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Current Challenges and Promising Advances in Recurrent Ovarian Cancer With Ursula Matulonis, MD

Ursula Matulonis, MD

Ovarian cancer accounts for 5% of cancer deaths among women in the United States and causes more deaths than any other cancer of the female reproductive system. An estimated 22,240 new cases are diagnosed annually, and 14,070 people die of the disease. Relative survival varies by age; women younger than 65 are much more likely to survive 5 years (77%) following diagnosis than women 65 and older (20%). Overall, the 5-year relative survival rate for ovarian cancer patients is 47%. If diagnosed at the localized or early stage, the 5-year survival rate is more than 90%; however, fewer than 15% of all cases are detected at this stage. Most cases (60%) are diagnosed with distant disease or advanced stage, which is associated with a 5-year survival rate of about 30%. In this interview, Ursula A. Matulonis, MD, Medical Director and Program Leader of the Medical Gynecologic Oncology Program at Dana-Farber Cancer Institute, discusses treatment challenges, recent progress, and future directions in the management of recurrent ovarian cancer.

What are some of the most challenging aspects of managing recurrent ovarian cancer?

Ursula Matulonis, MD: There are a few. One challenge is that most women with recurrent cancer will have increasing platinum and treatment-resistant cancer, and though treatment choices have increased, we need more access to newer therapies. The number of new treatments is expanding, but as a patient receives more treatment, her cancer becomes more overall treatment resistant. That is a major area of research that our labs are working on, but it's really a worldwide effort to try to understand why ovarian cancer is initially so treatment-sensitive and then becomes more treatment-refractory upon relapse and with recurring treatment. Ultimately, its great to see a newly diagnosed patient do so well with treatment, but it is frustrating to see that your treatments become less and less efficacious in the recurrent setting.This is what drives me to do clinical trials and drug development for ovarian cancer.

The good news is that there is a lot going on too. The number of clinical trials, labs, companies, and research efforts going on to discover and develop new therapeutic options for patients with recurrent disease is, without a doubt, the highest it's ever been. The field has definitely changed from even 5 years ago. The exciting part is that more options are being developed for patients, and so many clinical trials of very exciting new agents are undergoing clinical trial testing.

It is really important in rational clinical trial design to understand that ovarian cancer is not just one cancer. We need to think about it from a histologic, and therefore molecular, basis.

What best practices would you recommend to community oncologists who are managing recurrent ovarian cancer?

Dr. Matulonis: I recommend making sure that patients have undergone genetic testing since it is now recommended by several groups such as NCCN and SGO that all patients with a diagnosis of ovarian cancer, regardless of histology, age and family history should undergo genetic testing. Now, that can be traditionally germline, but there may be merit to doing tumor testing and if positive for a high risk gene, then proceeding to reflexive germline testing. We are looking for underlying reasons why the patient may have developed the cancer. There are at least 11 different genes that are now known to increase a patient's risk of developing ovarian cancer from a hereditary standpoint. So if you find one of these genes in a patient, it's really important to disseminate that information to her relatives. One way we can prevent ovarian cancer is by identifying a patient who is at high risk and then removing her ovaries and fallopian tubes.

Secondly, genetic testing can also lead to rational selection of potential therapies such as PARP (poly (ADP-ribose) polymerase) inhibitors or other molecularly-driven treatment options.

Thirdly, community oncologists need to be cognizant of the different novel therapies that are being offered to patients. It's hard because they have a difficult job. They have to take care of so many different types cancers. There was a large hiatus of time between 2006 and 2013 where there were no FDA approvals for ovarian and other gynecological cancers. Now, more than ever before, we are seeing FDA approvals happening weekly in all cancers. So the community oncologist has the very difficult job of keeping up with all of that.

What questions do you commonly encounter from patients about their treatment?

Dr. Matulonis: I get a lot of questions about whether or not immunotherapy can be used to treat ovarian cancer. It's important for physicians as well as patients to understand that the single agent checkpoint inhibitors have very low activity in an unselected patient population, and I do not use these agents unless they are part of a clinical trial.

To just give a patient an immune checkpoint inhibitor doesn't make sense unless that patient has microsatellite high or instable cancer per the pembrolizumab pan-MSI high tumor indication, but this is extremely uncommon in ovarian cancer .Ovarian cancer patients should only receive it as part of a clinical trial. It's also important that physicians who are dealing with PARP inhibitors understand the FDA approvals and the indications for PARP inhibitors.

Sometimes our patients can receive drugs such as carboplatin twice or more times. They get carboplatin in the upfront setting, and then they receive carboplatin for recurrence. They may receive it yet again. Patients do have an increased risk of allergic reactions, but there are published guidelines and protocols for safe delivery of drugs like carboplatin. If a patient with recurrent disease is still sensitive to platinum, it still may be possible to give her platinum despite an allergic reaction, especially if you think it will render a response.

What are some promising advances in ovarian cancer treatment that you expect to see in the near future?

Dr. Matulonis: We are definitely excited about PARP inhibitor combinations. There are a number of combinations being tested, including PARP inhibitors plus antivascular drugs such as bevacizumab and the drug cediranib. Then there are PARP inhibitors plus immunotherapy combinations that are currently in clinical trials too.

In patients where a single-agent PARP inhibitor may have a lower expected response rate such as platinum resistant cancers and those without an underlying BRCA mutation in their cancer, the expected response rate may be less than 10%, PARP inhibitor combinations may be a way to make the cancer more receptive to a PARP inhibitor. So those are exciting.

Another exciting avenue is antibody drug conjugates, and there are a number in clinical trial testing. The one that's furthest along is mirvetuximab, which is an antibody drug conjugate against the folate receptor alpha. That's in phase 3 trials right now, so we expect those results by mid 2019.

The use of PARP inhibitors in earlier states of ovarian cancer is another exciting area. SOLO1 is a trial analyzing post-chemotherapy olaparib in patients with BRCA-positive cancers. The results of SOLO 1 will be reported at ESMO this year. Those results via press release have been reportedly positive, but we don't know the exact magnitude of the results. I think this study may allow potential use of a PARP inhibitor in patients who are newly diagnosed as opposed to waiting for them to have recurrent disease.

Is there anything else that you would like to add for community oncologists?

Dr. Matulonis: I think it's really important for community oncologists to keep a dialogue open with a cancer center where there are experts in gynecologic malignancies who have that level of expertise around patient management. There may also be potential clinical trial opportunities for patients.

About Dr. Matulonis:

Ursula A. Matulonis, MD is Chief of the Division of Gynecologic Oncology Program at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. Her research focuses on targeted therapies for gynecologic malignancies, with a specific interest in the genetic changes in ovarian cancer that can inform targeted therapy selection. Dr. Matulonis is the Principal Investigator of several clinical trials and translational studies for ovarian cancer. In addition, she has presented at various regional, national, and international conferences and has co-authored more than 150 peer-reviewed publications in journals such as Journal of Clinical Oncology and New England Journal of Medicine.

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