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PARP Inhibitors for BRCA-Mutated TNBC

Panelists: Adam M. Brufsky, MD, PhD, University of Pittsburgh Cancer Institute; Carlos L. Arteaga, MD, Vanderbilt University; Jose Baselga, MD, PhD, Memorial Sloan Kettering Cancer Center; Kimberly Blackwell, MD, Duke Cancer Institute; Debu Tripathy, MD, University of Texas MD Anderson Cancer Center; Denise A. Yardley, MD, Sarah Cannon Research Institute; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Wednesday, Jul 26, 2017



Transcript:

Adam M. Brufsky, MD, PhD:
That brings us to the thing that’s really going to push BRCA1 and BRCA2 testing, and that is the OLYMPIAD study. Do you want to talk about that, Debu?

Debu Tripathy, MD: The OLYMPIAD study is one of several studies that were launched a couple of years ago, specifically looking at patients with germ line BRCA1 or BRCA2 mutations with metastatic disease and comparing PARP inhibition therapy to single-agent chemotherapy of physician’s choice. So this was the design of the OLYMPIAD study, which was the first to report their data a month ago or so. A press release stated that it was a positive finding, and it’s being presented at ASCO.

I think this is a big step forward. We, in the past, mostly were using BRCA for genetic counseling, familial counseling, and maybe choosing the right surgery. But now we have a medical therapy. We know from the ovarian cancer data, and we also know from other studies in BRCA tumors of diverse types, including pancreatic and prostate cancers, that these drugs are active. And now we have comparative data showing that it’s actually a better choice than chemotherapy.

The big question is, how durable are these responses going to be? How are patients going to do in the long term? We have PFS data so far. We know from ovarian cancer that resistance can develop. In fact, some of these tumors regain the wild-type sequence, and there are probably other mechanisms of resistance as well. So there’s much we have to learn, but this is a promising sign. It gives us one therapy for a very difficult-to-treat type of cancer. Most of these patients are triple-negative, but of course, in these trials, there were many hormone receptor–positive patients because of the BRCA2 mutations. There are several other studies that are ongoing looking at this.

The PARP inhibitors are different from one another. For instance, talazoparib has high PARP trapping, which makes it more effective as an inhibitor but also makes it more difficult to combine with chemotherapy, whereas veliparib is, on the other end of the spectrum, less PARP trapping but easier to combine with chemotherapy. So we’ll have to await the results of these trials.

Adam M. Brufsky, MD, PhD: And we’re seeing different results. The veliparib study with chemotherapy really wasn’t too promising.

Debu Tripathy, MD: It was not, right.

Adam M. Brufsky, MD, PhD: Right. Again, this is really exciting stuff, and I think that we’re going to now potentially have a label expansion into triple-negative breast cancer based on the data from OLYMPIAD. Debu Tripathy, MD: Well, this is in any BRCA status, so regardless.

Adam M. Brufsky, MD, PhD: Right, it could be anybody, any BRCA status. But I think that a lot of us will use it for triple-negative patients. The issue really becomes, what do we do with variants of unknown significance? If someone comes in with triple-negative breast cancer, and she has been through, say, a first round of chemotherapy, you decide to sequence her, and you get a variant of unknown significance. What do you do? Do you treat her?

Debu Tripathy, MD: Well, fortunately, with the database that many of the testers have developed, we now know that most of these mutations are probably not deleterious. Whereas in the less studied ones, like PALB2, the variants of unknown significance are truly unknown. As time goes on, I think we’re going to have fewer and fewer that really fall into that category. We’ll either know them as deleterious or not. You can make some predictions as to whether or not they’re deleterious by which amino acids are changed and so on and so forth, but it’s not as big a problem for BRCA1 and BRCA2.

Kimberly L. Blackwell, MD: In my practice, if I have a VUS (variant of unknown significance)—and let’s say the patient got carboplatinum—this is just what I’m going to do. You asked what I’m going to do.

Adam M. Brufsky, MD, PhD: Yes, because people out there are going to want to know what to do.

