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Ongoing PARP Inhibitor Research in Ovarian Cancer

Panelists: Bradley J. Monk, MD, University of Arizona and Creighton University School of Medicine at St. Joseph’s Hospital; Robert L. Coleman, MD, MD Anderson Cancer Center; Thomas Herzog, MD, University of Cincinnati; Kathleen N. Moore, MD, Stephenson Cancer Center; Angeles Alvarez Secord, MD, Duke University School of Medicine
Published: Thursday, Mar 09, 2017


Transcript:

Bradley J. Monk, MD:
Let’s talk about what we’re doing to try to answer some of these questions because many of these questions that I’m asking are really rhetorical. I’m just trying to get you guys going here. So, you mentioned the NOVA trial. Let’s talk about the niraparib studies that are ongoing. Tell us about your QUADRA trial, what that is and what’s that supposed to answer?

Kathleen N. Moore, MD: QUADRA will actually be, potentially, a confirmatory trial for NOVA. It’s a single-agent, single-arm study of niraparib, but the standard dose is 300 mg/day in patients who have high-grade serous ovarian cancer and they are in fourth- or fifth-line. That is how it’s open right now.

Bradley J. Monk, MD: But the purpose of QUADRA is treatment versus maintenance?

Kathleen N. Moore, MD: Correct.

Bradley J. Monk, MD: So, it’s a treatment?

Kathleen N. Moore, MD: It’s a treatment question, correct.

Bradley J. Monk, MD: And so, we can now switch over. This is the same thing that you have a treatment for with rucaparib, and now they have a maintenance trial and that maintenance trial is called ARIEL3. Tell us about that.

Robert L. Coleman, MD: ARIEL3 is an ongoing randomized trial that’s looking at this concept of switch maintenance. So, again, it’s a platinum-sensitive cohort induction and then randomization between rucaparib and placebo. But I will say, unlike the SOLO-2, it’s capturing patients who have HRD and it’s assessing that in a prospective way.

Bradley J. Monk, MD: So, would it be safe to say that NOVA and ARIEL3 are pretty similar?

Robert L. Coleman, MD: Except for the way that they assess for the HRD.

Bradley J. Monk, MD: ARIEL3-NOVA, NOVA-niraparib, and ARIEL3-rucaparib are similar. We’ve got QUADRA, similar to the existing olaparib indication treatment fourth-line and beyond. So, there are some similarities. What about frontline? We have SOLO-1, which is in olaparib and is frontline maintenance in germline BRCA. Who wants to tell us about PRIMA?

Angeles Alvarez Secord, MD: PRIMA is a niraparib trial, frontline maintenance, very similar to SOLO-1.

Bradley J. Monk, MD: In unselected patients?

Angeles Alvarez Secord, MD: Unselected fashion.

Bradley J. Monk, MD: And then trying to validate the HRD. So, I think that’s really a great opportunity.

Robert L. Coleman, MD: And I would add, if you’re talking about frontline maintenance, we have to talk about veliparib, too, just to be inclusive because that’s in there as well.

Bradley J. Monk, MD: Yes, we will. Of course we will. So, in PRIMA, we go ahead. You get maintenance, you respond to the platinum just like NOVA, but we’re also going to test for HRD to help enrich it. Now, to your point about veliparib. Why don’t we give the PARP inhibitor with the chemotherapy during the frontline? Tell us about it.

Robert L. Coleman, MD: Right. And that’s really the focus of this trial.

Bradley J. Monk, MD: GOG-3005.

Robert L. Coleman, MD: Yes, but we learned from our experience with olaparib, actually, in combining it with full-dose chemotherapy, it’s very difficult to give PARP inhibitors. So, that problem we talked about before, of myelosuppression, becomes a very real issue with DNA-damaging chemotherapy. But veliparib probably is less potent on that specific angle, and so it can be combined with full-dose chemotherapy. Kathy Bell-McGuinn did a fantastic job of running a very large phase I trial trying to sort out dose and schedule for this. And so, GOG-3005 is a prospective phase III trial that’s looking at the ability of veliparib to be combined with chemotherapy and to be used in a maintenance way as opposed to chemotherapy alone. That trial is ongoing now.

Bradley J. Monk, MD: So, you have an approval. You go to biomarkers, which we’re doing, expanding the HRD, earlier lines of therapy, and then you go to combinations. Go ahead, tell us, Tom, about the PARP inhibitor combination.

Thomas Herzog, MD: You’ve got other combinations. You’ve got olaparib with bevacizumab in the PAOLA-1 trial, and then in the ICON9 trial, you have olaparib that’s combined with cediranib.

Bradley J. Monk, MD: The 2 anti-VEGF?

Thomas Herzog, MD: Exactly. And immuno mania is not far away, so you’ll see combinations with immune checkpoint inhibitors, immunotherapies.

Bradley J. Monk, MD: Well, let’s talk about that. Is there a reason to study immunotherapy in ovarian cancer? Does that make sense?

Thomas Herzog, MD: Absolutely. So, you have a relatively high antigenic load, although we have higher amounts in cervical and endometrial cancers, but it’s still a very fascinating subject. Preliminary data have not been overwhelming as a single agent, certainly. But the combinations are very interesting in which we might be able to increase the number of tumor-infiltrating lymphocytes initially to change the outcomes for these patients.

Bradley J. Monk, MD: And there’s a lot of interest in adding checkpoint inhibitors to chemotherapy, to your point, so that the chemotherapy increases the neoantigens and mutational burden. And so, you’ve got atezolizumab with bevacizumab, kind of the Roche-Genentech strategy, and then the avelumab with chemotherapy, the Pfizer strategy. So, we have large phase III trials with atezolizumab and avelumab—frontline, resistant disease—and that’s maybe why what we should talk about next is immunotherapy. We just don’t have any approvals yet.

