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PARP Inhibitors for BRCA-Mutated TNBC

Panelists:Adam M. Brufsky, MD, PhD, FACP, University of Pittsburgh School of Medicine; Francisco Esteva, MD, PhD, Langone Medical Center; Komal Jhaveri, MD, FACP, Memorial Sloan Kettering Cancer Center; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Lee Schwartzberg, MD, FACP, The University of Texas Health Science Center
Published: Wednesday, Apr 04, 2018



Transcript: 

Adam M. Brufsky, MD, PhD, FACP: We have 2 more topics to talk about here that are really important in triple-negative breast cancer. The first one is PARP inhibitors. We all know that olaparib was just approved by the FDA. At San Antonio this year, we had data on the EMBRACA trial, which involves talazoparib. Lee, do you want to talk about that?

Lee Schwartzberg, MD, FACP: Yes, talazoparib was also compared with treatment of physician’s choice, and there were several agents. This was in germline BRCA-mutated patients, either BRCA1 or BRCA2 mutations that were known, and patients had previous lines of treatment. They had somewhat less treatment in general but were eligible if they had prior chemotherapy. They showed an improvement in progression-free survival, which was significant clinically as well as statistically for talazoparib.

Adam M. Brufsky, MD, PhD, FACP: What struck me about that is how close it was to the olaparib data. It’s fairly close. Do you agree that it was fairly close?

Lee Schwartzberg, MD, FACP: From a hazard ratio perspective for sure.

Hope S. Rugo, MD: It’s important to keep in mind that the patients in both trials did not have platinum-resistant disease. In the EMBRACA trial, we allowed patients who received prior platinum treatment in the early-stage setting, but you couldn’t have progressed on a platinum therapy. I think that’s really important because we think that there’s cross-resistance. The other thing that impressed me about both trials is that the response rates are unbelievable. You go from below 30% to over 60%, and they respond. In my clinical practice, they respond within minutes. A week goes by, their pain is gone, but then they progress right away. That’s very frustrating. You have such incredible responses, but we’re not quite doubling the PFS.

Lee Schwartzberg, MD, FACP: Yes, but there are amazing resistance mechanisms, some of which have been defined now, like reversion to normal BRCA.

Adam M. Brufsky, MD, PhD, FACP: They’re very fascinating; the whole story is very cool with reversion and PARP trapping. The next question now is, are you going to use these PARP inhibitors then? Assume you’re probably going to have talazoparib in the future. You have olaparib now. How are we going to use these?

Lee Schwartzberg, MD, FACP: It’s a new standard of care for germline BRCA-mutated patients.

Adam M. Brufsky, MD, PhD, FACP: First line, second line? In what line?

Hope S. Rugo, MD: First-line.

Adam M. Brufsky, MD, PhD, FACP: Platinum resistant, platinum sensitive, in which one?

Francisco Esteva, MD, PhD: Are they superior to platinum in EMBRACA?

Lee Schwartzberg, MD, FACP: We don’t know.

Adam M. Brufsky, MD, PhD, FACP: We have no idea.

Hope S. Rugo, MD: But it’s so much easier, and you don’t get thrombocytopenia. You can always give a platinum after that. The thing is that marrow suppression is an issue and olaparib…

Adam M. Brufsky, MD, PhD, FACP: Fatigue is one of the issues for me.

Komal Jhaveri, MD, FACP: Anemia.

Lee Schwartzberg, MD, FACP: Anemia is the issue I’ve seen.

Hope S. Rugo, MD: Anemia is big, and what happens with those patients is that then their marrow tolerance for further therapy may be impacted by the PARP inhibitor through some mechanism, which I don’t understand. So, it could just be that they’ve had cancer for a long time. It’s hard to know.

Adam M. Brufsky, MD, PhD, FACP: Can someone answer the question that’s no one has been able to do? Why don’t we do this like in ovarian cancer? Why don’t we treat with platinum and then use maintenance? Because in ovarian cancer, that’s how it’s done.

Hope S. Rugo, MD: We will be doing that.

Lee Schwartzberg, MD, FACP: We will.

Adam M. Brufsky, MD, PhD, FACP: Are there people doing those trials?

