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PI3K and PARP Inhibitors in HR+ Metastatic Breast Cancer

Panelists: Joyce A. OShaughnessy, MD, Baylor-Sammons Cancer Center; Andrew D. Seidman, MD, Memorial Sloan Kettering Cancer Center
Published: Tuesday, Dec 04, 2018



Transcript:

Joyce A. O’Shaughnessy, MD: I just want to mention a data set I’m really looking forward to the results of, which is the SOLAR-1 data that I hope will be presented at either ESMO [European Society for Medical Oncology 2018 Congress] in October or San Antonio [Breast Cancer Symposium] in December this year. It is the second-line therapy in ER [estrogen receptor]-positive metastatic of fulvestrant with or without the alpha-specific PI3-kinase inhibitor, alpelisib. PFS [progression-free survival] is the endpoint. And it is looking at patients with PIK3CA mutations and then a cohort that doesn’t have PIK3CA. But I believe it’s co-primary endpoint will be analyzed in a substantial number of patients who have PIK3CA mutations. So, fingers crossed because that would be fabulous, and I had the opportunity to use that in some patients, either as a single-patient IND [investigational new drug] or on clinical trials, and I am impressed. I have a patient right now, she’s a 20-year metastatic breast cancer survivor, just a responder. And it’s too numerous to count prior regimens. She has been on everything twice, and she’s having a major response to alpelisib with fulvestrant, even though she has had fulvestrant twice before, later-line therapy, liver and lung diseases. I’m impressed.

Andrew D. Seidman, MD: I hope that the SANDPIPER trial doesn’t dampen enthusiasm for PI3-kinase inhibition. I don’t think it will because other agents are very far along in their development. But this will certainly change the landscape for sure.

Joyce A. O’Shaughnessy, MD: That was the taselisib, just at ASCO [American Society of Clinical Oncology], big phase III trial with fulvestrant plus/minus taselisib again. Taselisib, they called it beta-sparing. It wasn’t just alpha-specific. It had a little bit more of PI3-kinase isoform inhibition but spared beta. But it being too toxic, unfortunately, was the problem. It met its primary endpoint, but it was too toxic and the improvement in PFS wasn’t huge enough to make up for that toxicity.

Andrew D. Seidman, MD: Yes, I know we’re going to dig into this subject more when we talk about some novel oral chemotherapeutics. But for our working group, one of the things that we really did a deep dive in was this balance between incremental improvement in PFS and toxicity and what cost patients are paying for a PFS advantage in terms of toxicity. And there aren’t that many great metrics that help gauge that balance, so it’s just something to keep the eye on the ball. But Dr Baselga presented a statistically positive trial that will never lead to an actionable, usable regimen.

Joyce A. O’Shaughnessy, MD: Yes, yes. And so, we’ll keep our fingers crossed on that. Andy, I wanted to get your thoughts. Another agent we haven’t had a chance to use that much, at least speaking for myself but I look forward to, is the PARP inhibitor for the right patient. Any experience with olaparib so far?

Andrew D. Seidman, MD: Yes. So, this is the opposite. We just talked about getting a PFS advantage and having a significant price to pay in terms of toxicity for that. My colleague, Mark Robson, reported the OlympiAD trial where olaparib compared with treatment of physician’s choice, which were chemotherapeutic agents in patients with germline BRCA mutations and metastatic breast cancer, not only prolonged PFS but had a toxicity profile that was similar, if not in many ways favorable, to chemotherapy. So, perhaps with the exception of some anemia, fatigue. For me, this was an example of having your cake and eating it, too, getting longer disease control and not paying a price in terms of excessive toxicity. I can’t say I’ve had that many patients thus far with germline BRCA mutations and ER-positive breast cancer where I’m trying to see where I should think about playing the olaparib card related to endocrine therapies. But, certainly, when I’m starting to think about it as an alternative to chemotherapy, it rises to the top.

Joyce A. O’Shaughnessy, MD: Yes. It certainly has driven us now to make sure we have germline status on our metastatic patients. The NCCN [National Comprehensive Cancer Network] guidelines, I wanted to give them a round of applause. I was surprised but very pleased to see the NCCN change their guidelines to say get germline BRCA status on all metastatic breast cancer patients who are HER2-negative that would have been eligible for the OlympiAD trial. And then the EMBRACA trial will probably have the talazoparib, the other oral PARP inhibitor. That was a very positive trial as well, and so that will no doubt be available from FDA approval very soon.

