PARP Inhibitors in the Management of Ovarian Cancer Rapid Recommendation Update

An interview with Dr. William Tew from Memorial Sloan Kettering Cancer Center in New York, NY, lead author on "Poly(ADP-Ribose) Polymerase Inhibitors in the Management of Ovarian Cancer: ASCO Guideline Rapid Recommendation Update." Dr. Tew reviews changes to the recommendations for PARPi therapy for patients with epithelial ovarian cancer, and the outstanding questions in the field. For more information, visit www.asco.org/gynecologic-cancer-guidelines. TRANSCRIPT 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 asco.org/podcasts.  My name is Brittany Harvey, and today, I'm interviewing Dr. William Tew from Memorial Sloan Kettering Cancer Center in New York, New York; lead author on “PARP Inhibitors in the Management of Ovarian Cancer, ASCO Guideline Rapid Recommendation Update.” Thank you for being here, Dr. Tew.  Dr. William Tew: Thank you, Brittany. Glad to be here.  Brittany Harvey: Great. Then first, I'd like to note that 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: I do not.  Brittany Harvey: Thank you. Then let's get into the content of this rapid update. So, what prompted this rapid update to the ASCO Guideline on PARP inhibitor therapy in the management of ovarian cancer, which was previously published in 2020?  Dr. William Tew: Yeah, there's been rapid change in the use of PARP inhibitors over the last five years. We have seen marked improvements and patient outcomes with the use of PARP inhibitors in the maintenance setting and treatment settings.  And new data has developed specifically in the last three months that we felt it was really important to help our patients and their providers, give them the best and safest treatments with PARP inhibitors.  Brittany Harvey: Understood. So, then based off this new data that you mentioned, what are the updated recommendations from the expert panel?  Dr. William Tew: Well, there's a few. First, at ASCO 2022 in June, there was the ATHENA-MONO phase III randomized control trial that was presented and published looking at rucaparib monotherapy in patients with stage III-IV epithelial ovarian cancer who were in complete or partial response to platinum-based therapy and in remission. And then studies showed a significant improvement in progression-free survival.  And that's what first prompted the update of the guideline. We felt it was an important note that now, there are three PARP inhibitors that are approved and showing significant benefit in patients in the first remission setting. And those are olaparib, niraparib, and rucaparib.  And then as we were working on the guideline, there has been several updates provided primarily through Dear Doctor letters directed through the U.S. FDA, as well as different labeling changes that were made to different PARP inhibitors.  However, the changes that were made are in the settings outside of the first line setting. So, we are talking about patients who had recurrence of their ovarian cancer and where PARPs are being used either as treatment or as a maintenance strategy after completion of another round of platinum-based treatment.  Brittany Harvey: Understood. So, these sound like important updates to the recommendations. So, then what should clinicians know as they implement these updated recommendations?  Dr. William Tew: Well, I think first and foremost, PARP inhibitors are a really critical treatment strategy for our patients. And patients that benefit the most from PARP inhibitors are women with a germline or somatic mutation in the BRCA gene. These are the patients that are going to benefit the most.  And then I think where the confusion lies is how best to use PARP inhibitors in patients that don't have a BRCA mutation. These groups of patients kind of fall into different categories.  One, a group of patients that have what's called homologous repair deficiency, or those patients that don't have a BRCA gene or have a BRCA gene mutation, or have this HRD positive status.  The emerging data that has been presented is really focused on mostly these patients, this non-BRCA patient population. And again, I want to just be cautious here because this is all evolving data and I suspect further data is going to emerge over the coming months and years.  And we wanted to give some flexibility as far as how patients and their providers use PARP inhibitors, but we felt given that this new emerging data specifically with signals affecting survival, was important to outline to our community.  Brittany Harvey: Excellent. And then you've just touched on those who respond best to PARP inhibitor therapy, but how does this rapid update impact patients with epithelial ovarian cancer?  Dr. William Tew: Yeah, I think what we described and outlined in this updated guideline is that, one, as a general rule, PARP inhibitors are not particularly recommended in patients as a treatment.  That is, if patients have recurrence of their ovarian cancer, using PARP inhibitors as a treatment rather than a maintenance strategy does not offer significant benefit and may have some survival decrements. At least, this is the data that we are following.  And so, as a general recommendation, we're expressing caution in the use of PARP inhibitors in patients that have platinum sensitive recurrence as a treatment. And we are continuing to recommend (this was in the initial 2020 guideline) that PARP inhibitor monotherapy is not recommended for patients with platinum-resistant recurrent ovarian cancer or BRCA wild-type.  The other broad category is PARP inhibitor maintenance, and where we've made some adjustments in the guideline is as far as the strength and the overall recommendations of the use of PARP inhibitors after completion of platinum-based therapy in the recurrent setting.  And specifically, we're expressing caution and the use of PARP inhibitors, particularly for those that have BRCA wild-type, meaning they don't have a germline or somatic BRCA mutation, and expressing some caution in patients that are just homologous repair deficient score positive.  Brittany Harvey: Well, I appreciate you reviewing the updated data that the panel reviewed and what those new recommendations that you all made.  So, you just mentioned that further data may emerge over the coming days and years. So, what are the outstanding questions regarding PARPi therapy in the management of ovarian cancer?  Dr. William Tew: Well, I think a few things. One, the way PARP inhibitors have been developed was first in the recurrent setting as a treatment, then in the recurrent setting as a maintenance, and most recently, in the frontline treatment as maintenance therapy.  And what we're seeing as this data evolves is that PARP inhibitor has remain a very important treatment strategy in the first line maintenance group. And patients with BRCA mutations continue to have significant improvements and outcomes.  But what I think the data that we're following closely, is what about those patients that have recurrent ovarian cancer and where PARPs now are being used as treatment and maintenance — we're seeing that as a treatment, there may be harm, although, again, cautioned because of the data that is used. There's faults with how we look at this data.  But really, these subgroups of patients, specifically those patients without a positive HRD score or those patients without a BRCA mutation, is the benefit going to still outweigh the risk in the PARP inhibitor maintenance setting, particularly in the recurrent setting.  Brittany Harvey: Yes, those are important questions and I'm sure the panel will keep their eye on those to update the guideline further as needed.  So, I want to thank you so much for your work on this rapid update, and thank you for your time today, Dr. Tew.  Dr. William Tew: You’re welcome.  Brittany: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. 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