Hope S. Rugo, MD: No, but we will be doing them. We only just got our first PARP inhibitor. It’s ridiculous that it took so long to get a PARP inhibitor in breast cancer.

Lee Schwartzberg, MD, FACP: But that’s the point, it took us so much longer in BRCA-mutated breast cancer than in ovarian cancers. They are farther ahead.

Adam M. Brufsky, MD, PhD, FACP: Because there was no BRCA-mutated requirement though. In ovarian, it’s for all-comers; it’s not just for BRCA-mutated patients.

Hope S. Rugo, MD: There’s so much less of ovarian cancer than there is breast cancer.

Adam M. Brufsky, MD, PhD, FACP: Is there less ovarian cancer than BRCA-mutated breast cancer? I don’t know.

Lee Schwartzberg, MD, FACP: I think there’s a genomic subgroup that’s similar.

Adam M. Brufsky, MD, PhD, FACP: Oh, I agree. There are when you look at the subgroups and actually look at DNA profiling or RNA profiling.

Lee Schwartzberg, MD, FACP: I think we should probably do germline testing now in all metastatic patients. Clearly, every triple-negative patient should be tested. The prevalence is high enough now that you have a new agent.

Adam M. Brufsky, MD, PhD, FACP: It’s 25% of triple-negative patients, and 4% of ER-positive patients are BRCA associated, actually.

Hope S. Rugo, MD: I thought it was in the teens.

Adam M. Brufsky, MD, PhD, FACP: It’s 25%, or 24%, looking at the data. Anyway, there are 2 quick topics before we move on to the next question. The first one is that we’re now doing next-generation sequencing on a lot of people. We could debate how frequent it is, a somatic BRCA mutation that when you germline test somebody, it’s negative. Do you treat those patients with olaparib or drugs like it, PARP inhibitors? Would you guys do that? Would you do that?

Francisco Esteva, MD, PhD: I would if it’s…

Lee Schwartzberg, MD, FACP: I’m doing it.

Adam M. Brufsky, MD, PhD, FACP: Off study? Because now we’re going to be able to get it. Well, I don’t know if we’re able to get it.

Hope S. Rugo, MD: Yes, you can.

Francisco Esteva, MD, PhD: No, for BRCA mutated patients.

Adam M. Brufsky, MD, PhD, FACP: For somatic patients.

Lee Schwartzberg, MD, FACP: What you just say in your documentation is that they’re BRCA mutated.

Adam M. Brufsky, MD, PhD, FACP: We’re not allowed to say that you guys. This is on TV.

Lee Schwartzberg, MD, FACP: If they ask for more information, more information is that it’s somatic.

Adam M. Brufsky, MD, PhD, FACP: Fair enough. You’re right.

Francisco Esteva, MD, PhD: If the tumor has this deficiency, I think it’s OK to treat with PARP inhibitors.

Hope S. Rugo, MD: I agree.

Adam M. Brufsky, MD, PhD, FACP: So, if you have a somatic mutation, you’ll treat it. Do you treat a somatic patient?

Komal Jhaveri, MD, FACP: Fortunately, I have 3 clinical trial options available for my patients with somatic alterations. I do not have to struggle with that decision in clinic, so I’ve been lucky not to worry about that. I think we definitely need a little bit more data defining what the somatic alterations are that fall under that umbrella. We have trials that are being conducted within the cooperative groups, and the Translational Breast Cancer Research Consortium is also looking into trials in that specific subtype. So, I think once we have those data, we’ll become more comfortable.

Hope S. Rugo, MD: And alternate mutations also.

Komal Jhaveri, MD, FACP: Exactly.

Adam M. Brufsky, MD, PhD, FACP: Right, alternate mutations to the HRD. Do you think it’s going to work in HRD or not?

Hope S. Rugo, MD: HRD defines BRCA mutations right now.

Lee Schwartzberg, MD, FACP: Well, beyond that?

Adam M. Brufsky, MD, PhD, FACP: In BRCA-negative HRD, you think it’s going to work?

Hope S. Rugo, MD: We don’t know.

Lee Schwartzberg, MD, FACP: We don’t know.

Adam M. Brufsky, MD, PhD, FACP: But right now, you wouldn’t do it?