Thomas Herzog, MD: Right.

Transcript Edited for Clarity
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Transcript:

Bradley J. Monk, MD:
Let’s talk about what we’re doing to try to answer some of these questions because many of these questions that I’m asking are really rhetorical. I’m just trying to get you guys going here. So, you mentioned the NOVA trial. Let’s talk about the niraparib studies that are ongoing. Tell us about your QUADRA trial, what that is and what’s that supposed to answer?

Kathleen N. Moore, MD: QUADRA will actually be, potentially, a confirmatory trial for NOVA. It’s a single-agent, single-arm study of niraparib, but the standard dose is 300 mg/day in patients who have high-grade serous ovarian cancer and they are in fourth- or fifth-line. That is how it’s open right now.

Bradley J. Monk, MD: But the purpose of QUADRA is treatment versus maintenance?

Kathleen N. Moore, MD: Correct.

Bradley J. Monk, MD: So, it’s a treatment?

Kathleen N. Moore, MD: It’s a treatment question, correct.

Bradley J. Monk, MD: And so, we can now switch over. This is the same thing that you have a treatment for with rucaparib, and now they have a maintenance trial and that maintenance trial is called ARIEL3. Tell us about that.

Robert L. Coleman, MD: ARIEL3 is an ongoing randomized trial that’s looking at this concept of switch maintenance. So, again, it’s a platinum-sensitive cohort induction and then randomization between rucaparib and placebo. But I will say, unlike the SOLO-2, it’s capturing patients who have HRD and it’s assessing that in a prospective way.

Bradley J. Monk, MD: So, would it be safe to say that NOVA and ARIEL3 are pretty similar?

Robert L. Coleman, MD: Except for the way that they assess for the HRD.

Bradley J. Monk, MD: ARIEL3-NOVA, NOVA-niraparib, and ARIEL3-rucaparib are similar. We’ve got QUADRA, similar to the existing olaparib indication treatment fourth-line and beyond. So, there are some similarities. What about frontline? We have SOLO-1, which is in olaparib and is frontline maintenance in germline BRCA. Who wants to tell us about PRIMA?

Angeles Alvarez Secord, MD: PRIMA is a niraparib trial, frontline maintenance, very similar to SOLO-1.

Bradley J. Monk, MD: In unselected patients?

Angeles Alvarez Secord, MD: Unselected fashion.

Bradley J. Monk, MD: And then trying to validate the HRD. So, I think that’s really a great opportunity.

Robert L. Coleman, MD: And I would add, if you’re talking about frontline maintenance, we have to talk about veliparib, too, just to be inclusive because that’s in there as well.

Bradley J. Monk, MD: Yes, we will. Of course we will. So, in PRIMA, we go ahead. You get maintenance, you respond to the platinum just like NOVA, but we’re also going to test for HRD to help enrich it. Now, to your point about veliparib. Why don’t we give the PARP inhibitor with the chemotherapy during the frontline? Tell us about it.

Robert L. Coleman, MD: Right. And that’s really the focus of this trial.

Bradley J. Monk, MD: GOG-3005.

Robert L. Coleman, MD: Yes, but we learned from our experience with olaparib, actually, in combining it with full-dose chemotherapy, it’s very difficult to give PARP inhibitors. So, that problem we talked about before, of myelosuppression, becomes a very real issue with DNA-damaging chemotherapy. But veliparib probably is less potent on that specific angle, and so it can be combined with full-dose chemotherapy. Kathy Bell-McGuinn did a fantastic job of running a very large phase I trial trying to sort out dose and schedule for this. And so, GOG-3005 is a prospective phase III trial that’s looking at the ability of veliparib to be combined with chemotherapy and to be used in a maintenance way as opposed to chemotherapy alone. That trial is ongoing now.

Bradley J. Monk, MD: So, you have an approval. You go to biomarkers, which we’re doing, expanding the HRD, earlier lines of therapy, and then you go to combinations. Go ahead, tell us, Tom, about the PARP inhibitor combination.

Thomas Herzog, MD: You’ve got other combinations. You’ve got olaparib with bevacizumab in the PAOLA-1 trial, and then in the ICON9 trial, you have olaparib that’s combined with cediranib.

Bradley J. Monk, MD: The 2 anti-VEGF?

Thomas Herzog, MD: Exactly. And immuno mania is not far away, so you’ll see combinations with immune checkpoint inhibitors, immunotherapies.

Bradley J. Monk, MD: Well, let’s talk about that. Is there a reason to study immunotherapy in ovarian cancer? Does that make sense?

Thomas Herzog, MD: Absolutely. So, you have a relatively high antigenic load, although we have higher amounts in cervical and endometrial cancers, but it’s still a very fascinating subject. Preliminary data have not been overwhelming as a single agent, certainly. But the combinations are very interesting in which we might be able to increase the number of tumor-infiltrating lymphocytes initially to change the outcomes for these patients.

Bradley J. Monk, MD: And there’s a lot of interest in adding checkpoint inhibitors to chemotherapy, to your point, so that the chemotherapy increases the neoantigens and mutational burden. And so, you’ve got atezolizumab with bevacizumab, kind of the Roche-Genentech strategy, and then the avelumab with chemotherapy, the Pfizer strategy. So, we have large phase III trials with atezolizumab and avelumab—frontline, resistant disease—and that’s maybe why what we should talk about next is immunotherapy. We just don’t have any approvals yet.

Thomas Herzog, MD: Right.

Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Clinical Vignette Series: 34th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow®Feb 28, 20182.0
Oncology Best Practice™: Expert Perspectives to Incorporate Evidence on PARP Inhibitors into Practice and Optimize the Medical Management of Ovarian CancerOct 31, 20181.0
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