients primary debulking surgery should be done versus neoadjuvant chemotherapy followed by interval debulking surgery and more chemotherapy. Dr Jubilee Brown of Atrium Health highlighted the importance of genetic testing in identifying women with mutations such as BRCA1/2 or homologous recombination deficiency (HRD) who may benefit from PARP inhibitors.

In regard to genetic testing, how do you choose when and how to test these patients?

Additionally, genetic testing can identify women who are at an increased risk for breast and ovarian cancer, so we can use this information to prevent other cancers. That is so striking to me—the fact that we can identify women who have a genetic predisposition to ovarian and breast cancer. Now, it is even beyond that; we are able to identify increased risk of pancreatic and other cancers. We can institute cancer screening, give treatments to try to prevent these cancers, or even surgery. We will be able to reduce ovarian, fallopian tube, and peritoneal cancer incidence by about 20%.As soon as someone has a diagnosis of ovarian, fallopian tube, or peritoneal cancer, I am talking to them about genetic testing. We have a fantastic program at Duke Cancer Institute, and we are very fortunate to have a genetic center that is available to us. The genetic counselors will [guide] patients regarding the different tests available, the importance of testing, and the different outcomes of the tests. For instance, they may have a test that indicates a pathologic mutation that puts [the patient] at an increased risk. Or, they could have a test that is negative. However, in the setting of significant family history, they are still at an increased risk.

We might not identify the gene of interest, or the patient could have a test that shows a variant of uncertain significance (VUS). A VUS means that we don't know if it deleterious, pathogenic, or neither. That can institute its own challenges in understanding for the patient. They could also have a negative test and family history that is not concerning, so they do not need to undergo unnecessary screening or procedures.

What are the most exciting agents that have come into the landscape of ovarian cancer?

We at Duke Cancer Institute are incredibly fortunate; not all practices have a genetic counselor or leader in the field on their site. They have to rely on other options for genetic counseling or just test all patients. However, they still might not be able to provide the extent of counseling needed.We are very fortunate right now in ovarian cancer. There was at least a decade where there was nothing really happening in [this disease]. All of a sudden, things started to change in 2014. We had an approval for bevacizumab (Avastin) in the recurrent setting for women with platinum-resistant disease initially, and then for women with platinum-sensitive recurrent disease. Recently, we received an approval in the frontline setting as well. Now we have options.

In addition, we have approvals for PARP inhibitors. Not just 1, but 3 PARP inhibitors [are available]. I am hoping now that we have approvals for 3 different drugs, that will influence pricing. We will see how that plays out. The bottom line is that now we have 4 drugs for ovarian cancer that we did not have before. All 3 PARP inhibitors are approved in the maintenance setting for all comers, but there are 2 PARP inhibitors that are approved in the treatment setting: olaparib (Lynparza) and rucaparib (Rubraca). Those are approved for patients who have specific biomarkers.

Where I would use a biomarker in the maintenance setting is when I am talking to a patient about their magnitude of benefit of adding a PARP inhibitor in the maintenance setting. If a patient has a BRCA mutation, I can tell them whether that is a germline or somatic BRCA mutation, the benefit that they will obtain from a PARP inhibitor, and how much time they are going to live progression free if they take a given PARP inhibitor—even accounting for toxicity. There are some fantastic quality-of-life studies done for these trials.

There are also patients who have HRD. If they have this defect, their magnitude of benefit will not be as high compared with those patients who have a mutation in BRCA, either germline or somatic. There is still a benefit for those patients and I can discuss that with them.

We also have a basket approval for pembrolizumab (Keytruda), which is an immunotherapy. Therefore, patients who have microsatellite inability—high or mismatch repair deficient [tumors] are candidates for immunotherapy at this point. That not only encompasses ovarian cancer—it is disease-type agnostic.

What are the differences seen between the PARP inhibitors?

We are moving on from the time where we had a one-size-fits-all approach into what I would say is a personalized approach to cancer care.Some of the differences that you see between the PARP inhibitors might be laboratory differences, but they are not clinically significant. Some of the PARP inhibitors might have issues with elevated creatinine, or elevated liver function tests—but that rarely translates into a clinically significant difference. Niraparib (Zejula) does have thrombocytopenia, so you need to be aware of dosing. I utilize weight-based dosing as a part of that equation, as well as their baseline level of platelets to determine if I need to dose-modify at onset. Then, careful monitoring is very important. I do weekly counts initially, and if there aren’t any issues with platelets, I will move onto monthly counts. If they have any concerns with their platelets, then I am quick to modify the dose as needed.

I have treated patients with all 3 of these agents, both on and off clinical trials. I don't think there is any difference in efficacy.