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Treatment Options for Patients with BRCA1/2

Panelists: Bradley Monk, MD, FACOG, FACS, St. Joseph's Hospital and Medical Center; Michael J. Birrer, MD, PhD, O'Neal Comprehensive Cancer Center; Jubilee Brown, MD, Levine Cancer Institute; Thomas Herzog, MD, UC College of Medicine; Krishnansu S. Tewari, MD, University of California, Irvine
Published: Friday, Aug 09, 2019



Transcript:

Bradley Monk, MD, FACOG, FACS: I feel badly having been involved in bevacizumab since the very beginning with many of you, that we don’t have a biomarker. But the opposite is true: I feel very confident and happy that we do have an olaparib PARP inhibitor biomarker, and that is, as you said, Krish, it’s germline BRCA and somatic BRCA. Michael, tell us about this trial, SOLO-1, and what that has done, now leading to FDA approval on December 19, a frontline olaparib in germline BRCA and somatic-mutated patients.

Michael J. Birrer, MD, PhD: For SOLO-1, I’ll start out by saying I think we’d all agree SOLO-1 was a game changer. It was a fairly large double-blinded randomized prospective phase III trial, evaluating olaparib in maintenance for patients who had been treated with a newly diagnosed advanced stage of ovarian cancer patients who had been responsive to a platinum regimen. And all patients had a BRCA mutation. It was about 391 patients. The vast majority of them had germline mutations. There were a few somatics put in there. And PFS [progression-free survival] was the primary endpoint in the placebo arm. The median PFS was 13.8 months, which is what we would expect. The median PFS on the olaparib arm has not yet been reached.

Bradley Monk, MD, FACOG, FACS: Big number, though.

Michael J. Birrer, MD, PhD: Big number, so obviously above the 50% cutoff. And if you look at those curves, I would actually argue maybe we shouldn’t call them curves because on the right side of it, it’s actually flat. So a lot of us are beginning to use the C word which we haven’t done before, which is could we actually be effectively curing a few patients?

Bradley Monk, MD, FACOG, FACS: So what Tom said: when you stopped the bevacizumab, the curves come together.

Michael J. Birrer, MD, PhD: Yeah.

Bradley Monk, MD, FACOG, FACS: When you give 2 years of bevacizumab, the curves, olaparib, the curves do not come together.

Michael J. Birrer, MD, PhD: That’s right.

Bradley Monk, MD, FACOG, FACS: And if they don’t come together, maybe there’s a cure.

Michael J. Birrer, MD, PhD: And you could even go to PFS2, which was highly significant in SOLO-1. Then finally, we have to mention the fact that, like all PARP inhibitors, it was exceedingly well tolerated.
Bradley Monk, MD, FACOG, FACS: Jubilee, we’ve transitioned to testing germline. We’ve always agreed, every patient needs germline testing: NCCN [National Comprehensive Cancer Network], ASCO [American Society of Clinical Oncology], SGO [Society of Gynecologic Oncology], everybody agrees. Do we now need to start testing every somatic, as Krish says, as long as the germline is negative?

Jubilee Brown, MD: Yes, I believe that’s the case.

Bradley Monk, MD, FACOG, FACS: And how do you operationalize that?

Jubilee Brown, MD: That’s been an interesting issue. I think up front, everyone absolutely gets tested for germline, and that’s a simple blood test. When that comes back negative for the vast majority of patients, then we can send the tumor off for somatic testing. And that’s how we’ve operationalized that in our system, because then you’re going to catch the additional ones, around 7% of patients, who have somatic mutations, and it’s absolutely essential to catch all those patients.

Bradley Monk, MD, FACOG, FACS: Plus, the 15 to 17 germline is a quarter of the population.

Jubilee Brown, MD: Right, exactly. And that’s key. As Mike said, that might translate into cure.

Bradley Monk, MD, FACOG, FACS: This is a lot of fun. Think of what we just said. IP [intraperitoneal] chemotherapy is dead. Bevacizumab is FDA approved.

Michael J. Birrer, MD, PhD: I don’t remember saying that.

Bradley Monk, MD, FACOG, FACS: Zero is close to being dead. I mean, a heart rate of 0 is dead. And then you said we’ve got to have biomarkers, and we have olaparib. So within 2018, we transitioned away from IP, got bevacizumab and olaparib in mutated-BRCA patients. I mean, that’s transformational.

Jubilee Brown, MD: Yes.

Thomas Herzog, MD: Right.

Bradley Monk, MD, FACOG, FACS: Tom, what’s your editorial on that? Do you think people agree with this, or are we just hyperbolic here? Parabolic, hyperbolic?

Thomas Herzog, MD: I don’t know.

