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PARP Inhibitors for BRCA-Associated TNBC

Panelists: Adam M. Brufsky, MD, PhD, University of Pittsburgh Cancer Institute; Michael Gnant, MD, Medical University of Vienna; Joyce A. OShaughnessy, MD, Baylor University Medical Center; Hope S. Rugo, MD, University of California San Francisco Helen Diller Family Comprehensive Cancer Center; Michael Untch, MD, Helios Klinikum Berlin-Buch
Published Online: Wednesday, Nov 08, 2017



Transcript: 

Adam M. Brufsky, MD, PhD: We have a short amount of time to talk about, I think, some very interesting and exciting data in the triple-negative subset of patients. I think we’ll start with the treatment of BRCA-associated breast cancer. And there are some very, very exciting data about PARP inhibitors and the OLYMPIAD trial. We’ll start with Joyce. Can you talk a little bit about OLYMPIAD?

Joyce A. O’Shaughnessy, MD: We saw the plenary discussion, or plenary presentation, at ASCO, immediately followed by a publication in the New England Journal of Medicine by Mark Robson about individuals with germline BRCA1/2-mutated metastatic breast cancer who were randomized to 1 of 3 chemotherapy agents—capecitabine, vinorelbine, or eribulin—versus olaparib. The study met its primary endpoint of progression-free survival with a substantial improvement up to over 7 months versus around 4 months or so with chemotherapy. There is no improvement yet in overall survival.

Patients with ER-negative breast cancer did better than those with ER-positive breast cancer, and platinum pretreatment decreased the effectiveness of the olaparib somewhat, but not entirely. But still, I think it’s a very important new tool for our patients with BRCA1/2 germline mutations. There was a 60% objective response rate with olaparib and very, very rapid responses. Durability is about 6, 7 months or so in most patients, but with very, very massive cytoreduction. A really interesting step. Of course, we’re all going to be looking to get immunotherapy involved with it pretty quickly to see if we can lengthen the durability of some of those responses. But it’s a very, very important proof of concept. Talazoparib also was...

Adam M. Brufsky, MD, PhD: Otherwise known as BMN 673. I follow it by its number.

Joyce A. O’Shaughnessy, MD: Yes. Initially BioMarin, then Medivation, and now Pfizer found a drug. So, talazoparib also looks very, very impressive in a phase II study in the
patients with germline BRCA mutations.

Adam M. Brufsky, MD, PhD: This is the ABRAZO trial?

Michael Gnant, MD: Yes.

Adam M. Brufsky, MD, PhD: Can someone describe that? Does someone know the design of ABRAZO?

Hope S. Rugo, MD: Yes, we had 2 cohorts. One was patients who received 3 or more lines of therapy, and one was a patient group who had received platinum therapy and was supposed to not have completely progressed on it. Most of the patients really had platinum-resistant disease. And interestingly, patients responded in both groups. The responses were a little bit higher in the group that was more heavily pretreated and not exposed to platinum. This is really interesting given the fact that the progression-free survival in the TNT trial of the patients with BRCA mutations—who were a tiny number—who received carboplatin, compared to that of the patients who received olaparib in OLYMPIAD, is relatively similar, suggesting that maybe we’ve already seen that there’s some similar resistance mechanism where patients who received platinum chemotherapy with ovarian cancer have less of a response to PARP inhibitors. And in breast cancer, it seems to be relatively the same. But we saw responses with talazoparib in both groups, and they were reasonably durable as well, which I think was quite impressive.

Adam M. Brufsky, MD, PhD: So, we have a trial. The first question to my colleagues—now, at least, I’m assuming that they’ll get a label expansion? We don’t know, obviously, in the United States.

Hope S. Rugo, MD: One would hope.

Adam M. Brufsky, MD, PhD: In Europe, I’m assuming they’ll get a label expansion as well. How are you guys going to use olaparib, at least up front? Because that’s that how it’s going to get approved first?

Joyce A. O’Shaughnessy, MD: I’ll give you an example of a patient of mine who had triple-negative breast cancer with a BRCA1 germline mutation and, after some years, presented with a solitary brain metastasis that was resected. I gave her some platinum-based therapies as adjuvant treatment. And then, I decided I would give olaparib to her as a maintenance therapy. So, I’m using; she’s on olaparib now. Basically, I’m probably going to go to it early on. I think in BRCA1/2 germline-mutant metastatic breast cancer, it’s probably going to be first-line treatment for those patients.

Hope S. Rugo, MD: Yes, and I’ve had the same experience. In fact, I just had a patient with a BRCA2 mutation and ER-positive, HER2-positive disease who developed some cardiac toxicity with trastuzumab in the adjuvant setting. But given her metastatic bone disease, I added olaparib to her hormone therapy. I think the thing is that we have this amazing doubling of response, but it’s not as durable as we’d like. Maybe by treating patients earlier, it will be more durable. Maybe it will require something else, like an adjuvant therapy or continuation with combining with other agents. It’s hard to know.

