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Combining PARP Inhibitors + Checkpoint Inhibitors in TNBC

Panelists: Aditya Bardia, MD, MPH, Massachusetts General Hospital Center; Claudine Isaacs, MD, Lombardi Comprehensive Cancer Center; Joyce O'Shaughnessy, MD, Baylor University Medical Center Texas Oncology; Tiffany Traina, MD, Memorial Sloan Kettering Cancer Center
Published: Tuesday, Mar 06, 2018



Transcript: 

Joyce A. O’Shaughnessy, MD: Tiffany, what about the preoperative use of the PARP inhibitors? I think there have been some veliparib data, hasn’t there been?

Tiffany Traina, MD: Sure. There has been. I think that the idea of combining PARP inhibitors and chemotherapy has a rationale there with PARP inhibition. If you have DNA damage repair and then you partner that with a cytotoxic agent that will create a lot of DNA damage, we would hope that that would be synergistic in some way and have a better outcome. I think that the BrighTNess study, which was a randomized trial of anthracycline and taxane-based treatment, adding in an arm with the platinum, adding in a combination arm of veliparib with platinum actually showed there wasn’t much incremental advantage at all to a PARP inhibitor over a platinum. So, I don’t know if that means perhaps that the platinum in and of itself is contributing so much that we don’t see an incremental advantage there to the PARP inhibitor. There have been some interesting data in the I-SPY mechanism that are somewhat encouraging. And so, I think we need to be careful about these combinations. There is certainly more toxicity when you combine PARP inhibition with some of these other platinum-based agents. And in the metastatic setting, it has actually been quite challenging to overlap drugs like olaparib with cisplatin or even carboplatin. I think that that addition in the preoperative setting was a negative trial.

Joyce A. O’Shaughnessy, MD: So, we don’t have, right now, data that would suggest that would be a useful strategy for patients at this moment preoperatively.

Tiffany Traina, MD: No.

Joyce A. O’Shaughnessy, MD: But, Claudine, just tell us a little bit about the OLYMPIA opportunity out there for early-stage BRCA patients.

Claudine Isaacs, MD: I think one of the things that we really think of is, is there a role for PARP inhibitors in a more protracted fashion, more like in a semi-maintenance–type setting? And so, the ongoing large OLYMPIA trial is looking at BRCA1 and BRCA2 carriers. Specifically, they have to have high enough risk disease, HER2-negative again, so hormone receptor-positive is allowed and it’s randomizing those patients to a year of olaparib or placebo, basically, in the patient population. So, I think that will give us some very important data in that group of patients, and it is not putting it on top of the chemotherapy. It’s after the chemotherapy is done. Patients are allowed to have gotten a platinum or not. They have to have gotten prior chemotherapy, so it’s really trying to address whether we can add anything, whether we can further improve outcomes in that group of patients.

Joyce A. O’Shaughnessy, MD: Super. Well, it’s such an important trial and amazing. Aditya, what about combining PARP inhibitors with checkpoint inhibitors, what’s the rationale for that? There’s a lot of interest now that maybe we’ll have access to both of those in practice pretty soon. We might be tempted to do a little of that. What’s going on there?

Aditya Bardia, MD, MPH: These days, checkpoint inhibitors are being combined with everything, and I think they’ll be combined with PARP inhibitors as well. But there is some preclinical rationale. The PARP inhibitors affect the repair of DNA, and that leads to some genomic instability and more expression of the antigens. That’s point No. 1, that it can affect the immunity and the presentation of antigens, which can potentially increase immunotherapy response. And the second is that there are data—not so much in breast cancer but more in ovarian cancer in preclinical models—that PARP inhibitors could actually increase PD-1 expression. So, if you use PARP inhibitors, the PD-1 expression is increased and then you add a PD-1 inhibitor, that could potentially lead to synergy. And in ovarian cancer, there have been trials looking at combination of PARP inhibitors with PD-1 with quite encouraging results. In breast cancer, there were data presented at the San Antonio meeting looking at the combination of a PARP inhibitor with a PD-1 inhibitor.

It was a phase Ib trial. The numbers are small, but the 2 take-home points were that first, it can be safely combined. The incidence of severe immunotherapy complications was very low. And the toxicities were not overlapping, so you could potentially combine a PARP inhibitor with a PD-1 inhibitor. And second, the efficacy looked good. There were complete responses seen. There were, I think, 5 or so patients who had partial responses, and the trial had criteria that you need to have a disease control rate, at 12 weeks, of 75%, which was a decently high bar. And in the trial, the disease control rate was 80%. So, it met its primary objective, demonstrated that you could potentially combine these agents, and I think we would likely see more trials that combine PD-1 inhibitors with PARP inhibitors.

Joyce A. O’Shaughnessy, MD: That makes a lot of sense. That was the olaparib with durvalumab, which is a PD-L1 inhibitor, is that right? Yes, that was interesting. Small numbers but encouraging, and certainly a signal to go forward. Particularly, it potentially might have some implications for combining checkpoint inhibitors with platinum-based agents in the neoadjuvant setting as we’ll get to it. So, really quite early but very, very interesting and promising. Thank you very much for that discussion about the PARP inhibitors.

