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Combinations With PARP Inhibitors for Ovarian Cancer

Insights From: Oliver Dorigo, MD, PhD, Stanford University Medical Center; Whitney Graybill, MD, MS, Medical University of South Carolina; Matthew Powell, MD, Washington University School of Medicine
Published: Friday, Feb 02, 2018



Transcript: 

Whitney S. Graybill, MD, MS: There are a lot of really exciting combinations currently being explored with PARP inhibitors. I think one of the more exciting combinations is olaparib and cediranib. Cediranib is a VEGF tyrosine kinase 1, 2, and 3 inhibitor, and it is thought to mediate BRCA downregulation.
The really cool thing is that we are hoping to leverage synthetic lethality and take tumors that are HR-proficient and basically turn them into tumors that are HR-deficient. This was explored in a phase II trial that looked at olaparib versus olaparib with cediranib in patients with platinum-sensitive recurrent disease. The group that got olaparib with cediranib had a significantly improved progression-free survival compared with the olaparib alone arm.

The median progression-free survival was significantly increased in patients who received cediranib and olaparib compared with olaparib alone. Now, these data were recently presented in an updated version, and interestingly, it was found that there was not a significant difference in progression-free survival in patients who had a known BRCA mutation, but there was an even larger difference in progression-free survival in patients who had an unknown, or not known, BRCA mutation, with 5 months compared with 23 months. To further explore this, there’s a phase III trial that is currently recruiting patients evaluating olaparib alone compared with olaparib and cediranib compared with platinum-based chemotherapy in patients with platinum-sensitive recurrent disease.

Oliver Dorigo, MD, PhD: In general, the combination of PARP inhibition and antiangiogenic therapy is biologically very plausible and very interesting to pursue. The antiangiogenic drugs deprive the tumor, obviously, of important nutrients and oxygen by decreasing the tumor vascular density. That by itself can most likely decrease the expression of genes and proteins that are involved in homologous recombination repair. That makes the tumor likely more sensitive to PARP inhibition. Therefore, I think that the combination of a PARP inhibitor with an antiangiogenic therapy is likely to have at least some additive efficacy. It’s hard to predict what combination—either olaparib with bevacizumab or another antiangiogenic drug, or niraparib with bevacizumab—will be of differential efficacy.

Given that PARP inhibitors at this point seem to have rather equal efficacy—I’m not comparing trials with each other—we have to, when we look at the data, say that there’s not much tangible difference in progression-free survival, at least not on the maintenance trial. That’s the case, and we assume that the biological efficacy is similar. Maybe the clinical efficacy in this combination will not depend necessarily on the PARP inhibitor but may be based on patient selection. Those patients might be the ones who are BRCA1 nonmutated.

We actually have data from one trial that Dr. Matulonis published a couple of years ago that show that with olaparib combined with cediranib, another antiangiogenic drug, those patients who don’t have BRCA mutations benefit the most from this combination. And that probably goes back to the idea that antiangiogenic drugs decrease the expression of HRD genes and hence increase sensitivity to PARP inhibition. Now, we have to verify these data in clinical trials. For any trial that will investigate a PARP inhibitor, or combinations of PARP inhibitors with antiangiogenic drugs or immunotherapy, we need to carefully look at mutation spectrums in the tumor and then correlate responses with those somatic mutations.

The combination of an immune checkpoint inhibitor like niraparib with pembrolizumab, which is actually ongoing, is a very exciting one. Immunotherapy is mostly effective in patients who have a high tumor mutational burden, who have a high expression of neoantigens. PARP inhibition can actually increase the expression of neoantigens and, hence, immunotherapy. We also know that those patients who have BRCA1 and BRCA2 mutations have a microenvironment in their tumor that might be much more responsive to immunotherapy. For example, we see more cytotoxic T cells infiltrating those tumors in patients who have BRCA1 and BRCA2 mutations, either in the germline or in the tumor tissue. Hence, the microenvironment might play a major role in conveying a response to this combination of immune checkpoint inhibition with PARP inhibition. I personally get excited about these types of trials because I think that combination will very likely increase the efficacy of PARP inhibition.

Matthew Powell, MD: When we look at other combinations with PARP inhibitors, perhaps we may be able to think about low-dose chemotherapy. We do have trials looking at veliparib, which is not FDA approved, in combination with up-front chemotherapy. We may see our ability to use some of the FDA-approved PARP inhibitors in combination with lower-dose chemotherapy. That may be a strategy that gets developed over the next few years. And then, obviously, there are very exciting combinations with our antivascular agents and our immunotherapy agents.
 