Transcript Edited for Clarity 

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Transcript: 

Adam M. Brufsky, MD, PhD: We have a short amount of time to talk about, I think, some very interesting and exciting data in the triple-negative subset of patients. I think we’ll start with the treatment of BRCA-associated breast cancer. And there are some very, very exciting data about PARP inhibitors and the OLYMPIAD trial. We’ll start with Joyce. Can you talk a little bit about OLYMPIAD?

Joyce A. O’Shaughnessy, MD: We saw the plenary discussion, or plenary presentation, at ASCO, immediately followed by a publication in the New England Journal of Medicine by Mark Robson about individuals with germline BRCA1/2-mutated metastatic breast cancer who were randomized to 1 of 3 chemotherapy agents—capecitabine, vinorelbine, or eribulin—versus olaparib. The study met its primary endpoint of progression-free survival with a substantial improvement up to over 7 months versus around 4 months or so with chemotherapy. There is no improvement yet in overall survival.

Patients with ER-negative breast cancer did better than those with ER-positive breast cancer, and platinum pretreatment decreased the effectiveness of the olaparib somewhat, but not entirely. But still, I think it’s a very important new tool for our patients with BRCA1/2 germline mutations. There was a 60% objective response rate with olaparib and very, very rapid responses. Durability is about 6, 7 months or so in most patients, but with very, very massive cytoreduction. A really interesting step. Of course, we’re all going to be looking to get immunotherapy involved with it pretty quickly to see if we can lengthen the durability of some of those responses. But it’s a very, very important proof of concept. Talazoparib also was...

Adam M. Brufsky, MD, PhD: Otherwise known as BMN 673. I follow it by its number.

Joyce A. O’Shaughnessy, MD: Yes. Initially BioMarin, then Medivation, and now Pfizer found a drug. So, talazoparib also looks very, very impressive in a phase II study in the
patients with germline BRCA mutations.

Adam M. Brufsky, MD, PhD: This is the ABRAZO trial?

Michael Gnant, MD: Yes.

Adam M. Brufsky, MD, PhD: Can someone describe that? Does someone know the design of ABRAZO?

Hope S. Rugo, MD: Yes, we had 2 cohorts. One was patients who received 3 or more lines of therapy, and one was a patient group who had received platinum therapy and was supposed to not have completely progressed on it. Most of the patients really had platinum-resistant disease. And interestingly, patients responded in both groups. The responses were a little bit higher in the group that was more heavily pretreated and not exposed to platinum. This is really interesting given the fact that the progression-free survival in the TNT trial of the patients with BRCA mutations—who were a tiny number—who received carboplatin, compared to that of the patients who received olaparib in OLYMPIAD, is relatively similar, suggesting that maybe we’ve already seen that there’s some similar resistance mechanism where patients who received platinum chemotherapy with ovarian cancer have less of a response to PARP inhibitors. And in breast cancer, it seems to be relatively the same. But we saw responses with talazoparib in both groups, and they were reasonably durable as well, which I think was quite impressive.

Adam M. Brufsky, MD, PhD: So, we have a trial. The first question to my colleagues—now, at least, I’m assuming that they’ll get a label expansion? We don’t know, obviously, in the United States.

Hope S. Rugo, MD: One would hope.

Adam M. Brufsky, MD, PhD: In Europe, I’m assuming they’ll get a label expansion as well. How are you guys going to use olaparib, at least up front? Because that’s that how it’s going to get approved first?

Joyce A. O’Shaughnessy, MD: I’ll give you an example of a patient of mine who had triple-negative breast cancer with a BRCA1 germline mutation and, after some years, presented with a solitary brain metastasis that was resected. I gave her some platinum-based therapies as adjuvant treatment. And then, I decided I would give olaparib to her as a maintenance therapy. So, I’m using; she’s on olaparib now. Basically, I’m probably going to go to it early on. I think in BRCA1/2 germline-mutant metastatic breast cancer, it’s probably going to be first-line treatment for those patients.

Hope S. Rugo, MD: Yes, and I’ve had the same experience. In fact, I just had a patient with a BRCA2 mutation and ER-positive, HER2-positive disease who developed some cardiac toxicity with trastuzumab in the adjuvant setting. But given her metastatic bone disease, I added olaparib to her hormone therapy. I think the thing is that we have this amazing doubling of response, but it’s not as durable as we’d like. Maybe by treating patients earlier, it will be more durable. Maybe it will require something else, like an adjuvant therapy or continuation with combining with other agents. It’s hard to know.

Transcript Edited for Clarity 
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: Leveraging New Evidence in the Context of Evolving Early-Stage Treatment Standards in HER2-Positive Breast CancerJan 30, 20181.5
14th Annual School of Breast Oncology® OnlineFeb 10, 201825
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