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PARP Inhibition in BRCA1/2+ or HRD- Ovarian Cancer

Panelists: Michael J. Birrer, MD, PhD, The University of Alabama at Birmingham; Robert L. Coleman, MD, FACOG, FACS, The University of Texas MD Anderson Cancer Center; Bradley J. Monk, MD, FACS, FACOG, The University of Arizona College of Medicine; Kathleen Moore, MD, The University of Oklahoma Health and Sciences Center; Shannon N. Westin, MD, MPH, The University of Texas MD Anderson Cancer Center
Published: Wednesday, Nov 06, 2019



Transcript:

Bradley J. Monk, MD, FACS, FACOG: I’m going to come back to my BRCA expert. You said that in SOLO-1 the hazard ratio was 0.3, but in the high-risk population it was in the range of 0.44; 0.3 and 0.4 kind of felt the same. I’m just trying to get some perspective. You said that the BRCA here was 0.44.

Robert L. Coleman, MD, FACOG, FACS: Yes.

Bradley J. Monk, MD, FACS, FACOG: Is a PARP inhibitor a PARP in BRCA patients?

Kathleen Moore, MD: I think a PARP is a PARP in BRCA patients. I actually do think that. It’s hard to compare hazard ratios across trials with different control arms. Here, it’s 22 months from diagnosis.

Robert L. Coleman, MD, FACOG, FACS: That’s right.

Kathleen Moore, MD: In SOLO-1, it would be about the same: 20 months. This may be a more similar population to SOLO-1, and one that is more representative.

Robert L. Coleman, MD, FACOG, FACS: Remember, this includes patients who could have progressed during frontline treatment.

Kathleen Moore, MD: Right.

Robert L. Coleman, MD, FACOG, FACS: And those who actually had stable disease. We had a pretty decent proportion of patients who had stable disease.

Bradley J. Monk, MD, FACS, FACOG: Because if they progress, they’re at stable disease; they weren’t eligible.

Robert L. Coleman, MD, FACOG, FACS: They weren’t eligible.

Kathleen Moore, MD: It’s still excellent. I think that it’s within range. I don’t know that you can say it’s equivalent or better, but I think it’s all within range.

Shannon N. Westin, MD, MPH: When you look at the confidence intervals, they all fit, right? They fit right on top of one another.

Bradley J. Monk, MD, FACS, FACOG: Let’s go ahead now and talk to our HRD [homologous recombination deficiency] expert. I just appointed you professor of HRD. In the primary endpoints of PRIMA, which was BRCA HRD, it was…

Michael J. Birrer, MD, PhD: 0.43.

Bradley J. Monk, MD, FACS, FACOG: 0.43, but if you take the BRCA group out of it, it’s 0.5.  I want to emphasize that it was an exploratory endpoint.

Michael J. Birrer, MD, PhD: Yes.

Bradley J. Monk, MD, FACS, FACOG: I like taking the BRCA out of the HRD, but it’s an exploratory endpoint. When you take the 0.5 in PRIMA and compare it with—again, taking the BRCA out of it—0.74 in VELIA. Rob, tell me why it’s an inappropriate comparison to take exploratory endpoints in 2 different trials and come up with a definitive conclusion.

Robert L. Coleman, MD, FACOG, FACS: It’s because of what you just said. Here’s the deal. First of all, I’m not sure why we have to do this.

Bradley J. Monk, MD, FACS, FACOG: This is what’s going to happen in the clinic. There are going to be patients who are HRD non-BRCA, and likely, both drugs are going to get approved. They’re going to have to make a decision, and it’s going to come back to familiarity and toxicity and all that.

Robert L. Coleman, MD, FACOG, FACS: Wait a minute. If VELIA is approved, it’s not going to be approved for HRD. It’s not going to require HRD knowledge.

Bradley J. Monk, MD, FACS, FACOG: No question.

Robert L. Coleman, MD, FACOG, FACS: If PRIMA gets approved, it’s not going to be...

Bradley J. Monk, MD, FACS, FACOG: I’m going to have HRD in my pocket. I want to know.

Robert L. Coleman, MD, FACOG, FACS: OK.

Bradley J. Monk, MD, FACS, FACOG: I’m going to use that information to make a rational decision.

Robert L. Coleman, MD, FACOG, FACS: Based on what?

Bradley J. Monk, MD, FACS, FACOG: Based on the...

