PARP Inhibitors in the Management of Ovarian Cancer Guideline

An interview with Dr. William P. Tew from Memorial Sloan Kettering Cancer Center on "PARP Inhibitors in the Management of Ovarian Cancer: ASCO Guideline." This guideline provides recommendations on the use of poly (ADP-ribose) polymerase inhibitors (PARPis) for management of epithelial ovarian, tubal, or primary peritoneal cancer. Read the full guideline at www.asco.org/gynecologic-cancer-guidelines.

Transcript

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Brittany Harvey: Hello, and welcome to the ASCO guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today, I'm interviewing Dr. William P. Tew from Memorial Sloan Kettering Cancer Center in New York, New York, lead author on PARP inhibitors and the management of ovarian cancer. Thank you for being here, Dr. Tew.

Dr. William Tew: Thank you, Brittany, for having me.

Brittany Harvey: First, I'd like to note the ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Tew, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. William Tew: No, I do not.

Brittany Harvey: OK, thank you. Then, can you give us a general overview of what this guideline covers?

Dr. William Tew: Sure. So my co-chair, Elise Kohn, and panel members, and ASCO staff put together a very comprehensive guideline on the use of PARP inhibitors in the management of women with ovarian cancer. And as many of your listeners may know, there has been a rapid speed of phase 3 practice changing trials that have been published and FDA approvals within the last year, and what we wanted to do was to put that all in one document and give guidance on how and when and which PARP inhibitor to use in your specific patient and at what point during the lifecycle of ovarian cancer of when to use it.

So we broke up the guideline into five sections. One is the use of PARP inhibitors as maintenance therapy after first line platinum based treatment in women with stage 3 and 4 ovarian cancer. Second, we looked at maintenance therapy after a second or higher platinum based treatment. Three, the use of PARP inhibitors as treatment for patients with recurrent epithelial ovarian cancer.

We then looked at different combinations of PARP inhibitors, whether it's with chemotherapy or biologics and the data that we have presently on those combinations. And then lastly, we looked at common side effects with PARP inhibitors and offering guidance on how to manage those toxicities.

Brittany Harvey: Great. Then you just mentioned that this covers several different sections, so I'd like to go through each of those sections and review those recommendations for our listeners. So first, what are the recommendations for PARP inhibitors for patients with newly diagnosed epithelial ovarian cancer?

Dr. William Tew: So for women with newly diagnosed ovarian cancer, there's been several studies that have been published in the last year and a half, and we broke this up into the different studies and the different patient populations. First and foremost, we wanted to stress that PARP inhibitors are not recommended for the use in the initial treatment of patients with early stage, meaning stage 1 or 2 ovarian cancer, because there really isn't sufficient evidence to support the use in this population. All of the trials looked at patients with stage 3 or 4 epithelial ovarian cancer and used primarily in the main setting, and what that basically means is that women that have had a complete or partial response to first line platinum based chemotherapy and have response by CT scan or CM 125, when do you use a PARP inhibitor?

Which are the women that you would say PARP inhibitor is going to benefit you with long-term outcome? So our first recommendation is based on a trial-- looking at a drug called olaparib. Olaparib was the first PARP inhibitor published in this population, and in that study, they included women with both germline or somatic pathogenic or likely pathogenic variants in the BRCA1 or BRCA2 gene. And so this is a group of women that you could offer olaparib for.

And generally, that is given at a dosage of 300 milligrams once every 12 hours for up to two years. The second study looked at a drug called niraparib, and in this trial, they included population of all women, regardless of BRCA status. And they offered it to women with high-grade serous or endometrial ovarian cancer. And the FDA has given approval for the use of niraparib for all patients, and that is at a dosage of 200 to 300 milligrams oral daily for three years, with the lower dose given for patients who have a low platelet count or low body weight to prevent the common toxicity of thrombocytopenia.

Then you could consider longer durations in select individuals, but generally, these drugs are given for a limited period of time and continued unless a patient has significant toxicity or progression. The other two studies in the newly diagnosed ovarian cancer population was a study that looked at olaparib with bevacizumab maintenance. This was a study that included patients with germline or somatic mutations and BRCA 1 or 2 and/or genomic instability or homologous repair deficiency, as determined by the myriad my choice test.

And again, this population, a partial or complete response to chemotherapy and their first line therapy should have included bevacizumab. And so if one is on bevacizumab with their platinum based therapy, they should have a response to treatment, one could continue bevacizumab and add the addition of olaparib as a PARP inhibitor. And then the final study that we addressed was called switch therapy, and that we don't really have enough data to support its use, specifically that's with the drug called veliparib, and veliparib was given in addition to the chemotherapy and then continued as a maintenance therapy.

We don't really have sufficient data to suggest this was superior, equal, or less toxic than the approaches discussed above, which is single agent PARP inhibitor or bevacizumab with PARP inhibitor. And it should be noted, also, veliparib is not yet an FDA approved drug and not commercially available.

Brittany Harvey: OK, then what are the recommendations for PARP inhibitors for patients with recurrent epithelial ovarian cancer?

