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Niraparib Maintenance Therapy 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: Tuesday, Feb 28, 2017


Transcript:

Bradley J. Monk, MD:
So, I told you guys that there were 3 PARP inhibitors. There’s olaparib, which is approved under accelerated approval. SOLO-2 trial, which is a maintenance trial, has been announced to be positive; we haven’t seen the data. We talked about rucaparib, which also is a phase II, and it’s submitted for accelerated approval—PDUFA date is February 23rd. But this idea of maintenance, which is EMA-approved in Europe for olaparib, is something we really like. And in niraparib now, the third PARP inhibitor, we finally have a phase III maintenance trial that’s positive and published in the New England Journal of Medicine. Tell us about it; it’s called NOVA.

Angeles Alvarez Secord, MD: That’s right, it’s the NOVA trial. It was over 500 patients, and they really were evaluating patients who had platinum-sensitive disease that were treated with chemotherapy, at least 4 cycles, and had either a complete response or a partial response. So, it’s truly a maintenance trial, as you discussed. They evaluated them in 2 cohorts: patients who had a germline mutation in BRCA and patients who had a nongermline mutation in BRCA. But then they had the test, the myChoice HRD test.

Bradley J. Monk, MD: By Myriad.

Angeles Alvarez Secord, MD: And so, then they evaluated these 3 different groups—and actually, they drill down even more, but in the manuscript, it’s basically these 3 different groups—and across the board, the maintenance niraparib approach resulted in improved progression-free survival in all 3 groups. The numbers there are pretty impressive. It was 22 months in the group that was treated with niraparib versus about 5 months in those who got placebo.

Bradley J. Monk, MD: Actually, I’m going to enjoy that. Think of that: 22 months PFS versus 5.

Angeles Alvarez Secord, MD: Well, I know you’re a hazard ratio guy. The hazard ratio was 0.27.

Bradley J. Monk, MD: Oh, that’s not as good as the Study 19 with olaparib, which is 0.18. Does that mean niraparib is not as good a drug? I’m a cross-trial comparison guy.

Angeles Alvarez Secord, MD: I’m not even going to go there. I’m going to move on.

Bradley J. Monk, MD: So, that was a phase II in olaparib, and it’s not fair to compare the maintenance.

Angeles Alvarez Secord, MD: It’s a phase III trial.

Bradley J. Monk, MD: This is a phase III. Thank you.

Angeles Alvarez Secord, MD: I think, regardless, they work. PARP inhibitors work in this setting to prevent disease progression. The next group, they did not have a germline mutation in BRCA, but they had a positive HRD test. And in that group, you had about a 9-month difference in progression-free survival. So, it was 12.9 months for the group that got niraparib and it was 3.8 months for the group that was treated with placebo, and the hazard ratio here was 0.38, so about 60% reduction. Now, let’s look at the last group. The last group was nongermline BRCA mutation, and this group had about a 6-month improvement. It was 9.3 months with the niraparib treatment versus 3.9 months. Hazard ratio there was 0.45. Here we’ve gone from the situation where I was thinking we would be directing more toward precision medicine, personalized care approach, or using biomarkers to determine who’s going to benefit from therapy at all. Now we’re in a situation where it may be everybody benefits, but we can determine who’s going to get the highest magnitude of benefit if they had the biomarker. I want to go back. Can I go back for a second?

Bradley J. Monk, MD: Yes, this is excellent.

Angeles Alvarez Secord, MD: If you read this paper, dive into the supplementary appendix. Because in the appendix, they’ll break down that group that has a nongermline BRCA mutation, but they’re HRD-positive. When I first saw this data I thought, “Well, the somatic patients, the patients who had a somatic tumor mutation, are going to be the ones driving this hazard ratio.” But actually, it was beneficial in the group that had a somatic mutation as well as the group that was germline somatic mutation–negative but HRD-positive, which was a pleasant surprise for me personally.

Robert L. Coleman, MD: In reality, this is what we would have expected to see. I think, given what we already know from olaparib and what we’ve seen actually in rucaparib, that HRD patient population—specifically if they have disease left after platinum induction therapy, which we know half the patients in that study did have—then I think that’s what we’re essentially seeing is response rates to resident disease.

