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Combining PARP and Checkpoint Inhibitors in TNBC

Panelists: Joyce O Shaughnessy, MD, Baylor-Sammons Cancer Center; Aditya Bardia, MD, MPH, Massachusetts General Hospital; Adan M. Brufsky, MD, PhD, Comprehensive Breast Cancer Center; Heather L. McArthur, MD, MPH, Cedars-Sinai Medical Center; Ruth O Regan, MD, University of Wisconsin Carbone Cancer Center; Tiffany A. Traina, MD, Memorial Sloan Kettering Cancer Center
Published: Wednesday, Feb 13, 2019



Transcript:

Joyce O’Shaughnessy, MD:
One combination that will be interesting, maybe, for our BRCA patients will be a PARP inhibitor with a checkpoint inhibitor. That would make a lot of sense, because we want to try to probably use the PARP inhibitors as soon as we can in the natural history of the BRCA1 and 2 patient population. And if they’re PD-L1 positive, we want to be using checkpoint inhibitors, too, you know what I mean? So, Adam, bring us up to speed a little bit with where we are with PARP inhibitors.

Adam M. Brufsky, MD, PhD: So, there are 2 randomized trials that we have. There’s OlympiAD and there’s EMBRACA. They both, basically, are very similar both in their design and their outcome. In OlympiAD, I think it was about 300 women, 302 women, with germline BRCA-associated breast cancer in second-line therapy and beyond. And there were subgroups relating to whether they were triple negative or ER [estrogen receptor] positive or prior platinum, which were randomized to physician choice of chemotherapy, which is the typical thing to use second line in triple-negative and ER-positive breast cancer, or olaparib.

And in the olaparib arm, the PFS [progression-free survival] overall, I think, was about 7½ months versus, I think, about 4 to 5 months. It was an improvement of about almost doubling—not quite doubling, if I’m not mistaken. And, basically, the women who had prior platinum did not have as good a response. Women who were triple negative had a better PFS delta. So, those seemed to be the subgroups that did better. There was no survival benefit, as far as I know, in that trial. And, interestingly enough, the adverse effect profile was very similar to chemotherapy, with the exception of hand-foot syndrome from capecitabine, which was more, and alopecia. Well, there was really no alopecia in that, because there were not alopecia-containing chemotherapies.

So, EMBRACA was a very similar design, although they allowed first-line patients. And I think about a certain percent of the patients—I think it was 40% or something—were first line in EMBRACA, and it was very similar. Again, it was talazoparib versus physician’s choice of chemotherapy. And the PFS, I believe, was a little over 8 months in the talazoparib arm and, I think, a little under 6 months in the control arm, the physician choice of chemotherapy. Those numbers were a little bit higher because they included the first-line patients. And the other thing that seemed to be very interesting: It looked like there was a trend toward overall survival on talazoparib, if I’m not mistaken. It wasn’t statistically significant. There weren’t enough events. But, basically, the bottom line is that those 2 trials were very similar, both in their design and outcomes.

Tiffany A. Traina, MD: I would say for the OlympiAD study, the primary author, Mark Robson, MD, presented at AACR [American Association for Cancer Research] some subset data on outcomes and survival. So the curves in folks that did get treatment, I think first and second line, had an improvement in overall survival. Granted, it’s a subset and a smaller group.

Adam M. Brufsky, MD, PhD: I agree with you. I’m saying that it’s only a trial design issue, I think, more than anything. I think that there probably will be a survival benefit. But here’s the issue: Let’s get back to the question you asked. So someone comes in and they’re one of those 8% to 10% of women who come in who are PD-1 and PD-L1 positive and BRCA positive.

Joyce O’Shaughnessy, MD: Germline BRCA.

Adam M. Brufsky, MD, PhD: Germline BRCA. What do you do? Which do you treat first? And I think that a lot of us have been talking on the sidelines of this meeting about this. And I think that there’s a clear survival benefit to the first-line therapy with atezolizumab and chemotherapy. There may be a trend, and the other thing that happens is that there does seem to be benefit in later lines with a PARP, where there was not benefit in later lines with the I-O [immuno-oncology], at least for now. So, for me, based on those 2 observations, I think in a double-positive person, I would give her I-O first. I think I would give her chemotherapy and I-O first.

