Levine Sheds Light on Precision Medicine in Gynecologic Malignancies

Douglas A. Levine, MD

Significant progress is being made in the treatment of gynecologic malignancies, especially in ovarian cancer, according to Douglas A. Levine, MD.

For example, PARP inhibition has gained impressive traction as a therapeutic option for patients with ovarian cancer. In 2014, olaparib (Lynparza) was approved for the treatment of patients with BRCA-positive advanced ovarian cancer following treatment with ≥3 prior lines of chemotherapy. Ongoing phase III trials are examining the agent as maintenance therapy or an alternative to chemotherapy in women with recurrent disease.

Rucaparib was granted a priority review by the FDA in August 2016 for patients with BRCA-positive advanced ovarian cancer who have received ≥2 prior lines of chemotherapy. A final decision is expected by February 23, 2017.

And in November 2016, a new drug application to the FDA was completed for niraparib as a maintenance treatment for women with recurrent platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer.

OncLive: Please provide an overview of your presentation.

What are some of the immediate next steps to take?

What potential combination regimens are emerging with PARP inhibitors?

What impact do you expect agents like rucaparib and niraparib to have on the treatment landscape?

What can you say in terms of the tolerability of these agents?

What are some of the main challenges in ovarian cancer that you hope to tackle?

In an interview with OncLive at the recent 2016 Chemotherapy Foundation Symposium, Levine, professor, Department of Obstetrics and Gynecology, director, Division of Gynecologic Oncology, NYU Langone Medical Center, discussed these agents and other advances toward precision medicine in the treatment of patients with gynecologic malignances.Levine: When it comes to precision medicine, there are many important aspects that will affect the way we take care of cancer patients. One part of my talk focused on diagnostic dilemmas, because treating the cancer patient really starts with a correct diagnosis, and we partner with our pathologists very closely. The gynecologic pathologist is a very important part of the gynecologic oncology team, and it’s important to have a correct diagnosis to treat somebody. Precision medicine can help us make sure we’re treating the right patient with the right tumor when we use novel molecular diagnostics with traditional pathology. Traditional pathology gets you to the right place, and molecular pathology can then hone in on the diagnosis.As of now, we have a very exciting class of drugs called PARP inhibitors, and they’re very effective in women who have tumors with a BRCA mutation, but the exciting part now is to figure out what other tumors are going to respond to PARP inhibitors, and how we can combine PARP inhibitors with other agents to make them more broadly available to the oncology community.Combining PARP inhibitors with chemotherapy agents has been a little bit difficult, but we do have an ongoing trial, and we’ll see what that shows. I think in the recurrent setting is where they’re really going to be the most effective, and combining them with immunotherapy, with angiogenic therapy, and with other agents that we can’t even think about today—you know, cell cycle inhibitors, where we can really harness that potential—it’ll be very exciting.I think there will be many PARP inhibitors to choose from over time, and some of the big questions are where to give them and how to give them. Whether to give them in the maintenance setting or the treatment setting, whether to use them early or late—these are very good questions. Personally, I prefer to use them early on in the treatment cycle. As far as using them in the maintenance setting or the actual treatment setting, I think that is something we’ll learn about as time goes on.There are many concerns about tolerability and toxicity. Even though these are oral agents, they do have substantial toxicities, including fatigue, anemia, a need for blood transfusions, and other sorts of concerns. That’s why some people think that the maintenance setting may not be the best place, and the treatment setting may be more appropriate. So we have to carefully balance the toxicity with the benefit, which is true of all of our new cancer treatments.I hope we’ll be able to stratify patients better. We’ve certainly come a long way with those patients who have BRCA mutations. We’re making progress in getting every patient with ovarian cancer tested for BRCA germline mutations.

What would you like the community oncologist to take away from all of this?

What can you say about recent progress in other gynecologic malignancies?

We have a very aggressive group that has cyclin E1 amplifications, and there’s exciting laboratory research going on, and I look forward to translating that into the clinic. Then we have this group that some of us call “the others.” They don’t have the BRCA mutation, they don’t have a homologous recombination deficit, and they don’t have a cyclin E amplification. They have something else. How can we develop therapies that will target that group? I think that’s what we’ll see in the future.I’d like people to realize that we are making progress. Patients with ovarian cancer are living longer and better. We have great opportunities for prevention. We can make a dramatic impact in the mortality of ovarian cancer simply from prevention, and we can do that today. It’s also important to understand how PARP inhibitors and other agents work, and there will be a lot of new therapies in clinical trials and new approvals in the coming years.We have made great progress in the cervix and the fallopian tube, because we believe much of ovarian cancer begins in the fallopian tube. There are lots of ongoing studies looking at taking out the fallopian tubes when they’re no longer needed. That may help to prevent ovarian cancer.

On the cervical cancer side of things, with HPV vaccination, we’re making huge strides in preventing the disease. And when enough people get HPV vaccinated, we’re going to see an even more dramatic drop than we’ve already seen with the Pap smear.

Is screening for these malignancies becoming more widespread? Are there any persisting challenges with screening?

On the therapeutic side, we’re learning more about cervical cancer. We have effective treatments with angiogenic inhibitors, and we’re actually now studying how to apply PARP inhibitors to cervical cancer. So everything is changing, and from my perspective, it’s very exciting. I do think we are helping people and advancing our mission.Screening for cervical cancer is highly effective. People who seek medical attention and can get medical care should get very good cervical cancer screening.

Are there any ongoing studies with gynecologic malignancies that you’re particularly excited about?

Why does endometrial cancer have all those identifiable targets?

For ovarian cancer screening, it has not been very effective, and that’s where prevention comes in. So ovarian cancer prevention will be where we’re now focusing our efforts actively in the clinic, while in the laboratory, we try to develop better methods for ovarian cancer screening, which has somewhat alluded us to date.We’re excited about all different targeted therapeutics. Endometrial cancer is a disease where we have lots of targets and lots of drugs, and they haven’t been directly correlated as far as the targets and the responses to targeted therapeutics. So, how can we figure out which subsets of patients will respond best to targeted therapeutics? That’s very exciting. There are national trials that are completed where the science is now being conducted to figure that out, and there are other ongoing trials where that type of work is built into the trial design.Well, cervical cancer is, of course, primarily a disease of HPV. And ovarian cancer is a disease of genomic instability, where there are not a lot of mutations, but there are lots of copy number alterations and changes across the genome.

Looking at the future of gynecologic malignancies, what does the treatment landscape look like in 5 to 10 years?

Endometrial cancer, for the most part, is a disease of mutations, just like colon cancer is also a disease of mutations. So we have lots of mutations, we know them very well, we can subclassify them, and we have targeted agents that work on those pathways in general. So how can we overcome very strong pathway activation with either a single drug or a drug that targets multiple parts of the pathway?It looks like stratification. It looks like patients with gynecologic malignancies will have certain molecular tests done at certain times after, of course, our pathology colleagues give us the correct and most appropriate diagnosis. People will have more tests, the tests will come cheaper, they’ll become easier for doctors to understand the results, they will help some people, and there will still be a group of people where the molecular testing is not able to directly lead to better therapies. That’s why, unfortunately, we’ll still be in business for another couple of decades.