Dr. William Tew: Yeah, and this data has been around a little bit longer, and I think any oncologists that treat them with ovarian cancer are more comfortable with the evidence with these studies. So what we're talking about here is that patients who were in clinical remission and then their ovarian cancer recurs. And the first group of women that we look at is patients that are then retreated with platinum based therapy. Those women that have platinum sensitive disease, and then whether to offer PARP maintenance in the second line or more remission settings.

And there is very good data to support the use of PARP monotherapy in second or greater maintenance. This has been shown with all three commercially available PARP inhibitors, olaparib, rucaparib, and niraparib. We do know that women who have a germline or somatic pathogenic or likely pathogenic variant in the BRCA 1 or 2 genes have the highest benefit of maintenance PARP inhibition, and those patients have the strongest evidence to receive those drug.

So the only other point I wanted to make with current ovarian cancer is if a patient has received a PARP inhibitor in the past, there is no evidence to give a second exposure to PARP inhibitor. Those studies are being developed now, but PARP inhibitor use once in the life cycle is what's recommended. And then there's also evidence to use PARP inhibitor as an actual treatment. So not in the maintenance setting, and the drug most commonly used as one called niraparib or olaparib, and these are patients that have measurable disease or generally have platinum sensitive disease, and those women that have homologous repair deficiency, as determined by the Myriad myChoice test, and again, have platinum sensitive to disease do have benefit for treatment with PARP inhibitors.

Brittany Harvey: OK, then, so you just mentioned this, but is it correct that PARPi therapy for epithelial ovarian cancer should not be repeated over the course of treatment?

Dr. William Tew: Right now, that is what we recommend. All of the studies that looked at the use of PARP inhibitors disqualified women who have had prior PARP inhibitors. So as of now, we don't have any evidence to support the use of repeated PARP inhibition.

Brittany Harvey: And what does the guidelines say about using PARP inhibitors in combination with chemotherapy or other targeted agents?

Dr. William Tew: There are many studies going on currently looking at the use of PARP inhibitors in combination with immunotherapy, chemotherapy, and other targeted agents, but currently, at least in the recurrent setting, there is no data to support its use in combination with another anti-cancer treatment. Now, of course, in the context of a clinical trial, this would be very reasonable, and we encourage clinical trial participation.

The only studies that looked at PARP in combination with other anti-cancer treatments are in the first line setting, as I discussed earlier, including PARP inhibitors with bevacizumab, as in the case with olaparib or PARP inhibitors with chemotherapy, as is often the case with veliparib.

Brittany Harvey: OK, thank you. And then how should clinicians manage the adverse effects associated with PARP inhibitors?

Dr. William Tew: I think the first and foremost thing is to be aware of the specific side effect profile of each PARP inhibitor, because they can vary slightly between parts. The most common side effects include fatigue, nausea, change in appetite, and effects on the blood counts, and we gave guidance on each of those specific side effects. As far as the effects on the blood counts, anemia, I'd say, is one of the more common side effects across all PARPi's, and the use of blood transfusions is generally recommended if patients are symptomatic and their hemoglobin is below 8 to 7.

And then for neutropenia, usually, this requires hold of dosing, and we did not encourage the use of growth support, although it may be used in certain settings when the drugs on hold. And then the final cytopenia issue is the issue with platelets, and this is unfortunately very common side effect with niraparib. And we discussed earlier about starting at a lower dose, 200 milligrams of niraparib based on a weight and platelet count to help temper the degree of thrombocytopenia. But with thrombocytopenia, clearly, the drugs sometimes need to be held or discontinued if it's significant.

And with cytopenias, we do recommend close observation of laboratory blood work, particularly in the first month of use of PARP inhibitors, and then always being mindful if patients are on PARP inhibitors for prolonged periods of time that there has been reports of treatment related myelodysplastic syndromes and leukemias and that should be further worked up if there is any evidence of dysplasia.

Brittany Harvey: So then, what is the importance of this guideline in your view, and how will its implementation affect clinical practice?

Dr. William Tew: Well, I think this is the most up-to-date and comprehensive guideline on PARP inhibitors and will help, both clinicians and patients, understand all the practice changing studies, the populations, and the settings they will use, and all these studies that were published over the last five years. I think this last year we've seen such a rapid growth of clinical trial results and FDA approvals that this manuscript, I think, successfully puts them all together in table form and brief recommendations to better treat and provide proper management to your patients with ovarian cancer.

Brittany Harvey: And then finally, how will these guideline recommendations impact patients with ovarian cancer?

Dr. William Tew: We were very fortunate to have two patient advocates as part of our panel, and what they told us was that these recommendations will help them understand the scientific trials, will put in context when to use PARP inhibitors, and also to prepare them for those conversations that they have with their clinicians in discussing if they're a good candidate for a PARP inhibitor now or in the future. So we're really proud of that, that we were able to get our patients perspective in developing these guidelines.

Brittany Harvey: Definitely. Well, thank you for your work on these important and timely guidelines and for taking the time to join me on the podcast today, Dr. Tew.

Dr. William Tew: My pleasure. Thank you so much, Brittany, for having me.

Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/gynecologic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available on iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.