Heather L. McArthur, MD, MPH: I think the survival benefit makes that decision.

Adam M. Brufsky, MD, PhD: But there’s probably going to be a survival benefit, too, if we look at the data longer with PARPs.

Heather L. McArthur, MD, MPH: A little longer, maybe.

Adam M. Brufsky, MD, PhD: But I agree with you, I think the survival data really do make the reason to give it first.

Joyce O’Shaughnessy, MD: And the subset of the first line in OlympiAD, the subset that Mark Robson put at AACR, showed a statistically significant improvement in survival with olaparib compared with chemotherapy in the first line. So it’s statistically significant and it’s a subset analysis.

Adam M. Brufsky, MD, PhD: So, which one do you use first?

Joyce O’Shaughnessy, MD: Well, for the triple-negative patients, I do like to use the PARP inhibitor because we’ve had those. We haven’t had the checkpoint inhibitor yet, but I’ve been using the PARP inhibitor first-line for triple-negative patients.

Adam M. Brufsky, MD, PhD: Now you’re going to have a checkpoint inhibitor. What are you going to do?

Joyce O’Shaughnessy, MD: Well, you know there are safety data. There are safety data combining checkpoint inhibitors with PARP inhibitors. There’s the MEDIOLA trial. The DORA trial is ongoing, combining PARP inhibitors. There’s the TOPACIO trial, too, so there are a number of data sets now. Not surprisingly, there are not a lot of surprising toxicities with that.

Adam M. Brufsky, MD, PhD: Or expected.

Joyce O’Shaughnessy, MD: Yes, yes.

Tiffany A. Traina, MD: We also need to just keep remembering the eligibility criteria for all these different trials. So, for the PARP, those patients, although they might have had prior exposure to a platinum, they could not have progressed on a platinum.

Adam M. Brufsky, MD, PhD: Right.

Tiffany A. Traina, MD: We have to remember that in the adjuvant setting and the neoadjuvant setting, a lot of these patients are getting a platinum, potentially. We have to remember the disease-free interval on a study like IMpassion. I’m sure there will be more coming, but I’m hoping that some of those characteristics might help in deciding, for those few patients that have both biomarkers, which way to go.

Joyce O’Shaughnessy, MD: Albeit, we need more data, but if I took out the crystal ball, I think the PARP inhibitor first line plus a checkpoint inhibitor would end up being a reasonable way to go for the patients.

Heather L. McArthur, MD, MPH: Yes, and I would just point out, to add to Adam’s comments, that it’s these exceptional responders. So it’s the promise of durable sustained responses with immune therapy, and so that’s really the promise. And we all have a handful of these patients in our practice with triple-negative breast cancer who are more than a year out. I have some that are more than a year out, not only any therapy, and they’re NED [no evidence of disease].

Adam M. Brufsky, MD, PhD: Same thing.

Heather L. McArthur, MD, MPH: I think a lot of us have those patients now, and so that’s the embodiment of the hope that this offers.

Joyce O’Shaughnessy, MD: And were they mainly first-line patients, Heather?

Heather L. McArthur, MD, MPH: Not necessarily—patients who I’ve treated on trial that have been heavily pretreated.

Adam M. Brufsky, MD, PhD: When you respond, you respond for a long time.

Heather L. McArthur, MD, MPH: Exactly.

Adam M. Brufsky, MD, PhD: But here’s the question: Why didn’t we ever use PARP inhibitors like they do in ovarian cancer? Look at the SOLAR trial that came out where they basically used olaparib maintenance and had a PFS of around 3 or 4 years. Why didn’t we do that in breast cancer?

Tiffany A. Traina, MD: DORA looks a little bit at that question.

Adam M. Brufsky, MD, PhD: A little bit.

Tiffany A. Traina, MD: Because they’re using platinum as a surrogate for response to a PARP and then using the PARP as maintenance. But I think we have to remember breast cancer is not ovary cancer, right?

Adam M. Brufsky, MD, PhD: But maintenance is maintenance, right? Remember, we had all these trials creeping around of chemotherapy maintenance for years that show a survival benefit that we always ignore because they’re just chemotherapy. I mean, there may be something to this in breast cancer. I don’t know.

