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Sequencing Therapies for 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 02, 2017


Transcript:

Bradley J. Monk, MD:
Katie, you’ve talked about lots of lines of therapy. I think, at least in my practice, I am going to use the HRD test, and if the HRD test is positive, I might use PARP inhibitors earlier. See what I’m saying? Because it’s about sequencing.

Kathleen N. Moore, MD: Right.

Bradley J. Monk, MD: And the thing we do the worst is sequence. I don’t know which drug to give before what drug.

Kathleen N. Moore, MD: Well, we’ve been entirely empiric for our whole life. So, I think yes and maybe not quite yes. On one hand, you have a platinum-sensitive patient. You send the Myriad myChoice, or potentially someday the Clovis test, and you know who your patient is who’s most likely to benefit and maybe that helps you select your strategy for treating that patient. Are you going to go down a bevacizumab and then bevacizumab maintenance pathway with an overall survival benefit, but nowhere near that PFS benefit that we’re seeing, or are you going to move niraparib up into that line of therapy as more switch maintenance, where you do whatever chemotherapy backbone you choose to do—which is clinically doxorubicin in that line because it doesn’t matter—and then move to niraparib because of that PFS benefit? Again, we’re comparing completely different patient populations. The patients who were enrolled on this study had to respond to their frontline therapy or their recurrent therapy, and then they went on. Whereas, in your study, you’re basing it from the time they become platinum-sensitive and they get chemotherapy. Half of those patients never made it to niraparib, so you can’t compare. It’s real hard to compare the PFSs and say, “This is better than that.”

Robert L. Coleman, MD: I think the nuance here is really important, because in all of these trials that have a switch maintenance, there’s a large portion of patients who didn’t have a complete response.

Thomas Herzog, MD: That’s what I was going to say. It changes the whole paradigm in maintenance, right?

Robert L. Coleman, MD: So, to me, that needs to be sorted out. I’m sorry, but I find it very hard to take a patient off of active therapy I know is working to put them on a trial with a switch maintenance, where it’s placebo-controlled. That’s not my practice. My practice is take CR patients or patients who are intolerant to chemotherapy and then maybe try that particular option. Let me see that data and then I’m going to be practice-changing.

Bradley J. Monk, MD: In the December 6, 2016, bevacizumab approval, it’s true maintenance. You get chemotherapy/bevacizumab. Whether it’s carboplatin/gemcitabine or carboplatin/paclitaxel and the chemotherapy ultimately stops, the bevacizumab continues. Now, what you’re talking about, you respond to platinum and then it’s maintenance—but you switch it. Thomas Herzog, MD: But you might have just a partial response, which is a real change.

Bradley J. Monk, MD: That’s what I want to know. It’s a matter of what’s the difference between maintenance and treatment?

Robert L. Coleman, MD: Exactly.

Thomas Herzog, MD: That’s exactly right. It’s really switch treatment.

Bradley J. Monk, MD: It’s switch treatment?

Kathleen N. Moore, MD: Right. You’re switching to something different.

Robert L. Coleman, MD: And it’s switch treatment to placebo. So, look at the control group. The 3-month difference is basically the first CAT scan, right?

Bradley J. Monk, MD: Sometimes it’s 5.

Robert L. Coleman, MD: No, I’m saying, if you have a proportion of patients that have a complete response, then I would expect to see that, right?

Bradley J. Monk, MD: It’s 2 assessments.

Robert L. Coleman, MD: Right. But what is the progression-free survival in a platinum-sensitive patient who gets a complete response?

Bradley J. Monk, MD: And that’s why I use the HRD example because HRD is going to guide me to more treatment-based approaches with these agents because these patients need a holiday at some point. And sequencing the holiday is some of the most difficult issues. Is it truly maintenance then only when there’s a CR? Is that what you’re saying?

Angeles Alvarez Secord, MD: Well, what’s going to help address that question is exploratory analysis of GOG-213, and I’m sure you have that in your protocol to evaluate patients who have BRCA versus non-BRCA mutations.