Bradley Monk, MD, FACOG, FACS: It’s a new standard, don’t you think?

Thomas Herzog, MD: I think it is. I don’t think you can overexaggerate the impact. If you look at before that, go back to really before 2016, you look at how long it’s been since we’ve really had any progress. And again it goes back to endpoint interpretations, other things that were going on in the marketplace. But we had very little investment in gynecologic malignancy clinical trials that were really transformative. And now, as you’ll see as we move on in this discourse, you’ll see how much there is to talk about.

Bradley Monk, MD, FACOG, FACS: Yes, not hyperbole. And I’m very happy. As I said in my introductory comments, the best opportunity—impact, long-term outcome—is frontline, and that’s with a deep prioritization of intraperitoneal chemotherapy and expansion of bevacizumab, molecular testing for germline and somatic BRCA, and olaparib in the appropriate patient.

Thomas Herzog, MD: Yeah. I just want to say 1 thing about testing that intrigues me, and that is it would be a lot cheaper if we were able to do somatic and then reflex to germline. The obvious concern is there are limited data, but there’s the concern of false negatives in that group of 5%, 7%. Some of the people I talk to who are experts in that area think they can close that gap to less than 1%.

Bradley Monk, MD, FACOG, FACS: But it’s not just…

Thomas Herzog, MD: For accounting, for large rearrangements, things like that.

Bradley Monk, MD, FACOG, FACS: You taught me this. When you do germline testing, you do a panel. I get that it helps for triaging the BRCA germline testing, but it’s 1 next-generation sequencing. It really doesn’t improve the value, because you’re going to do next-gen sequencing of the germline DNA to look at the entire panel. I mean, I get that argument.

Thomas Herzog, MD: Right, but you’re going to do that for the tumor. You’re going to get that all from the tumor.

Bradley Monk, MD, FACOG, FACS: But I don’t have any confidence—any confidence—that the germline mutations for the non-BRCA genes are in the tumor necessarily. I get it. And so that creates an extra level of uncertainty. You’re right. We don’t even understand the correlation with BRCA for somatic and germline. But if you look at the panel now, which is over 20 genes, we have to check off each 1 of those boxes. I think it’s just easier to do germline and somatic, but it’s a process.

Thomas Herzog, MD: It’s an evolving field.

Michael J. Birrer, MD, PhD: And I would support that intention. On the other hand, I don’t want to sound too cynical about this, but in the context of now really approving olaparib for 2 years and BEV [bevacizumab] going on for 15 months, the amount of cost on that is a drop in the bucket.

Thomas Herzog, MD: Oh right, absolutely.

Transcript Edited for Clarity

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Transcript:

Bradley Monk, MD, FACOG, FACS: I feel badly having been involved in bevacizumab since the very beginning with many of you, that we don’t have a biomarker. But the opposite is true: I feel very confident and happy that we do have an olaparib PARP inhibitor biomarker, and that is, as you said, Krish, it’s germline BRCA and somatic BRCA. Michael, tell us about this trial, SOLO-1, and what that has done, now leading to FDA approval on December 19, a frontline olaparib in germline BRCA and somatic-mutated patients.

Michael J. Birrer, MD, PhD: For SOLO-1, I’ll start out by saying I think we’d all agree SOLO-1 was a game changer. It was a fairly large double-blinded randomized prospective phase III trial, evaluating olaparib in maintenance for patients who had been treated with a newly diagnosed advanced stage of ovarian cancer patients who had been responsive to a platinum regimen. And all patients had a BRCA mutation. It was about 391 patients. The vast majority of them had germline mutations. There were a few somatics put in there. And PFS [progression-free survival] was the primary endpoint in the placebo arm. The median PFS was 13.8 months, which is what we would expect. The median PFS on the olaparib arm has not yet been reached.

Bradley Monk, MD, FACOG, FACS: Big number, though.

Michael J. Birrer, MD, PhD: Big number, so obviously above the 50% cutoff. And if you look at those curves, I would actually argue maybe we shouldn’t call them curves because on the right side of it, it’s actually flat. So a lot of us are beginning to use the C word which we haven’t done before, which is could we actually be effectively curing a few patients?

Bradley Monk, MD, FACOG, FACS: So what Tom said: when you stopped the bevacizumab, the curves come together.

Michael J. Birrer, MD, PhD: Yeah.

Bradley Monk, MD, FACOG, FACS: When you give 2 years of bevacizumab, the curves, olaparib, the curves do not come together.

Michael J. Birrer, MD, PhD: That’s right.

Bradley Monk, MD, FACOG, FACS: And if they don’t come together, maybe there’s a cure.