Komal Jhaveri, MD, FACP: Correct.

Hope S. Rugo, MD: No.

Adam M. Brufsky, MD, PhD, FACP: You would not do it, all right.

Transcript Edited for Clarity 

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Transcript: 

Adam M. Brufsky, MD, PhD, FACP: We have 2 more topics to talk about here that are really important in triple-negative breast cancer. The first one is PARP inhibitors. We all know that olaparib was just approved by the FDA. At San Antonio this year, we had data on the EMBRACA trial, which involves talazoparib. Lee, do you want to talk about that?

Lee Schwartzberg, MD, FACP: Yes, talazoparib was also compared with treatment of physician’s choice, and there were several agents. This was in germline BRCA-mutated patients, either BRCA1 or BRCA2 mutations that were known, and patients had previous lines of treatment. They had somewhat less treatment in general but were eligible if they had prior chemotherapy. They showed an improvement in progression-free survival, which was significant clinically as well as statistically for talazoparib.

Adam M. Brufsky, MD, PhD, FACP: What struck me about that is how close it was to the olaparib data. It’s fairly close. Do you agree that it was fairly close?

Lee Schwartzberg, MD, FACP: From a hazard ratio perspective for sure.

Hope S. Rugo, MD: It’s important to keep in mind that the patients in both trials did not have platinum-resistant disease. In the EMBRACA trial, we allowed patients who received prior platinum treatment in the early-stage setting, but you couldn’t have progressed on a platinum therapy. I think that’s really important because we think that there’s cross-resistance. The other thing that impressed me about both trials is that the response rates are unbelievable. You go from below 30% to over 60%, and they respond. In my clinical practice, they respond within minutes. A week goes by, their pain is gone, but then they progress right away. That’s very frustrating. You have such incredible responses, but we’re not quite doubling the PFS.

Lee Schwartzberg, MD, FACP: Yes, but there are amazing resistance mechanisms, some of which have been defined now, like reversion to normal BRCA.

Adam M. Brufsky, MD, PhD, FACP: They’re very fascinating; the whole story is very cool with reversion and PARP trapping. The next question now is, are you going to use these PARP inhibitors then? Assume you’re probably going to have talazoparib in the future. You have olaparib now. How are we going to use these?

Lee Schwartzberg, MD, FACP: It’s a new standard of care for germline BRCA-mutated patients.

Adam M. Brufsky, MD, PhD, FACP: First line, second line? In what line?

Hope S. Rugo, MD: First-line.

Adam M. Brufsky, MD, PhD, FACP: Platinum resistant, platinum sensitive, in which one?

Francisco Esteva, MD, PhD: Are they superior to platinum in EMBRACA?

Lee Schwartzberg, MD, FACP: We don’t know.

Adam M. Brufsky, MD, PhD, FACP: We have no idea.

Hope S. Rugo, MD: But it’s so much easier, and you don’t get thrombocytopenia. You can always give a platinum after that. The thing is that marrow suppression is an issue and olaparib…

Adam M. Brufsky, MD, PhD, FACP: Fatigue is one of the issues for me.

Komal Jhaveri, MD, FACP: Anemia.

Lee Schwartzberg, MD, FACP: Anemia is the issue I’ve seen.

Hope S. Rugo, MD: Anemia is big, and what happens with those patients is that then their marrow tolerance for further therapy may be impacted by the PARP inhibitor through some mechanism, which I don’t understand. So, it could just be that they’ve had cancer for a long time. It’s hard to know.

Adam M. Brufsky, MD, PhD, FACP: Can someone answer the question that’s no one has been able to do? Why don’t we do this like in ovarian cancer? Why don’t we treat with platinum and then use maintenance? Because in ovarian cancer, that’s how it’s done.

Hope S. Rugo, MD: We will be doing that.

Lee Schwartzberg, MD, FACP: We will.

Adam M. Brufsky, MD, PhD, FACP: Are there people doing those trials?

Hope S. Rugo, MD: No, but we will be doing them. We only just got our first PARP inhibitor. It’s ridiculous that it took so long to get a PARP inhibitor in breast cancer.