Robert L. Coleman, MD: Yes.

Angeles Alvarez Secord, MD: That’s going to help guide us in the future and address this question, because I don’t think there will be a benefit in that group with bevacizumab because the GOG-218 data were essentially negative, right? But it might be helpful, in terms of seeing what the difference is in outcome, to get those numbers.

Bradley J. Monk, MD: I want to move past this, but I want to get some clarity. So, we love to teach people and that’s why we’re here today. You’re teaching me and I appreciate it. I’m still confused about this maintenance idea. In the NOVA trial, maintenance is in the title, but half of the patients still have cancer. How can I call that maintenance if they had PRs until their last treatment?

Angeles Alvarez Secord, MD: I always learned that when somebody had a CR and you continued therapy, that’s consolidation. But I think what’s happened is we’ve just used maintenance for everything, right? We still use that terminology, “consolidation,” correct?

Thomas Herzog, MD: Yes. I think a lot of people have kicked that around. Consolidation really comes out of the liquid-based tumors.

Robert L. Coleman, MD: Right. It’s usually a different regimen.

Thomas Herzog, MD: That’s right, and that’s really where that has come from. In our trials heretofore that we’ve done in gynecologic malignancies, we’ve required a complete response—biochemical based on CA-125 and radiologic and physical exams.

Angeles Alvarez Secord, MD: But not for GOG-218?

Kathleen N. Moore, MD: Not for GOG-218.

Robert L. Coleman, MD: No. All the trials that had concurrent followed by maintenance all allowed that. But if you look at GOG-212…

Thomas Herzog, MD: Yes, once it had…

Robert L. Coleman, MD: ACR (American College of Radiology) Appropriateness Criteria to go on to that.

Bradley J. Monk, MD: So, that’s interesting. It doesn’t sound like we’re going to get that solved, but I think we’re expanding the awareness and the subtleties of these definitions.

Transcript Edited for Clarity
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Transcript:

Bradley J. Monk, MD:
Katie, you’ve talked about lots of lines of therapy. I think, at least in my practice, I am going to use the HRD test, and if the HRD test is positive, I might use PARP inhibitors earlier. See what I’m saying? Because it’s about sequencing.

Kathleen N. Moore, MD: Right.

Bradley J. Monk, MD: And the thing we do the worst is sequence. I don’t know which drug to give before what drug.

Kathleen N. Moore, MD: Well, we’ve been entirely empiric for our whole life. So, I think yes and maybe not quite yes. On one hand, you have a platinum-sensitive patient. You send the Myriad myChoice, or potentially someday the Clovis test, and you know who your patient is who’s most likely to benefit and maybe that helps you select your strategy for treating that patient. Are you going to go down a bevacizumab and then bevacizumab maintenance pathway with an overall survival benefit, but nowhere near that PFS benefit that we’re seeing, or are you going to move niraparib up into that line of therapy as more switch maintenance, where you do whatever chemotherapy backbone you choose to do—which is clinically doxorubicin in that line because it doesn’t matter—and then move to niraparib because of that PFS benefit? Again, we’re comparing completely different patient populations. The patients who were enrolled on this study had to respond to their frontline therapy or their recurrent therapy, and then they went on. Whereas, in your study, you’re basing it from the time they become platinum-sensitive and they get chemotherapy. Half of those patients never made it to niraparib, so you can’t compare. It’s real hard to compare the PFSs and say, “This is better than that.”

Robert L. Coleman, MD: I think the nuance here is really important, because in all of these trials that have a switch maintenance, there’s a large portion of patients who didn’t have a complete response.

Thomas Herzog, MD: That’s what I was going to say. It changes the whole paradigm in maintenance, right?