Andrew D. Seidman, MD: Yes. If you don’t know you can’t do one, right?

Joyce A. O’Shaughnessy, MD: Right.

Andrew D. Seidman, MD: It’s not natural for doctors to think about germline testing for treatment selection for metastatic breast cancer. You do germline testing to decide about prophylactic mastectomy and oophorectomy, so this is a whole other...

Joyce A. O’Shaughnessy, MD: Yes, and I must say I’m still working to get it into the hard drive, into the flow in clinic. Remember? Oh goodness.

Andrew D. Seidman, MD: Right, and I guess this makes it reimbursable perhaps, right?

Joyce A. O’Shaughnessy, MD: Yes.

Andrew D. Seidman, MD: If you’re doing it for that reason, right?

Joyce A. O’Shaughnessy, MD: Right, exactly. It’s on the NCCN guidelines for help. But I would use olaparib basically as soon as I could. In other words, if I have a patient now with a known germline BRCA1 or BRCA2, and she’s getting whatever therapy and she’s ER-positive, once she’s finished endocrine therapy options, that’s personally where I would probably bring it in. Before I would go to capecitabine or right after. I guess in both the OlympiAD and the EMBRACA trial, patients have had some prior chemotherapy, so you could certainly use it after chemotherapy. But I think ideally I would probably transition it after endocrine therapy, although one could use it after CDK4/6 inhibitor therapy, for example, before going on to another endocrine agent or mTOR inhibition. But as soon as possible.

I’m remembering the OlympiAD data set. There was an update of the data at AACR this year, and it looked at patients who were receiving the olaparib in the first-line setting because they had had prior chemotherapy, and, of course, it was HER2-negative patients, so they could be triple-negative or ER-positive. And there was a survival advantage for the earlier use of this. Of course, that’s a subset analysis. The overall trial did not have a survival advantage, but it really made the point that probably getting this into the earlier lines of therapy might really have the greatest impact.

Andrew D. Seidman, MD: Well, certainly the neoadjuvant talazoparib data would be consistent with that theme, that early exposure could be a real positive.

Joyce A. O’Shaughnessy, MD: Yes. It was a small trial but the pathological CR rate with just single-agent talazoparib was like 60% or something like this. It was remarkable, just right up there with platinum-based regimens. That’s a nice option for patients certainly.

Transcript Edited for Clarity

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Transcript:

Joyce A. O’Shaughnessy, MD: I just want to mention a data set I’m really looking forward to the results of, which is the SOLAR-1 data that I hope will be presented at either ESMO [European Society for Medical Oncology 2018 Congress] in October or San Antonio [Breast Cancer Symposium] in December this year. It is the second-line therapy in ER [estrogen receptor]-positive metastatic of fulvestrant with or without the alpha-specific PI3-kinase inhibitor, alpelisib. PFS [progression-free survival] is the endpoint. And it is looking at patients with PIK3CA mutations and then a cohort that doesn’t have PIK3CA. But I believe it’s co-primary endpoint will be analyzed in a substantial number of patients who have PIK3CA mutations. So, fingers crossed because that would be fabulous, and I had the opportunity to use that in some patients, either as a single-patient IND [investigational new drug] or on clinical trials, and I am impressed. I have a patient right now, she’s a 20-year metastatic breast cancer survivor, just a responder. And it’s too numerous to count prior regimens. She has been on everything twice, and she’s having a major response to alpelisib with fulvestrant, even though she has had fulvestrant twice before, later-line therapy, liver and lung diseases. I’m impressed.

Andrew D. Seidman, MD: I hope that the SANDPIPER trial doesn’t dampen enthusiasm for PI3-kinase inhibition. I don’t think it will because other agents are very far along in their development. But this will certainly change the landscape for sure.

Joyce A. O’Shaughnessy, MD: That was the taselisib, just at ASCO [American Society of Clinical Oncology], big phase III trial with fulvestrant plus/minus taselisib again. Taselisib, they called it beta-sparing. It wasn’t just alpha-specific. It had a little bit more of PI3-kinase isoform inhibition but spared beta. But it being too toxic, unfortunately, was the problem. It met its primary endpoint, but it was too toxic and the improvement in PFS wasn’t huge enough to make up for that toxicity.

