Researchers Seek to Optimize PARP Inhibitors in Ovarian Cancer

Shannon Westin, MD

Since the FDA approval of the PARP inhibitor olaparib (Lynparza) in December 2014, PARP inhibition is increasingly becoming a standard of care in ovarian cancer, particularly for patients with recurrent disease.

Olaparib was approved for the treatment of women with BRCA-positive advanced ovarian cancer following treatment with 3 or more prior lines of chemotherapy. The approval was based on a 34% objective response rate seen in 137 patients with BRCA-positive ovarian cancer who had received at least 3 lines of chemotherapy in a single-arm phase II study.

OncLive: Can you tell us a little bit about restoring PARP inhibitor sensitivity?

Researchers are now working on refining the use of PARP inhibitors in ovarian cancer by gaining a greater understanding of mechanisms of resistance and exploring combination and sequencing possibilities. For expert insight on these topics, OncLive sat down with Shannon Westin, MD, at the 2016 Society of Gynecologic Oncology Annual Meeting.Westin: Now that PARP inhibitors are becoming a standard of therapy, especially for women with recurrent ovarian cancer, there is, of course, the develop of resistance, just like we're seeing with so many other medications and treatments.

Right now, a lot of the mechanisms of resistance are very theoretical. For example, there are innate, or acquired, forms of resistance. Things like being able to pump the drug out easier, or the expression levels of PARP not being as high. Therefore, the tumor wouldn't respond to an inhibitor of PARP, as well.

More interesting to us at MD Anderson is that we’re doing research in adaptive resistance. This involves studying what happens to the tumor when you treat with a drug, looking at the tumor afterward, and seeing what pathways are upregulated. Then, you would use that information against the tumor.

What are the next steps after noticing certain pathways are being upregulated?

You would not just treat with PARP inhibitors until progression and say, “Okay, what do we do now?" Instead, you take tissue samples before and after PARP and you know that this patient had a PARP inhibitor and then these 3 pathways went up. Therefore, you try to target this tumor with these 3 pathways and use that information not only for the patient, but also in use for combinations and future clinical trials.There are theories that certain cells are sensitive to PARP inhibitors, and then there are those that are resistant. If you determine that and you start targeting the resistant cells with something else, you'd still want to keep targeting those sensitive cells with PARP. It seems that a combination would make sense but, ultimately, we have to do clinical trials to really answer that question.

Where do these theories stem from?

Using novel trial designs like randomized discontinuation trials will help elucidate that—we would take a patient with progression and randomize her, and she either keeps on with the PARP inhibitor plus something else, or she goes on something completely different and then you can determine which does better. You then figure out if you need to keep that PARP inhibitor going, or if you need to turn to something else.One of my collaborators, Dr Gordon Mills, has seen that it happens with any targeted therapy. All of these targeted pathways are interrelated and cross-linked, so it's not just 1 in a vacuum. If you target 1 pathway, it's going to find a way around that. Cancer cells are smart, and they're going to find a way to stimulate their growth and stimulate their survival through another pathway.

If you can use that information that you gain—and this goes for any targeted therapy—you hit on that target and then you look at what the cancer does to try and survive. This way you can either hit both targets upfront at the same time, or you can do a sequential treatment.

Can these theories have major impacts within the realm of gynecologic cancers?

What's great about this platform is that it is not just about PARP. It can be expanded to numerous other targeted therapies, as well.These theories are meant to show that this is why we're doing the trials we are doing, and this is why you need patients to participate in research. Just hitting single-agent PARP is likely not going to be enough. We know that even in the patients with BRCA mutations, who we would expect to universally respond PARP, they don't.

Therefore, what is that next step? Right now, that next step is doing the research to determine what are the combinations that are needed, and what is the sequential treatment that is necessary to continue to get that benefit.

What is the current treatment paradigm for patients with BRCA mutations?

We're barely scratching the surface of success in ovarian cancer. This is meant to inform the community oncologists that, when you're out there and you're treating the patients, this can happen. What do you do next? Right now, the ultimate answer is clinical trials, so we can figure those answers out. In a couple of years I think we'll know what to do.Right now, patients within the United States are really treated the same way as any patient with a high-grade serious ovarian cancer. This involves a combination of a debulking surgery and chemotherapy followed by long-term follow-up without treatment and then the patient relapses. In the United States right now, the only thing we do differently with BRCA mutant patients is that, after 3 or more prior therapies, those patients are eligible for PARP.

How does olaparib fit into that treatment paradigm?

There are several clinical trials ongoing looking at maintenance therapy, looking at both the upfront setting after the completion of treatment and, in the current setting, after the completion of treatment. If those maintenance trials show what we hope they will, that may be an option for patients in the future. After they complete their primary therapy they go on and receive a PARP inhibitor as maintenance therapy. That still remains to be seen based on the results of ongoing trials.Olaparib is an FDA-approved PARP inhibitor for the treatment of women with BRCA-positive advanced ovarian cancer after 3 or more prior therapies. If the patient has recurrent ovarian cancer, has had 3 or more prior therapies, then that's when olaparib becomes an option.

There are patients in the European Union who are getting this as a maintenance treatment upfront after completion of therapy, but that's not something we are able to offer yet in the United States.

There are promising results looking at PARP inhibitors in the maintenance setting. Olaparib was examined as a maintenance option, but the study was a retrospective analysis. It was a non-planned subanalysis, and the FDA wants to see the results of planned randomized phase III trials before they make a decision of whether or not olaparib as a maintenance therapy would be an option. Based on everything we've seen, within 1 or 2 years olaparib could get there.

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