Matulonis Discusses Integrating Olaparib Into Clinical Practice

Ursula Matulonis, MD

In December, the FDA approved olaparib (Lynparza) for the treatment of women with BRCA-positive advanced ovarian cancer following treatment with three or more prior lines of chemotherapy. To gain insight into the integration of the agent into clinical practice, OncLive interviewed Ursula A. Matulonis, MD, medical director of gynecologic oncology at Dana-Farber Cancer Institute.

What does the approval of olaparib mean for community oncologists?

I think this represents a terrific step and an important step for patients who have recurrent ovarian cancer and have received at least three prior lines of treatment and have a germline BRCA mutation. These patients can do well for a while, but this is another therapy for these patients, and it’s well tolerated.

Could olaparib fit earlier in the treatment regimen for these patients?

There are two trials looking at this: SOLO1 and SOLO2. SOLO1 is a trial that’s looking at women who are newly diagnosed at any stage, and have received chemotherapy. At the completion of chemotherapy, the standard of care is to do nothing. SOLO1 actually randomizes to women 2:1 to receive olaparib or placebo.

SOLO2 looks at women with germline BRCA-mutated, high-grade serous, and platinum-sensitive disease. SOLO2 is comparing olaparib to placebo as maintenance therapy.

There is also SOLO3, which is trying to recapitulate the results that led to the FDA approval. This trial is looking at women who are germline BRCA carriers who have received three or more lines of chemotherapy.

Olaparib was approved along with a companion diagnostic. Do you think using this companion diagnostic will require adjustment for clinicians? Will the test be covered by insurance?

No, it’s fairly easy to use. It’s a little tube and comes in a kit. A clinician will draw the blood and send that tube back to Myriad. I don’t think that it’s a big deal — the actual testing is very straightforward. My hope is that the test will be easily covered by insurance.

In late June, the FDA's ODAC panel voted against the approval of olaparib as maintenance therapy but now it’s been approved to treat advanced disease. What changed since then?

This approval was based on an objective response rate of 34%, and there’s been some debate about using progression-free survival as a trial endpoint in ovarian cancer. What are your thoughts on using some of these ‘non-traditional’ endpoints in ovarian cancer trials?

There’s some precedent using progression-free survival as an endpoint in trials. Until recently, all ovarian cancers have been treated like one cancer. Many trials have been done using eligibility criteria of “recurrent ovarian cancer,” without specifying histology or even the presence of a germline BRCA mutation.

Regarding trials done to date, with the exception of PARP inhibitors, there have not been biomarkers and there have not been eligibility screens to narrow down patient populations and fit them with specific agents. Bevacizumab has not shown a survival benefit, but also it does not have a biomarker. That’s nothing against the agent, but that example points to the problem. You’ve got very distinct patient populations and clinically, these types of cancers behave differently.

We’ve been diluting out the potential benefits of drugs because we’re selecting patient populations that are too broad.

A lot of us clinicians have thought a lot about why we can’t generate overall survival benefits. Right now, the best that we have is looking at progression-free survival.

What challenges still remain in treating this group of patients with a germline BRCA mutation?

We still need to determine which patients will derive the greatest benefit from olaparib. The question remains if we can further define who we treat with this agent.

We’re also focusing on mechanisms of resistance. How do ovarian cancer cells, if they’re responding initially to olaparib, become resistant?

Thirdly, what do we do for these patients when they’ve become resistant? Do we treat them with drug combinations with PARP inhibitors?

We’re trying to answer all of these questions — and more — in clinical trials.

I can’t speak for the FDA, but the bottom line is that the olaparib has efficacy in germline BRCA-mutated, recurrent ovarian cancer. We’ve been doing clinical trials with this agent since 2008, and I have been impressed with the level of activity of this drug in my patients. This is anecdotal, but my patients tell me this is the best that they’ve ever felt on a treatment regimen for ovarian cancer. You’d have to ask the FDA how they came to their decision in June.