Bradley J. Monk, MD: So, let me put a different spin on it. It works great in a germline BRCA. It works pretty well in the HRD-positive. But even without the test it still works. Even in the HRD-negative, it still has a hazard ratio of about 0.7 and a 3-month PFS.

Angeles Alvarez Secord, MD: No, the hazard ratio in the HRD-negative group was 0.45.

Bradley J. Monk, MD: Okay.

Thomas Herzog, MD: I think it’s 0.58.

Angeles Alvarez Secord, MD: Oh, maybe if you drill down to just the negative group.

Thomas Herzog, MD: You do germline-negative, HRD-negative.

Angeles Alvarez Secord, MD: Oh, yes, you’re right.

Kathleen N. Moore, MD: It’s really, really good.

Bradley J. Monk, MD: It was 0.6, with about a difference in the median of 3.

Angeles Alvarez Secord, MD: It’s still 40% reduction.

Bradley J. Monk, MD: Yes. So, do we need the HRD test? That’s what I’m trying to get at. The numbers are less important.

Angeles Alvarez Secord, MD: I think you do because what we’re all recognizing is that personalized therapy or precision medicine isn’t just about the biomarker to direct therapy. It’s also about discussing with patients the toxicities and quality-of-life issue. And so, this way when we use the test, I can say, “This is the benefit that you’re going to receive from the drug and here are the side effects” and see what that value is for the patient.

Bradley J. Monk, MD: What do you think, Tom? It has a chance of working either way, but with the information, you could have more confidence.

Thomas Herzog, MD: Well, there are 2 ways of looking at it. One is that niraparib is very, very effective in all-comers. The magnitude of effect rivals that of any chemotherapy that you would see in that setting, so you could argue not to have the test. On the other hand, I agree with Angeles in the sense that we have multiple therapies coming and a number of therapies to choose from now. And when you’re looking at a difference of 3.1 months versus the profound differences that you saw of 17 months and some of the other ones, you have to balance that. Having that information, in my opinion, would be helpful. The question is, how much is that going to cost to get that information and how does that fit into the whole rubric of how we’re going to spend our healthcare resources?

Transcript Edited for Clarity
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Transcript:

Bradley J. Monk, MD:
So, I told you guys that there were 3 PARP inhibitors. There’s olaparib, which is approved under accelerated approval. SOLO-2 trial, which is a maintenance trial, has been announced to be positive; we haven’t seen the data. We talked about rucaparib, which also is a phase II, and it’s submitted for accelerated approval—PDUFA date is February 23rd. But this idea of maintenance, which is EMA-approved in Europe for olaparib, is something we really like. And in niraparib now, the third PARP inhibitor, we finally have a phase III maintenance trial that’s positive and published in the New England Journal of Medicine. Tell us about it; it’s called NOVA.

Angeles Alvarez Secord, MD: That’s right, it’s the NOVA trial. It was over 500 patients, and they really were evaluating patients who had platinum-sensitive disease that were treated with chemotherapy, at least 4 cycles, and had either a complete response or a partial response. So, it’s truly a maintenance trial, as you discussed. They evaluated them in 2 cohorts: patients who had a germline mutation in BRCA and patients who had a nongermline mutation in BRCA. But then they had the test, the myChoice HRD test.

Bradley J. Monk, MD: By Myriad.

Angeles Alvarez Secord, MD: And so, then they evaluated these 3 different groups—and actually, they drill down even more, but in the manuscript, it’s basically these 3 different groups—and across the board, the maintenance niraparib approach resulted in improved progression-free survival in all 3 groups. The numbers there are pretty impressive. It was 22 months in the group that was treated with niraparib versus about 5 months in those who got placebo.

Bradley J. Monk, MD: Actually, I’m going to enjoy that. Think of that: 22 months PFS versus 5.

Angeles Alvarez Secord, MD: Well, I know you’re a hazard ratio guy. The hazard ratio was 0.27.

Bradley J. Monk, MD: Oh, that’s not as good as the Study 19 with olaparib, which is 0.18. Does that mean niraparib is not as good a drug? I’m a cross-trial comparison guy.

Angeles Alvarez Secord, MD: I’m not even going to go there. I’m going to move on.