Robert L. Coleman, MD, FACOG, FACS: Wait a minute. Hold on. Let me ask you a question. Which strategy—PARP inhibitor, BEV [bevacizumab], no treatment—is going to be based on an HRD assay?

Bradley J. Monk, MD, FACS, FACOG: These guys told me that if you have an HRD molecular signature, they’re going to prefer a PARP inhibitor. I’ve got 2 decisions: PARP or BEV [bevacizumab]. PARP is preferred if it’s HRD.

Robert L. Coleman, MD, FACOG, FACS: OK.

Bradley J. Monk, MD, FACS, FACOG: I have to decide which PARP, and that’s what I’m trying to address. Which PARP inhibitor?

Robert L. Coleman, MD, FACOG, FACS: So the HRD is going to...

Bradley J. Monk, MD, FACS, FACOG: Veliparib or niraparib.

Robert L. Coleman, MD, FACOG, FACS: The result of an HRD assay is going to inform your choice of a PARP inhibitor.

Bradley J. Monk, MD, FACS, FACOG: It’s going to contribute to it. Go ahead.

Michael J. Birrer, MD, PhD: You’re coming at it from 2 different...

Robert L. Coleman, MD, FACOG, FACS: Two different cut points for the assay.

Michael J. Birrer, MD, PhD: Yes, you’re coming at it from 2 different angles. One is the scientific approach, which is what Rob is objecting to. The other 1 is what’s practical in the clinic. I think what Brad is saying is absolutely true. It’s just like people saying, “I’m going to give BEV [bevacizumab] to this patient because there was ad hoc analysis of ICON7 saying that patients with ascites and big tumors benefited. That was all ad hoc, but it worked its way into the United States population.

As Rob just mentioned, the truth is that, scientifically, there’s another big issue here. The 2 assays are not equivalent. They used a cutoff of 0.33 here. What does it mean? It means that there are wild-type patients, or non-HRD, reclassified.

Robert L. Coleman, MD, FACOG, FACS: Stuck in there.

Michael J. Birrer, MD, PhD: That raises the hazard ratio. It’s a little difficult to interpret.

Bradley J. Monk, MD, FACS, FACOG: Shannon, what do you think? I get that you’re contaminated by the Coleman effect at The University of Texas MD Anderson Cancer Center.

Shannon N. Westin, MD, MPH: No, but I’m also rationally treating my patients.

Robert L. Coleman, MD, FACOG, FACS: I’m just trying to be smart.

Michael J. Birrer, MD, PhD: But you’re at MD Anderson. That’s not rational.

Shannon N. Westin, MD, MPH: That’s true. I’m going to use this, because we really do need something.

Bradley J. Monk, MD, FACS, FACOG: You mean the HRD assay.

Shannon N. Westin, MD, MPH: Yes, you’ve got to use something, and eventually we’re going to have a really great study that’s all for HRD-negative patients. Then we’ll be able to use it even more. For now, we need to give them an idea of what their general likelihood of getting benefit is and help them make a decision about whether they want to get PARP inhibitors with chemotherapy, PARP inhibitors after chemo, BEV [bevacizumab], or BEV [bevacizumab]–PARP. There are so many.

Robert L. Coleman, MD, FACOG, FACS: Yes, but you’re basing that on what?

Bradley J. Monk, MD, FACS, FACOG: Exploratory analysis.

Shannon N. Westin, MD, MPH: Exploratory…

Robert L. Coleman, MD, FACOG, FACS: Were they balanced? Were they controlled? Were they actually analyzed? Was there a P value in there?

Bradley J. Monk, MD, FACS, FACOG: No, exploratory...

Robert L. Coleman, MD, FACOG, FACS: OK, I just want to make sure.

Bradley J. Monk, MD, FACS, FACOG: Katie, go ahead. You can referee.

Robert L. Coleman, MD, FACOG, FACS: Sorry, I’m just asking a question.

Kathleen Moore, MD: I agree with Mike. I think that both of you are right. This is exactly what we did in the platinum-sensitive recurrent setting. It’s the exact same thing where you have an all-comers approval for all 3 PARP inhibitors. You can either say, “I believe the data, and I’m going to use a PARP inhibitor first, because I don’t know if she’s going to be able to get a PARP again,” even though it’s changed now with frontline. It’s a pragmatic selection. Or you get the HRD and decide if you’re going to use BEV [bevacizumab] or PARP based on that, all of which is based on exploratory analysis. People in the clinic are doing both. I think they’re probably doing more of the latter than just using it following the label. I agree with Shannon. I think that folks are going to use this to make decisions clinically and counsel patients, even though it is statistically inappropriate.

