Precision Medicine Rapidly Being Incorporated Into Ovarian Cancer Care

Douglas A. Levine, MD

While precision medicine has been a modern go-to approach by physicians in various malignancies, it is demonstrating a particular benefit in ovarian cancer, especially using the method for clinical trial enrollment and in determining whether patients are eligible to receive treatment with PARP inhibitors, according to Douglas A. Levine, MD.

For example, updated findings of a phase II trial presented at the 2017 ASCO Annual Meeting demonstrated that the combination of the PARP inhibitor olaparib (Lynparza) and the angiogenesis inhibitor cediranib maleate continued to show superior progression-free survival (PFS) versus olaparib alone for women with BRCA-negative recurrent platinum-sensitive ovarian cancer.

In the updated analysis, which was conducted after 67 PFS events, median PFS continued to favor the combination over monotherapy at 16.5 months versus 8.2 months, respectively (HR, 0.50; P = .007). Specifically, in patients without a known germline BRCA mutation, the updated median PFS was still superior in the cediranib/olaparib arm compared with monotherapy at 23.7 months versus 5.7 months (HR, 0.32; P = .002).

Additionally, an ongoing phase II trial is exploring the safety and efficacy of TPIV200/huFR-1, a multi-epitope antifolate receptor vaccine in combination with the PD-L1 inhibitor durvalumab (Imfinzi) in patients with platinum-resistant ovarian cancer (NCT02764333).

OncLive: Can you provide an overview of your lecture?

What are the sequencing challenges currently being faced in the ovarian cancer landscape?

In an interview with OncLive, Levine, professor, Department of Obstetrics and Gynecology, director, Division of Gynecologic Oncology, NYU Langone's Perlmutter Cancer Center, shared his insight on how the ovarian cancer landscape has developed a more personalized treatment approach. Levine co-chaired the 2017 OncLive^® State of the Science Summit^TM on Treatment Options in Ovarian Cancer, where he discussed the topic in greater detail.Levine: I talked about incorporating precision medicine into gynecologic cancers, particularly in ovarian cancer. I began by talking about different sequencing methods and how far we've come with sequencing from the Human Genome Project to The Cancer Genome Atlas Project and the application of sequencing and precision medicine in daily clinical care. Specifically, we gave some examples of how to use precision medicine to direct people toward clinical trials, both for ovarian cancer and endometrial cancer, and how to use precision medicine to stratify patients for treatment with PARP inhibitors. The good thing about precision medicine is that doing the actual sequencing is quite easy nowadays. We've gotten pretty good at sequencing, and there are some established laboratories [that are also good] at interpreting the sequencing. Now, it is the interpretation that remains much more challenging than the actual sequencing.

What has it been like for you to see the paradigm transforming to include a more precision medicine approach?

Speaking of PARP inhibitors, can you discuss their utility and selecting patients to receive them?

Laboratories that have been around for a long time do this quite well. In some of the newer commercial labs, it is very important to figure out how the validation is done and make sure the details of the sequence analysis are done properly, which sometimes can be difficult to figure out. As far as doing the sequencing, we can now use sequencing to determine what mutations are in a patient's tumor and then to direct that patient toward a clinical trial or possibly for off-label use of clinical therapies. Precision medicine has really been successful in part due to the importance of genetic testing for BRCA 1/2 mutations. That got the concept of sequencing into the clinic and to the patient population. Now, patients are coming in saying, “I want BRCA 1/2 sequencing.” Once we became familiar with that type of sequencing, it wasn’t a big stretch from sequencing the germline to sequencing the tumors. Once we could sequence the tumors, people then became familiar with targeted therapies. Certainly, the FDA approvals of various PARP inhibitors have turned sequencing into an everyday event. The PARP inhibitors do have different approved indications. Some are approved in the maintenance setting and some for active treatment or treatment of active disease. The PARP inhibitors themselves are similarly efficacious; they all work quite well. They all work the best in women who have BRCA mutations. They work second best in women who have dysfunction in DNA repair.

What types of ongoing trials in this space are geared toward your discussion?

Then, one study suggested that there was some activity in women who have tumors without any defects when given in the maintenance setting. That effect was much more modest than for tumors in women who do have defects for DNA repair. We have a number of trials that [range from] testing standard agents, such as PARP inhibitors and angiogenesis inhibitors, to more interesting and sophisticated trials that take antibodies and combine them to antibody-drug conjugates, or test immunotherapy in ovarian cancer and endometrial cancers.

We have a number of trials that are really testing targeted inhibitors; we have a very exciting folate receptor trial in recurrent ovarian cancer, because ovarian cancers do express the folate receptor and there is some thought that even endometrial cancers might express the folate receptor. There is some discussion about developing a trial for the folate receptor antibody in endometrial cancer.

Other trials that are exciting in ovarian cancer include the combination of a PARP inhibitor and angiogenesis inhibitors. Cediranib and olaparib is one combination, and there are other combination therapies with PARP inhibitors.

Combining PARP inhibitors with other agents to treat women who do not have BRCA mutations is a very exciting area, because we know the PARP inhibitors work best in women who carry BRCA mutations either inherited or within the tumor, and also work well in women with defects in DNA repair. How to combine them with agents to apply them to the rest of the population is something that we’re actively studying because, after all, 50% or less of women will be in those categories that I mentioned.

Another exciting area is the microsatellite-instability (MSI)-high/positive endometrial cancers. MSI positivity accounts for about 35% of endometrioid endometrial cancers or about 20% of overall endometrial cancers. Now, a few months ago, checkpoint blockade with pembrolizumab (Keytruda) was approved for use in MSI-high/positive tumors. Obviously, it is very exciting because it is approved for a molecular indication that would include endometrial cancers, colorectal cancers, gastric cancers, and really any cancer that happens to have MSI-positivity or be an microsatellite unstable disease.

The exciting part about immunotherapy is that it really capitalizes what we already knew about the endometrial cancers and, of course, some MSI-high tumors are actually inherited through a defect in mismatch-repair (MMR) genes, so that is also important for genetic screening and genetic counseling. We have another link between inherited genetic events that are now tangentially leading to actually very effective treatments. Therefore, we have the inherited BRCA mutations that put people at risk for ovarian cancer and are now a therapeutic target with PARP inhibitors.

You co-chaired this State of the Science Summit^TM. What is the value in community physicians attending a more intimate event like this?

Now, we have the MMR genes, which can put you at inherited risk for colorectal cancer and endometrial cancer, and now the therapeutic target with checkpoint blockade, so these are very exciting and gratifying solutions for years of research. This State of the Science Summit on ovarian cancer was really designed to share the latest in various aspects of ovarian cancer research and treatment with the community, and the regional area here. We wanted to talk about the research going on in the lab, prevention, screening, early detection, primary treatment, recurrent treatment, and novel therapeutics, such as immunotherapy and PARP inhibitors, and that is what was featured prominently in this event.

Liu J, Barry WT, Birrer M, et al. Overall survival and updated progression-free survival results from a randomized phase 2 trial comparing the combination of olaparib and cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer. J Clin Oncol. 2017;35 (suppl; abstr 5535).