Robert L. Coleman, MD: So, to me, that needs to be sorted out. I’m sorry, but I find it very hard to take a patient off of active therapy I know is working to put them on a trial with a switch maintenance, where it’s placebo-controlled. That’s not my practice. My practice is take CR patients or patients who are intolerant to chemotherapy and then maybe try that particular option. Let me see that data and then I’m going to be practice-changing.

Bradley J. Monk, MD: In the December 6, 2016, bevacizumab approval, it’s true maintenance. You get chemotherapy/bevacizumab. Whether it’s carboplatin/gemcitabine or carboplatin/paclitaxel and the chemotherapy ultimately stops, the bevacizumab continues. Now, what you’re talking about, you respond to platinum and then it’s maintenance—but you switch it. Thomas Herzog, MD: But you might have just a partial response, which is a real change.

Bradley J. Monk, MD: That’s what I want to know. It’s a matter of what’s the difference between maintenance and treatment?

Robert L. Coleman, MD: Exactly.

Thomas Herzog, MD: That’s exactly right. It’s really switch treatment.

Bradley J. Monk, MD: It’s switch treatment?

Kathleen N. Moore, MD: Right. You’re switching to something different.

Robert L. Coleman, MD: And it’s switch treatment to placebo. So, look at the control group. The 3-month difference is basically the first CAT scan, right?

Bradley J. Monk, MD: Sometimes it’s 5.

Robert L. Coleman, MD: No, I’m saying, if you have a proportion of patients that have a complete response, then I would expect to see that, right?

Bradley J. Monk, MD: It’s 2 assessments.

Robert L. Coleman, MD: Right. But what is the progression-free survival in a platinum-sensitive patient who gets a complete response?

Bradley J. Monk, MD: And that’s why I use the HRD example because HRD is going to guide me to more treatment-based approaches with these agents because these patients need a holiday at some point. And sequencing the holiday is some of the most difficult issues. Is it truly maintenance then only when there’s a CR? Is that what you’re saying?

Angeles Alvarez Secord, MD: Well, what’s going to help address that question is exploratory analysis of GOG-213, and I’m sure you have that in your protocol to evaluate patients who have BRCA versus non-BRCA mutations.

Robert L. Coleman, MD: Yes.

Angeles Alvarez Secord, MD: That’s going to help guide us in the future and address this question, because I don’t think there will be a benefit in that group with bevacizumab because the GOG-218 data were essentially negative, right? But it might be helpful, in terms of seeing what the difference is in outcome, to get those numbers.

Bradley J. Monk, MD: I want to move past this, but I want to get some clarity. So, we love to teach people and that’s why we’re here today. You’re teaching me and I appreciate it. I’m still confused about this maintenance idea. In the NOVA trial, maintenance is in the title, but half of the patients still have cancer. How can I call that maintenance if they had PRs until their last treatment?

Angeles Alvarez Secord, MD: I always learned that when somebody had a CR and you continued therapy, that’s consolidation. But I think what’s happened is we’ve just used maintenance for everything, right? We still use that terminology, “consolidation,” correct?

Thomas Herzog, MD: Yes. I think a lot of people have kicked that around. Consolidation really comes out of the liquid-based tumors.

Robert L. Coleman, MD: Right. It’s usually a different regimen.

Thomas Herzog, MD: That’s right, and that’s really where that has come from. In our trials heretofore that we’ve done in gynecologic malignancies, we’ve required a complete response—biochemical based on CA-125 and radiologic and physical exams.

Angeles Alvarez Secord, MD: But not for GOG-218?

Kathleen N. Moore, MD: Not for GOG-218.

Robert L. Coleman, MD: No. All the trials that had concurrent followed by maintenance all allowed that. But if you look at GOG-212…

Thomas Herzog, MD: Yes, once it had…

Robert L. Coleman, MD: ACR (American College of Radiology) Appropriateness Criteria to go on to that.

Bradley J. Monk, MD: So, that’s interesting. It doesn’t sound like we’re going to get that solved, but I think we’re expanding the awareness and the subtleties of these definitions.

Transcript Edited for Clarity
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