Heather L. McArthur, MD, MPH: Just to clarify, too, that the DORA trial used the platinum to select for responders, but then it’s olaparib with durvalumab, so incorporating checkpoint blockade with PARP inhibition.

Transcript edited for clarity.

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Transcript:

Joyce O’Shaughnessy, MD:
One combination that will be interesting, maybe, for our BRCA patients will be a PARP inhibitor with a checkpoint inhibitor. That would make a lot of sense, because we want to try to probably use the PARP inhibitors as soon as we can in the natural history of the BRCA1 and 2 patient population. And if they’re PD-L1 positive, we want to be using checkpoint inhibitors, too, you know what I mean? So, Adam, bring us up to speed a little bit with where we are with PARP inhibitors.

Adam M. Brufsky, MD, PhD: So, there are 2 randomized trials that we have. There’s OlympiAD and there’s EMBRACA. They both, basically, are very similar both in their design and their outcome. In OlympiAD, I think it was about 300 women, 302 women, with germline BRCA-associated breast cancer in second-line therapy and beyond. And there were subgroups relating to whether they were triple negative or ER [estrogen receptor] positive or prior platinum, which were randomized to physician choice of chemotherapy, which is the typical thing to use second line in triple-negative and ER-positive breast cancer, or olaparib.

And in the olaparib arm, the PFS [progression-free survival] overall, I think, was about 7½ months versus, I think, about 4 to 5 months. It was an improvement of about almost doubling—not quite doubling, if I’m not mistaken. And, basically, the women who had prior platinum did not have as good a response. Women who were triple negative had a better PFS delta. So, those seemed to be the subgroups that did better. There was no survival benefit, as far as I know, in that trial. And, interestingly enough, the adverse effect profile was very similar to chemotherapy, with the exception of hand-foot syndrome from capecitabine, which was more, and alopecia. Well, there was really no alopecia in that, because there were not alopecia-containing chemotherapies.

So, EMBRACA was a very similar design, although they allowed first-line patients. And I think about a certain percent of the patients—I think it was 40% or something—were first line in EMBRACA, and it was very similar. Again, it was talazoparib versus physician’s choice of chemotherapy. And the PFS, I believe, was a little over 8 months in the talazoparib arm and, I think, a little under 6 months in the control arm, the physician choice of chemotherapy. Those numbers were a little bit higher because they included the first-line patients. And the other thing that seemed to be very interesting: It looked like there was a trend toward overall survival on talazoparib, if I’m not mistaken. It wasn’t statistically significant. There weren’t enough events. But, basically, the bottom line is that those 2 trials were very similar, both in their design and outcomes.

Tiffany A. Traina, MD: I would say for the OlympiAD study, the primary author, Mark Robson, MD, presented at AACR [American Association for Cancer Research] some subset data on outcomes and survival. So the curves in folks that did get treatment, I think first and second line, had an improvement in overall survival. Granted, it’s a subset and a smaller group.

Adam M. Brufsky, MD, PhD: I agree with you. I’m saying that it’s only a trial design issue, I think, more than anything. I think that there probably will be a survival benefit. But here’s the issue: Let’s get back to the question you asked. So someone comes in and they’re one of those 8% to 10% of women who come in who are PD-1 and PD-L1 positive and BRCA positive.

Joyce O’Shaughnessy, MD: Germline BRCA.

Adam M. Brufsky, MD, PhD: Germline BRCA. What do you do? Which do you treat first? And I think that a lot of us have been talking on the sidelines of this meeting about this. And I think that there’s a clear survival benefit to the first-line therapy with atezolizumab and chemotherapy. There may be a trend, and the other thing that happens is that there does seem to be benefit in later lines with a PARP, where there was not benefit in later lines with the I-O [immuno-oncology], at least for now. So, for me, based on those 2 observations, I think in a double-positive person, I would give her I-O first. I think I would give her chemotherapy and I-O first.

Heather L. McArthur, MD, MPH: I think the survival benefit makes that decision.

Adam M. Brufsky, MD, PhD: But there’s probably going to be a survival benefit, too, if we look at the data longer with PARPs.