Bradley J. Monk, MD: So, that was a phase II in olaparib, and it’s not fair to compare the maintenance.

Angeles Alvarez Secord, MD: It’s a phase III trial.

Bradley J. Monk, MD: This is a phase III. Thank you.

Angeles Alvarez Secord, MD: I think, regardless, they work. PARP inhibitors work in this setting to prevent disease progression. The next group, they did not have a germline mutation in BRCA, but they had a positive HRD test. And in that group, you had about a 9-month difference in progression-free survival. So, it was 12.9 months for the group that got niraparib and it was 3.8 months for the group that was treated with placebo, and the hazard ratio here was 0.38, so about 60% reduction. Now, let’s look at the last group. The last group was nongermline BRCA mutation, and this group had about a 6-month improvement. It was 9.3 months with the niraparib treatment versus 3.9 months. Hazard ratio there was 0.45. Here we’ve gone from the situation where I was thinking we would be directing more toward precision medicine, personalized care approach, or using biomarkers to determine who’s going to benefit from therapy at all. Now we’re in a situation where it may be everybody benefits, but we can determine who’s going to get the highest magnitude of benefit if they had the biomarker. I want to go back. Can I go back for a second?

Bradley J. Monk, MD: Yes, this is excellent.

Angeles Alvarez Secord, MD: If you read this paper, dive into the supplementary appendix. Because in the appendix, they’ll break down that group that has a nongermline BRCA mutation, but they’re HRD-positive. When I first saw this data I thought, “Well, the somatic patients, the patients who had a somatic tumor mutation, are going to be the ones driving this hazard ratio.” But actually, it was beneficial in the group that had a somatic mutation as well as the group that was germline somatic mutation–negative but HRD-positive, which was a pleasant surprise for me personally.

Robert L. Coleman, MD: In reality, this is what we would have expected to see. I think, given what we already know from olaparib and what we’ve seen actually in rucaparib, that HRD patient population—specifically if they have disease left after platinum induction therapy, which we know half the patients in that study did have—then I think that’s what we’re essentially seeing is response rates to resident disease.

Bradley J. Monk, MD: So, let me put a different spin on it. It works great in a germline BRCA. It works pretty well in the HRD-positive. But even without the test it still works. Even in the HRD-negative, it still has a hazard ratio of about 0.7 and a 3-month PFS.

Angeles Alvarez Secord, MD: No, the hazard ratio in the HRD-negative group was 0.45.

Bradley J. Monk, MD: Okay.

Thomas Herzog, MD: I think it’s 0.58.

Angeles Alvarez Secord, MD: Oh, maybe if you drill down to just the negative group.

Thomas Herzog, MD: You do germline-negative, HRD-negative.

Angeles Alvarez Secord, MD: Oh, yes, you’re right.

Kathleen N. Moore, MD: It’s really, really good.

Bradley J. Monk, MD: It was 0.6, with about a difference in the median of 3.

Angeles Alvarez Secord, MD: It’s still 40% reduction.

Bradley J. Monk, MD: Yes. So, do we need the HRD test? That’s what I’m trying to get at. The numbers are less important.

Angeles Alvarez Secord, MD: I think you do because what we’re all recognizing is that personalized therapy or precision medicine isn’t just about the biomarker to direct therapy. It’s also about discussing with patients the toxicities and quality-of-life issue. And so, this way when we use the test, I can say, “This is the benefit that you’re going to receive from the drug and here are the side effects” and see what that value is for the patient.

Bradley J. Monk, MD: What do you think, Tom? It has a chance of working either way, but with the information, you could have more confidence.

Thomas Herzog, MD: Well, there are 2 ways of looking at it. One is that niraparib is very, very effective in all-comers. The magnitude of effect rivals that of any chemotherapy that you would see in that setting, so you could argue not to have the test. On the other hand, I agree with Angeles in the sense that we have multiple therapies coming and a number of therapies to choose from now. And when you’re looking at a difference of 3.1 months versus the profound differences that you saw of 17 months and some of the other ones, you have to balance that. Having that information, in my opinion, would be helpful. The question is, how much is that going to cost to get that information and how does that fit into the whole rubric of how we’re going to spend our healthcare resources?

Transcript Edited for Clarity
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