Kimberly L. Blackwell, MD: She gets 4 cycles of carboplatin, 4 months, and her disease melts away. I’m probably going to offer that person a PARP inhibitor if I can get it covered because at least there’s something messed up with their DNA repair system. I don’t know what it is. I don’t know if it is the VUS, but I don’t want to penalize the woman just because our databases aren’t big enough to help us figure out if it’s important or not.

Debu Tripathy, MD: I’m not sure if I agree with that. I think that that might be a measure, but there are some studies going on right now looking at other measures. Some of them are looking at the genome itself, looking at genomic scars that are the result of homologous recombination deficiency, and there are some expression signatures as well. So I think that we will, over time, gain some knowledge as to which ones with wild-type BRCA may have sufficient deficiencies in DNA repair that may respond. In ovarian cancer, there are already some data from these signals.

Adam M. Brufsky, MD, PhD: So do you believe in the HRD, Carlos? Do you believe it’s going to be a biomarker?

Carlos L. Arteaga, MD: I think it could be a biomarker, but I want to talk about the VUS question. And with all due respect to Kim, I cannot equate—without more information—that with BRCA deficiency. So that’s the phenotype we’re looking for, right—BRCA deficiency, an inability to repair homologous recombination and sensitivity to PARP inhibitors versus platinum? And we cannot do that, so the first thing I want to know is, does that person have a wild-type allele? And we have done that exercise. We use Foundation Medicine, and sometimes those patients have a wild-type allele. They’re not BRCA deficient. The sequence is real, maybe functional, but guess what—it’s just an allele frequency of 10%.

Adam M. Brufsky, MD, PhD: Very good point.

Carlos L. Arteaga, MD: So we cannot equate that. This is why molecular tumor boards are important. Sometimes, I cannot rule out that you may need to actually engineer that mutation in the laboratory and address its significance, because it may be the first time that it was detected.

Adam M. Brufsky, MD, PhD: It’s a very good point.

Kimberly L. Blackwell, MD: I think for me, clinically, just as a last point, is how we’ll utilize these drugs. I’m looking forward to clinical trials that will allow me to access these drugs for patients who have germ line mutations in the other HRD genes—so TET2, PALB. I think that actually, there are more data for those than there are for the VUSs, and there are trials that are opening to help us address that.

Transcript Edited for Clarity

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Transcript:

Adam M. Brufsky, MD, PhD:
That brings us to the thing that’s really going to push BRCA1 and BRCA2 testing, and that is the OLYMPIAD study. Do you want to talk about that, Debu?

Debu Tripathy, MD: The OLYMPIAD study is one of several studies that were launched a couple of years ago, specifically looking at patients with germ line BRCA1 or BRCA2 mutations with metastatic disease and comparing PARP inhibition therapy to single-agent chemotherapy of physician’s choice. So this was the design of the OLYMPIAD study, which was the first to report their data a month ago or so. A press release stated that it was a positive finding, and it’s being presented at ASCO.

I think this is a big step forward. We, in the past, mostly were using BRCA for genetic counseling, familial counseling, and maybe choosing the right surgery. But now we have a medical therapy. We know from the ovarian cancer data, and we also know from other studies in BRCA tumors of diverse types, including pancreatic and prostate cancers, that these drugs are active. And now we have comparative data showing that it’s actually a better choice than chemotherapy.

The big question is, how durable are these responses going to be? How are patients going to do in the long term? We have PFS data so far. We know from ovarian cancer that resistance can develop. In fact, some of these tumors regain the wild-type sequence, and there are probably other mechanisms of resistance as well. So there’s much we have to learn, but this is a promising sign. It gives us one therapy for a very difficult-to-treat type of cancer. Most of these patients are triple-negative, but of course, in these trials, there were many hormone receptor–positive patients because of the BRCA2 mutations. There are several other studies that are ongoing looking at this.

The PARP inhibitors are different from one another. For instance, talazoparib has high PARP trapping, which makes it more effective as an inhibitor but also makes it more difficult to combine with chemotherapy, whereas veliparib is, on the other end of the spectrum, less PARP trapping but easier to combine with chemotherapy. So we’ll have to await the results of these trials.