Transcript Edited for Clarity 
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Transcript: 

Whitney S. Graybill, MD, MS: There are a lot of really exciting combinations currently being explored with PARP inhibitors. I think one of the more exciting combinations is olaparib and cediranib. Cediranib is a VEGF tyrosine kinase 1, 2, and 3 inhibitor, and it is thought to mediate BRCA downregulation.
The really cool thing is that we are hoping to leverage synthetic lethality and take tumors that are HR-proficient and basically turn them into tumors that are HR-deficient. This was explored in a phase II trial that looked at olaparib versus olaparib with cediranib in patients with platinum-sensitive recurrent disease. The group that got olaparib with cediranib had a significantly improved progression-free survival compared with the olaparib alone arm.

The median progression-free survival was significantly increased in patients who received cediranib and olaparib compared with olaparib alone. Now, these data were recently presented in an updated version, and interestingly, it was found that there was not a significant difference in progression-free survival in patients who had a known BRCA mutation, but there was an even larger difference in progression-free survival in patients who had an unknown, or not known, BRCA mutation, with 5 months compared with 23 months. To further explore this, there’s a phase III trial that is currently recruiting patients evaluating olaparib alone compared with olaparib and cediranib compared with platinum-based chemotherapy in patients with platinum-sensitive recurrent disease.

Oliver Dorigo, MD, PhD: In general, the combination of PARP inhibition and antiangiogenic therapy is biologically very plausible and very interesting to pursue. The antiangiogenic drugs deprive the tumor, obviously, of important nutrients and oxygen by decreasing the tumor vascular density. That by itself can most likely decrease the expression of genes and proteins that are involved in homologous recombination repair. That makes the tumor likely more sensitive to PARP inhibition. Therefore, I think that the combination of a PARP inhibitor with an antiangiogenic therapy is likely to have at least some additive efficacy. It’s hard to predict what combination—either olaparib with bevacizumab or another antiangiogenic drug, or niraparib with bevacizumab—will be of differential efficacy.

Given that PARP inhibitors at this point seem to have rather equal efficacy—I’m not comparing trials with each other—we have to, when we look at the data, say that there’s not much tangible difference in progression-free survival, at least not on the maintenance trial. That’s the case, and we assume that the biological efficacy is similar. Maybe the clinical efficacy in this combination will not depend necessarily on the PARP inhibitor but may be based on patient selection. Those patients might be the ones who are BRCA1 nonmutated.

We actually have data from one trial that Dr. Matulonis published a couple of years ago that show that with olaparib combined with cediranib, another antiangiogenic drug, those patients who don’t have BRCA mutations benefit the most from this combination. And that probably goes back to the idea that antiangiogenic drugs decrease the expression of HRD genes and hence increase sensitivity to PARP inhibition. Now, we have to verify these data in clinical trials. For any trial that will investigate a PARP inhibitor, or combinations of PARP inhibitors with antiangiogenic drugs or immunotherapy, we need to carefully look at mutation spectrums in the tumor and then correlate responses with those somatic mutations.

The combination of an immune checkpoint inhibitor like niraparib with pembrolizumab, which is actually ongoing, is a very exciting one. Immunotherapy is mostly effective in patients who have a high tumor mutational burden, who have a high expression of neoantigens. PARP inhibition can actually increase the expression of neoantigens and, hence, immunotherapy. We also know that those patients who have BRCA1 and BRCA2 mutations have a microenvironment in their tumor that might be much more responsive to immunotherapy. For example, we see more cytotoxic T cells infiltrating those tumors in patients who have BRCA1 and BRCA2 mutations, either in the germline or in the tumor tissue. Hence, the microenvironment might play a major role in conveying a response to this combination of immune checkpoint inhibition with PARP inhibition. I personally get excited about these types of trials because I think that combination will very likely increase the efficacy of PARP inhibition.

Matthew Powell, MD: When we look at other combinations with PARP inhibitors, perhaps we may be able to think about low-dose chemotherapy. We do have trials looking at veliparib, which is not FDA approved, in combination with up-front chemotherapy. We may see our ability to use some of the FDA-approved PARP inhibitors in combination with lower-dose chemotherapy. That may be a strategy that gets developed over the next few years. And then, obviously, there are very exciting combinations with our antivascular agents and our immunotherapy agents.
 
Transcript Edited for Clarity 
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