Bradley J. Monk, MD, FACS, FACOG: It’s not the only determinant.

Transcript Edited for Clarity

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Transcript:

Bradley J. Monk, MD, FACS, FACOG: I’m going to come back to my BRCA expert. You said that in SOLO-1 the hazard ratio was 0.3, but in the high-risk population it was in the range of 0.44; 0.3 and 0.4 kind of felt the same. I’m just trying to get some perspective. You said that the BRCA here was 0.44.

Robert L. Coleman, MD, FACOG, FACS: Yes.

Bradley J. Monk, MD, FACS, FACOG: Is a PARP inhibitor a PARP in BRCA patients?

Kathleen Moore, MD: I think a PARP is a PARP in BRCA patients. I actually do think that. It’s hard to compare hazard ratios across trials with different control arms. Here, it’s 22 months from diagnosis.

Robert L. Coleman, MD, FACOG, FACS: That’s right.

Kathleen Moore, MD: In SOLO-1, it would be about the same: 20 months. This may be a more similar population to SOLO-1, and one that is more representative.

Robert L. Coleman, MD, FACOG, FACS: Remember, this includes patients who could have progressed during frontline treatment.

Kathleen Moore, MD: Right.

Robert L. Coleman, MD, FACOG, FACS: And those who actually had stable disease. We had a pretty decent proportion of patients who had stable disease.

Bradley J. Monk, MD, FACS, FACOG: Because if they progress, they’re at stable disease; they weren’t eligible.

Robert L. Coleman, MD, FACOG, FACS: They weren’t eligible.

Kathleen Moore, MD: It’s still excellent. I think that it’s within range. I don’t know that you can say it’s equivalent or better, but I think it’s all within range.

Shannon N. Westin, MD, MPH: When you look at the confidence intervals, they all fit, right? They fit right on top of one another.

Bradley J. Monk, MD, FACS, FACOG: Let’s go ahead now and talk to our HRD [homologous recombination deficiency] expert. I just appointed you professor of HRD. In the primary endpoints of PRIMA, which was BRCA HRD, it was…

Michael J. Birrer, MD, PhD: 0.43.

Bradley J. Monk, MD, FACS, FACOG: 0.43, but if you take the BRCA group out of it, it’s 0.5.  I want to emphasize that it was an exploratory endpoint.

Michael J. Birrer, MD, PhD: Yes.

Bradley J. Monk, MD, FACS, FACOG: I like taking the BRCA out of the HRD, but it’s an exploratory endpoint. When you take the 0.5 in PRIMA and compare it with—again, taking the BRCA out of it—0.74 in VELIA. Rob, tell me why it’s an inappropriate comparison to take exploratory endpoints in 2 different trials and come up with a definitive conclusion.

Robert L. Coleman, MD, FACOG, FACS: It’s because of what you just said. Here’s the deal. First of all, I’m not sure why we have to do this.

Bradley J. Monk, MD, FACS, FACOG: This is what’s going to happen in the clinic. There are going to be patients who are HRD non-BRCA, and likely, both drugs are going to get approved. They’re going to have to make a decision, and it’s going to come back to familiarity and toxicity and all that.

Robert L. Coleman, MD, FACOG, FACS: Wait a minute. If VELIA is approved, it’s not going to be approved for HRD. It’s not going to require HRD knowledge.

Bradley J. Monk, MD, FACS, FACOG: No question.

Robert L. Coleman, MD, FACOG, FACS: If PRIMA gets approved, it’s not going to be...

Bradley J. Monk, MD, FACS, FACOG: I’m going to have HRD in my pocket. I want to know.

Robert L. Coleman, MD, FACOG, FACS: OK.

Bradley J. Monk, MD, FACS, FACOG: I’m going to use that information to make a rational decision.

Robert L. Coleman, MD, FACOG, FACS: Based on what?

Bradley J. Monk, MD, FACS, FACOG: Based on the...

Robert L. Coleman, MD, FACOG, FACS: Wait a minute. Hold on. Let me ask you a question. Which strategy—PARP inhibitor, BEV [bevacizumab], no treatment—is going to be based on an HRD assay?