Andrew D. Seidman, MD: Yes, I know we’re going to dig into this subject more when we talk about some novel oral chemotherapeutics. But for our working group, one of the things that we really did a deep dive in was this balance between incremental improvement in PFS and toxicity and what cost patients are paying for a PFS advantage in terms of toxicity. And there aren’t that many great metrics that help gauge that balance, so it’s just something to keep the eye on the ball. But Dr Baselga presented a statistically positive trial that will never lead to an actionable, usable regimen.

Joyce A. O’Shaughnessy, MD: Yes, yes. And so, we’ll keep our fingers crossed on that. Andy, I wanted to get your thoughts. Another agent we haven’t had a chance to use that much, at least speaking for myself but I look forward to, is the PARP inhibitor for the right patient. Any experience with olaparib so far?

Andrew D. Seidman, MD: Yes. So, this is the opposite. We just talked about getting a PFS advantage and having a significant price to pay in terms of toxicity for that. My colleague, Mark Robson, reported the OlympiAD trial where olaparib compared with treatment of physician’s choice, which were chemotherapeutic agents in patients with germline BRCA mutations and metastatic breast cancer, not only prolonged PFS but had a toxicity profile that was similar, if not in many ways favorable, to chemotherapy. So, perhaps with the exception of some anemia, fatigue. For me, this was an example of having your cake and eating it, too, getting longer disease control and not paying a price in terms of excessive toxicity. I can’t say I’ve had that many patients thus far with germline BRCA mutations and ER-positive breast cancer where I’m trying to see where I should think about playing the olaparib card related to endocrine therapies. But, certainly, when I’m starting to think about it as an alternative to chemotherapy, it rises to the top.

Joyce A. O’Shaughnessy, MD: Yes. It certainly has driven us now to make sure we have germline status on our metastatic patients. The NCCN [National Comprehensive Cancer Network] guidelines, I wanted to give them a round of applause. I was surprised but very pleased to see the NCCN change their guidelines to say get germline BRCA status on all metastatic breast cancer patients who are HER2-negative that would have been eligible for the OlympiAD trial. And then the EMBRACA trial will probably have the talazoparib, the other oral PARP inhibitor. That was a very positive trial as well, and so that will no doubt be available from FDA approval very soon.

Andrew D. Seidman, MD: Yes. If you don’t know you can’t do one, right?

Joyce A. O’Shaughnessy, MD: Right.

Andrew D. Seidman, MD: It’s not natural for doctors to think about germline testing for treatment selection for metastatic breast cancer. You do germline testing to decide about prophylactic mastectomy and oophorectomy, so this is a whole other...

Joyce A. O’Shaughnessy, MD: Yes, and I must say I’m still working to get it into the hard drive, into the flow in clinic. Remember? Oh goodness.

Andrew D. Seidman, MD: Right, and I guess this makes it reimbursable perhaps, right?

Joyce A. O’Shaughnessy, MD: Yes.

Andrew D. Seidman, MD: If you’re doing it for that reason, right?

Joyce A. O’Shaughnessy, MD: Right, exactly. It’s on the NCCN guidelines for help. But I would use olaparib basically as soon as I could. In other words, if I have a patient now with a known germline BRCA1 or BRCA2, and she’s getting whatever therapy and she’s ER-positive, once she’s finished endocrine therapy options, that’s personally where I would probably bring it in. Before I would go to capecitabine or right after. I guess in both the OlympiAD and the EMBRACA trial, patients have had some prior chemotherapy, so you could certainly use it after chemotherapy. But I think ideally I would probably transition it after endocrine therapy, although one could use it after CDK4/6 inhibitor therapy, for example, before going on to another endocrine agent or mTOR inhibition. But as soon as possible.

I’m remembering the OlympiAD data set. There was an update of the data at AACR this year, and it looked at patients who were receiving the olaparib in the first-line setting because they had had prior chemotherapy, and, of course, it was HER2-negative patients, so they could be triple-negative or ER-positive. And there was a survival advantage for the earlier use of this. Of course, that’s a subset analysis. The overall trial did not have a survival advantage, but it really made the point that probably getting this into the earlier lines of therapy might really have the greatest impact.

Andrew D. Seidman, MD: Well, certainly the neoadjuvant talazoparib data would be consistent with that theme, that early exposure could be a real positive.

Joyce A. O’Shaughnessy, MD: Yes. It was a small trial but the pathological CR rate with just single-agent talazoparib was like 60% or something like this. It was remarkable, just right up there with platinum-based regimens. That’s a nice option for patients certainly.

Transcript Edited for Clarity
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