Heather L. McArthur, MD, MPH: A little longer, maybe.

Adam M. Brufsky, MD, PhD: But I agree with you, I think the survival data really do make the reason to give it first.

Joyce O’Shaughnessy, MD: And the subset of the first line in OlympiAD, the subset that Mark Robson put at AACR, showed a statistically significant improvement in survival with olaparib compared with chemotherapy in the first line. So it’s statistically significant and it’s a subset analysis.

Adam M. Brufsky, MD, PhD: So, which one do you use first?

Joyce O’Shaughnessy, MD: Well, for the triple-negative patients, I do like to use the PARP inhibitor because we’ve had those. We haven’t had the checkpoint inhibitor yet, but I’ve been using the PARP inhibitor first-line for triple-negative patients.

Adam M. Brufsky, MD, PhD: Now you’re going to have a checkpoint inhibitor. What are you going to do?

Joyce O’Shaughnessy, MD: Well, you know there are safety data. There are safety data combining checkpoint inhibitors with PARP inhibitors. There’s the MEDIOLA trial. The DORA trial is ongoing, combining PARP inhibitors. There’s the TOPACIO trial, too, so there are a number of data sets now. Not surprisingly, there are not a lot of surprising toxicities with that.

Adam M. Brufsky, MD, PhD: Or expected.

Joyce O’Shaughnessy, MD: Yes, yes.

Tiffany A. Traina, MD: We also need to just keep remembering the eligibility criteria for all these different trials. So, for the PARP, those patients, although they might have had prior exposure to a platinum, they could not have progressed on a platinum.

Adam M. Brufsky, MD, PhD: Right.

Tiffany A. Traina, MD: We have to remember that in the adjuvant setting and the neoadjuvant setting, a lot of these patients are getting a platinum, potentially. We have to remember the disease-free interval on a study like IMpassion. I’m sure there will be more coming, but I’m hoping that some of those characteristics might help in deciding, for those few patients that have both biomarkers, which way to go.

Joyce O’Shaughnessy, MD: Albeit, we need more data, but if I took out the crystal ball, I think the PARP inhibitor first line plus a checkpoint inhibitor would end up being a reasonable way to go for the patients.

Heather L. McArthur, MD, MPH: Yes, and I would just point out, to add to Adam’s comments, that it’s these exceptional responders. So it’s the promise of durable sustained responses with immune therapy, and so that’s really the promise. And we all have a handful of these patients in our practice with triple-negative breast cancer who are more than a year out. I have some that are more than a year out, not only any therapy, and they’re NED [no evidence of disease].

Adam M. Brufsky, MD, PhD: Same thing.

Heather L. McArthur, MD, MPH: I think a lot of us have those patients now, and so that’s the embodiment of the hope that this offers.

Joyce O’Shaughnessy, MD: And were they mainly first-line patients, Heather?

Heather L. McArthur, MD, MPH: Not necessarily—patients who I’ve treated on trial that have been heavily pretreated.

Adam M. Brufsky, MD, PhD: When you respond, you respond for a long time.

Heather L. McArthur, MD, MPH: Exactly.

Adam M. Brufsky, MD, PhD: But here’s the question: Why didn’t we ever use PARP inhibitors like they do in ovarian cancer? Look at the SOLAR trial that came out where they basically used olaparib maintenance and had a PFS of around 3 or 4 years. Why didn’t we do that in breast cancer?

Tiffany A. Traina, MD: DORA looks a little bit at that question.

Adam M. Brufsky, MD, PhD: A little bit.

Tiffany A. Traina, MD: Because they’re using platinum as a surrogate for response to a PARP and then using the PARP as maintenance. But I think we have to remember breast cancer is not ovary cancer, right?

Adam M. Brufsky, MD, PhD: But maintenance is maintenance, right? Remember, we had all these trials creeping around of chemotherapy maintenance for years that show a survival benefit that we always ignore because they’re just chemotherapy. I mean, there may be something to this in breast cancer. I don’t know.

Heather L. McArthur, MD, MPH: Just to clarify, too, that the DORA trial used the platinum to select for responders, but then it’s olaparib with durvalumab, so incorporating checkpoint blockade with PARP inhibition.

Transcript edited for clarity.
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