Adam M. Brufsky, MD, PhD: And we’re seeing different results. The veliparib study with chemotherapy really wasn’t too promising.

Debu Tripathy, MD: It was not, right.

Adam M. Brufsky, MD, PhD: Right. Again, this is really exciting stuff, and I think that we’re going to now potentially have a label expansion into triple-negative breast cancer based on the data from OLYMPIAD. Debu Tripathy, MD: Well, this is in any BRCA status, so regardless.

Adam M. Brufsky, MD, PhD: Right, it could be anybody, any BRCA status. But I think that a lot of us will use it for triple-negative patients. The issue really becomes, what do we do with variants of unknown significance? If someone comes in with triple-negative breast cancer, and she has been through, say, a first round of chemotherapy, you decide to sequence her, and you get a variant of unknown significance. What do you do? Do you treat her?

Debu Tripathy, MD: Well, fortunately, with the database that many of the testers have developed, we now know that most of these mutations are probably not deleterious. Whereas in the less studied ones, like PALB2, the variants of unknown significance are truly unknown. As time goes on, I think we’re going to have fewer and fewer that really fall into that category. We’ll either know them as deleterious or not. You can make some predictions as to whether or not they’re deleterious by which amino acids are changed and so on and so forth, but it’s not as big a problem for BRCA1 and BRCA2.

Kimberly L. Blackwell, MD: In my practice, if I have a VUS (variant of unknown significance)—and let’s say the patient got carboplatinum—this is just what I’m going to do. You asked what I’m going to do.

Adam M. Brufsky, MD, PhD: Yes, because people out there are going to want to know what to do.

Kimberly L. Blackwell, MD: She gets 4 cycles of carboplatin, 4 months, and her disease melts away. I’m probably going to offer that person a PARP inhibitor if I can get it covered because at least there’s something messed up with their DNA repair system. I don’t know what it is. I don’t know if it is the VUS, but I don’t want to penalize the woman just because our databases aren’t big enough to help us figure out if it’s important or not.

Debu Tripathy, MD: I’m not sure if I agree with that. I think that that might be a measure, but there are some studies going on right now looking at other measures. Some of them are looking at the genome itself, looking at genomic scars that are the result of homologous recombination deficiency, and there are some expression signatures as well. So I think that we will, over time, gain some knowledge as to which ones with wild-type BRCA may have sufficient deficiencies in DNA repair that may respond. In ovarian cancer, there are already some data from these signals.

Adam M. Brufsky, MD, PhD: So do you believe in the HRD, Carlos? Do you believe it’s going to be a biomarker?

Carlos L. Arteaga, MD: I think it could be a biomarker, but I want to talk about the VUS question. And with all due respect to Kim, I cannot equate—without more information—that with BRCA deficiency. So that’s the phenotype we’re looking for, right—BRCA deficiency, an inability to repair homologous recombination and sensitivity to PARP inhibitors versus platinum? And we cannot do that, so the first thing I want to know is, does that person have a wild-type allele? And we have done that exercise. We use Foundation Medicine, and sometimes those patients have a wild-type allele. They’re not BRCA deficient. The sequence is real, maybe functional, but guess what—it’s just an allele frequency of 10%.

Adam M. Brufsky, MD, PhD: Very good point.

Carlos L. Arteaga, MD: So we cannot equate that. This is why molecular tumor boards are important. Sometimes, I cannot rule out that you may need to actually engineer that mutation in the laboratory and address its significance, because it may be the first time that it was detected.

Adam M. Brufsky, MD, PhD: It’s a very good point.

Kimberly L. Blackwell, MD: I think for me, clinically, just as a last point, is how we’ll utilize these drugs. I’m looking forward to clinical trials that will allow me to access these drugs for patients who have germ line mutations in the other HRD genes—so TET2, PALB. I think that actually, there are more data for those than there are for the VUSs, and there are trials that are opening to help us address that.

Transcript Edited for Clarity
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