Transcript Edited for Clarity 

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Transcript: 

Joyce A. O’Shaughnessy, MD: Tiffany, what about the preoperative use of the PARP inhibitors? I think there have been some veliparib data, hasn’t there been?

Tiffany Traina, MD: Sure. There has been. I think that the idea of combining PARP inhibitors and chemotherapy has a rationale there with PARP inhibition. If you have DNA damage repair and then you partner that with a cytotoxic agent that will create a lot of DNA damage, we would hope that that would be synergistic in some way and have a better outcome. I think that the BrighTNess study, which was a randomized trial of anthracycline and taxane-based treatment, adding in an arm with the platinum, adding in a combination arm of veliparib with platinum actually showed there wasn’t much incremental advantage at all to a PARP inhibitor over a platinum. So, I don’t know if that means perhaps that the platinum in and of itself is contributing so much that we don’t see an incremental advantage there to the PARP inhibitor. There have been some interesting data in the I-SPY mechanism that are somewhat encouraging. And so, I think we need to be careful about these combinations. There is certainly more toxicity when you combine PARP inhibition with some of these other platinum-based agents. And in the metastatic setting, it has actually been quite challenging to overlap drugs like olaparib with cisplatin or even carboplatin. I think that that addition in the preoperative setting was a negative trial.

Joyce A. O’Shaughnessy, MD: So, we don’t have, right now, data that would suggest that would be a useful strategy for patients at this moment preoperatively.

Tiffany Traina, MD: No.

Joyce A. O’Shaughnessy, MD: But, Claudine, just tell us a little bit about the OLYMPIA opportunity out there for early-stage BRCA patients.

Claudine Isaacs, MD: I think one of the things that we really think of is, is there a role for PARP inhibitors in a more protracted fashion, more like in a semi-maintenance–type setting? And so, the ongoing large OLYMPIA trial is looking at BRCA1 and BRCA2 carriers. Specifically, they have to have high enough risk disease, HER2-negative again, so hormone receptor-positive is allowed and it’s randomizing those patients to a year of olaparib or placebo, basically, in the patient population. So, I think that will give us some very important data in that group of patients, and it is not putting it on top of the chemotherapy. It’s after the chemotherapy is done. Patients are allowed to have gotten a platinum or not. They have to have gotten prior chemotherapy, so it’s really trying to address whether we can add anything, whether we can further improve outcomes in that group of patients.

Joyce A. O’Shaughnessy, MD: Super. Well, it’s such an important trial and amazing. Aditya, what about combining PARP inhibitors with checkpoint inhibitors, what’s the rationale for that? There’s a lot of interest now that maybe we’ll have access to both of those in practice pretty soon. We might be tempted to do a little of that. What’s going on there?

Aditya Bardia, MD, MPH: These days, checkpoint inhibitors are being combined with everything, and I think they’ll be combined with PARP inhibitors as well. But there is some preclinical rationale. The PARP inhibitors affect the repair of DNA, and that leads to some genomic instability and more expression of the antigens. That’s point No. 1, that it can affect the immunity and the presentation of antigens, which can potentially increase immunotherapy response. And the second is that there are data—not so much in breast cancer but more in ovarian cancer in preclinical models—that PARP inhibitors could actually increase PD-1 expression. So, if you use PARP inhibitors, the PD-1 expression is increased and then you add a PD-1 inhibitor, that could potentially lead to synergy. And in ovarian cancer, there have been trials looking at combination of PARP inhibitors with PD-1 with quite encouraging results. In breast cancer, there were data presented at the San Antonio meeting looking at the combination of a PARP inhibitor with a PD-1 inhibitor.

It was a phase Ib trial. The numbers are small, but the 2 take-home points were that first, it can be safely combined. The incidence of severe immunotherapy complications was very low. And the toxicities were not overlapping, so you could potentially combine a PARP inhibitor with a PD-1 inhibitor. And second, the efficacy looked good. There were complete responses seen. There were, I think, 5 or so patients who had partial responses, and the trial had criteria that you need to have a disease control rate, at 12 weeks, of 75%, which was a decently high bar. And in the trial, the disease control rate was 80%. So, it met its primary objective, demonstrated that you could potentially combine these agents, and I think we would likely see more trials that combine PD-1 inhibitors with PARP inhibitors.

Joyce A. O’Shaughnessy, MD: That makes a lot of sense. That was the olaparib with durvalumab, which is a PD-L1 inhibitor, is that right? Yes, that was interesting. Small numbers but encouraging, and certainly a signal to go forward. Particularly, it potentially might have some implications for combining checkpoint inhibitors with platinum-based agents in the neoadjuvant setting as we’ll get to it. So, really quite early but very, very interesting and promising. Thank you very much for that discussion about the PARP inhibitors.

Transcript Edited for Clarity 
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