Lee Schwartzberg, MD, FACP: But that’s the point, it took us so much longer in BRCA-mutated breast cancer than in ovarian cancers. They are farther ahead.

Adam M. Brufsky, MD, PhD, FACP: Because there was no BRCA-mutated requirement though. In ovarian, it’s for all-comers; it’s not just for BRCA-mutated patients.

Hope S. Rugo, MD: There’s so much less of ovarian cancer than there is breast cancer.

Adam M. Brufsky, MD, PhD, FACP: Is there less ovarian cancer than BRCA-mutated breast cancer? I don’t know.

Lee Schwartzberg, MD, FACP: I think there’s a genomic subgroup that’s similar.

Adam M. Brufsky, MD, PhD, FACP: Oh, I agree. There are when you look at the subgroups and actually look at DNA profiling or RNA profiling.

Lee Schwartzberg, MD, FACP: I think we should probably do germline testing now in all metastatic patients. Clearly, every triple-negative patient should be tested. The prevalence is high enough now that you have a new agent.

Adam M. Brufsky, MD, PhD, FACP: It’s 25% of triple-negative patients, and 4% of ER-positive patients are BRCA associated, actually.

Hope S. Rugo, MD: I thought it was in the teens.

Adam M. Brufsky, MD, PhD, FACP: It’s 25%, or 24%, looking at the data. Anyway, there are 2 quick topics before we move on to the next question. The first one is that we’re now doing next-generation sequencing on a lot of people. We could debate how frequent it is, a somatic BRCA mutation that when you germline test somebody, it’s negative. Do you treat those patients with olaparib or drugs like it, PARP inhibitors? Would you guys do that? Would you do that?

Francisco Esteva, MD, PhD: I would if it’s…

Lee Schwartzberg, MD, FACP: I’m doing it.

Adam M. Brufsky, MD, PhD, FACP: Off study? Because now we’re going to be able to get it. Well, I don’t know if we’re able to get it.

Hope S. Rugo, MD: Yes, you can.

Francisco Esteva, MD, PhD: No, for BRCA mutated patients.

Adam M. Brufsky, MD, PhD, FACP: For somatic patients.

Lee Schwartzberg, MD, FACP: What you just say in your documentation is that they’re BRCA mutated.

Adam M. Brufsky, MD, PhD, FACP: We’re not allowed to say that you guys. This is on TV.

Lee Schwartzberg, MD, FACP: If they ask for more information, more information is that it’s somatic.

Adam M. Brufsky, MD, PhD, FACP: Fair enough. You’re right.

Francisco Esteva, MD, PhD: If the tumor has this deficiency, I think it’s OK to treat with PARP inhibitors.

Hope S. Rugo, MD: I agree.

Adam M. Brufsky, MD, PhD, FACP: So, if you have a somatic mutation, you’ll treat it. Do you treat a somatic patient?

Komal Jhaveri, MD, FACP: Fortunately, I have 3 clinical trial options available for my patients with somatic alterations. I do not have to struggle with that decision in clinic, so I’ve been lucky not to worry about that. I think we definitely need a little bit more data defining what the somatic alterations are that fall under that umbrella. We have trials that are being conducted within the cooperative groups, and the Translational Breast Cancer Research Consortium is also looking into trials in that specific subtype. So, I think once we have those data, we’ll become more comfortable.

Hope S. Rugo, MD: And alternate mutations also.

Komal Jhaveri, MD, FACP: Exactly.

Adam M. Brufsky, MD, PhD, FACP: Right, alternate mutations to the HRD. Do you think it’s going to work in HRD or not?

Hope S. Rugo, MD: HRD defines BRCA mutations right now.

Lee Schwartzberg, MD, FACP: Well, beyond that?

Adam M. Brufsky, MD, PhD, FACP: In BRCA-negative HRD, you think it’s going to work?

Hope S. Rugo, MD: We don’t know.

Lee Schwartzberg, MD, FACP: We don’t know.

Adam M. Brufsky, MD, PhD, FACP: But right now, you wouldn’t do it?

Komal Jhaveri, MD, FACP: Correct.

Hope S. Rugo, MD: No.

Adam M. Brufsky, MD, PhD, FACP: You would not do it, all right.

Transcript Edited for Clarity 
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