Bradley J. Monk, MD, FACS, FACOG: These guys told me that if you have an HRD molecular signature, they’re going to prefer a PARP inhibitor. I’ve got 2 decisions: PARP or BEV [bevacizumab]. PARP is preferred if it’s HRD.

Robert L. Coleman, MD, FACOG, FACS: OK.

Bradley J. Monk, MD, FACS, FACOG: I have to decide which PARP, and that’s what I’m trying to address. Which PARP inhibitor?

Robert L. Coleman, MD, FACOG, FACS: So the HRD is going to...

Bradley J. Monk, MD, FACS, FACOG: Veliparib or niraparib.

Robert L. Coleman, MD, FACOG, FACS: The result of an HRD assay is going to inform your choice of a PARP inhibitor.

Bradley J. Monk, MD, FACS, FACOG: It’s going to contribute to it. Go ahead.

Michael J. Birrer, MD, PhD: You’re coming at it from 2 different...

Robert L. Coleman, MD, FACOG, FACS: Two different cut points for the assay.

Michael J. Birrer, MD, PhD: Yes, you’re coming at it from 2 different angles. One is the scientific approach, which is what Rob is objecting to. The other 1 is what’s practical in the clinic. I think what Brad is saying is absolutely true. It’s just like people saying, “I’m going to give BEV [bevacizumab] to this patient because there was ad hoc analysis of ICON7 saying that patients with ascites and big tumors benefited. That was all ad hoc, but it worked its way into the United States population.

As Rob just mentioned, the truth is that, scientifically, there’s another big issue here. The 2 assays are not equivalent. They used a cutoff of 0.33 here. What does it mean? It means that there are wild-type patients, or non-HRD, reclassified.

Robert L. Coleman, MD, FACOG, FACS: Stuck in there.

Michael J. Birrer, MD, PhD: That raises the hazard ratio. It’s a little difficult to interpret.

Bradley J. Monk, MD, FACS, FACOG: Shannon, what do you think? I get that you’re contaminated by the Coleman effect at The University of Texas MD Anderson Cancer Center.

Shannon N. Westin, MD, MPH: No, but I’m also rationally treating my patients.

Robert L. Coleman, MD, FACOG, FACS: I’m just trying to be smart.

Michael J. Birrer, MD, PhD: But you’re at MD Anderson. That’s not rational.

Shannon N. Westin, MD, MPH: That’s true. I’m going to use this, because we really do need something.

Bradley J. Monk, MD, FACS, FACOG: You mean the HRD assay.

Shannon N. Westin, MD, MPH: Yes, you’ve got to use something, and eventually we’re going to have a really great study that’s all for HRD-negative patients. Then we’ll be able to use it even more. For now, we need to give them an idea of what their general likelihood of getting benefit is and help them make a decision about whether they want to get PARP inhibitors with chemotherapy, PARP inhibitors after chemo, BEV [bevacizumab], or BEV [bevacizumab]–PARP. There are so many.

Robert L. Coleman, MD, FACOG, FACS: Yes, but you’re basing that on what?

Bradley J. Monk, MD, FACS, FACOG: Exploratory analysis.

Shannon N. Westin, MD, MPH: Exploratory…

Robert L. Coleman, MD, FACOG, FACS: Were they balanced? Were they controlled? Were they actually analyzed? Was there a P value in there?

Bradley J. Monk, MD, FACS, FACOG: No, exploratory...

Robert L. Coleman, MD, FACOG, FACS: OK, I just want to make sure.

Bradley J. Monk, MD, FACS, FACOG: Katie, go ahead. You can referee.

Robert L. Coleman, MD, FACOG, FACS: Sorry, I’m just asking a question.

Kathleen Moore, MD: I agree with Mike. I think that both of you are right. This is exactly what we did in the platinum-sensitive recurrent setting. It’s the exact same thing where you have an all-comers approval for all 3 PARP inhibitors. You can either say, “I believe the data, and I’m going to use a PARP inhibitor first, because I don’t know if she’s going to be able to get a PARP again,” even though it’s changed now with frontline. It’s a pragmatic selection. Or you get the HRD and decide if you’re going to use BEV [bevacizumab] or PARP based on that, all of which is based on exploratory analysis. People in the clinic are doing both. I think they’re probably doing more of the latter than just using it following the label. I agree with Shannon. I think that folks are going to use this to make decisions clinically and counsel patients, even though it is statistically inappropriate.

Bradley J. Monk, MD, FACS, FACOG: It’s not the only determinant.

Transcript Edited for Clarity
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