Michael J. Birrer, MD, PhD: And you could even go to PFS2, which was highly significant in SOLO-1. Then finally, we have to mention the fact that, like all PARP inhibitors, it was exceedingly well tolerated.
Bradley Monk, MD, FACOG, FACS: Jubilee, we’ve transitioned to testing germline. We’ve always agreed, every patient needs germline testing: NCCN [National Comprehensive Cancer Network], ASCO [American Society of Clinical Oncology], SGO [Society of Gynecologic Oncology], everybody agrees. Do we now need to start testing every somatic, as Krish says, as long as the germline is negative?

Jubilee Brown, MD: Yes, I believe that’s the case.

Bradley Monk, MD, FACOG, FACS: And how do you operationalize that?

Jubilee Brown, MD: That’s been an interesting issue. I think up front, everyone absolutely gets tested for germline, and that’s a simple blood test. When that comes back negative for the vast majority of patients, then we can send the tumor off for somatic testing. And that’s how we’ve operationalized that in our system, because then you’re going to catch the additional ones, around 7% of patients, who have somatic mutations, and it’s absolutely essential to catch all those patients.

Bradley Monk, MD, FACOG, FACS: Plus, the 15 to 17 germline is a quarter of the population.

Jubilee Brown, MD: Right, exactly. And that’s key. As Mike said, that might translate into cure.

Bradley Monk, MD, FACOG, FACS: This is a lot of fun. Think of what we just said. IP [intraperitoneal] chemotherapy is dead. Bevacizumab is FDA approved.

Michael J. Birrer, MD, PhD: I don’t remember saying that.

Bradley Monk, MD, FACOG, FACS: Zero is close to being dead. I mean, a heart rate of 0 is dead. And then you said we’ve got to have biomarkers, and we have olaparib. So within 2018, we transitioned away from IP, got bevacizumab and olaparib in mutated-BRCA patients. I mean, that’s transformational.

Jubilee Brown, MD: Yes.

Thomas Herzog, MD: Right.

Bradley Monk, MD, FACOG, FACS: Tom, what’s your editorial on that? Do you think people agree with this, or are we just hyperbolic here? Parabolic, hyperbolic?

Thomas Herzog, MD: I don’t know.

Bradley Monk, MD, FACOG, FACS: It’s a new standard, don’t you think?

Thomas Herzog, MD: I think it is. I don’t think you can overexaggerate the impact. If you look at before that, go back to really before 2016, you look at how long it’s been since we’ve really had any progress. And again it goes back to endpoint interpretations, other things that were going on in the marketplace. But we had very little investment in gynecologic malignancy clinical trials that were really transformative. And now, as you’ll see as we move on in this discourse, you’ll see how much there is to talk about.

Bradley Monk, MD, FACOG, FACS: Yes, not hyperbole. And I’m very happy. As I said in my introductory comments, the best opportunity—impact, long-term outcome—is frontline, and that’s with a deep prioritization of intraperitoneal chemotherapy and expansion of bevacizumab, molecular testing for germline and somatic BRCA, and olaparib in the appropriate patient.

Thomas Herzog, MD: Yeah. I just want to say 1 thing about testing that intrigues me, and that is it would be a lot cheaper if we were able to do somatic and then reflex to germline. The obvious concern is there are limited data, but there’s the concern of false negatives in that group of 5%, 7%. Some of the people I talk to who are experts in that area think they can close that gap to less than 1%.

Bradley Monk, MD, FACOG, FACS: But it’s not just…

Thomas Herzog, MD: For accounting, for large rearrangements, things like that.

Bradley Monk, MD, FACOG, FACS: You taught me this. When you do germline testing, you do a panel. I get that it helps for triaging the BRCA germline testing, but it’s 1 next-generation sequencing. It really doesn’t improve the value, because you’re going to do next-gen sequencing of the germline DNA to look at the entire panel. I mean, I get that argument.

Thomas Herzog, MD: Right, but you’re going to do that for the tumor. You’re going to get that all from the tumor.

Bradley Monk, MD, FACOG, FACS: But I don’t have any confidence—any confidence—that the germline mutations for the non-BRCA genes are in the tumor necessarily. I get it. And so that creates an extra level of uncertainty. You’re right. We don’t even understand the correlation with BRCA for somatic and germline. But if you look at the panel now, which is over 20 genes, we have to check off each 1 of those boxes. I think it’s just easier to do germline and somatic, but it’s a process.

Thomas Herzog, MD: It’s an evolving field.

Michael J. Birrer, MD, PhD: And I would support that intention. On the other hand, I don’t want to sound too cynical about this, but in the context of now really approving olaparib for 2 years and BEV [bevacizumab] going on for 15 months, the amount of cost on that is a drop in the bucket.

Thomas Herzog, MD: Oh right, absolutely.

Transcript Edited for Clarity
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