Researchers Seek to Optimize PARP Inhibitors in Ovarian Cancer

Greg Kennelty
Published: Monday, Mar 21, 2016

Shannon Westin, MD

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.

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.

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

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.

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.

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

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.

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.

Where do these theories stem from?

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.

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.

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

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.

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