Will all women with ovarian cancer eventually benefit from poly (ADP-ribose) polymerase (PARP) inhibitors? It’s a great question, and one which offers new hope for many ovarian cancer survivors.
Who do PARP inhibitors help?
While there are several trials underway into the eventual wider-spread efficacy of PARP inhibitors, there are some patients who are obvious candidates to benefit from a PARP inhibitor already: namely, those women who have deleterious underlying BRCA mutations and whose cancers exhibit platinum sensitivity. We know that patients facing those medical conditions are prime candidates because we’ve completed clinical tests that have shown favorable results from that treatment. Once such study was the groundbreaking SOLO-1 with olaparib, which demonstrated that if the cancer is responding to platinum, a PARP inhibitor is going to increase the chance for progression-free survival. In the SOLO-1 test, 60% of the patients who had received olaparib remained progression-free three years into the trial, compared to just 27% of the placebo arm of that study.
What happens when a PARP inhibitor stops working?
One of the issues or challenges on which researchers are actively working is what to do when women are on a PARP inhibitor and the inhibitor stops working. At that point the cancer is progressing, and therefore is no longer responsive to a PARP inhibitor.
In those situations, we’re looking at PARP inhibitor combinations—ways to pair the PARP inhibitor with other treatments, bringing about a synergistic effect with the PARP inhibitor’s function.
What are some PARP Inhibitor combinations?
Researchers are investigating several PARP inhibitor combinations.
One potential PARP inhibitor combination that’s undergoing trials brings a PARP inhibitor together with angiogenesis inhibitors, which are drugs that limit blood flow to tumors. These angiogenesis inhibitors work by preventing the growth of new blood cells. In a recent trial, physicians compared treating recurrent platinum-sensitive ovarian cancer with the PARP inhibitor olaparib alone (i.e. monotherapy) versus treating the cancer with a combination of the PARP inhibitor with an oral antiangiogenic inhibitor (cediranib). The median progression-free survival was favorable for the combined therapy, at 17.7 months for the combination versus 9.0 months for the PARP inhibitor by itself.
There are a lot of other PARP inhibitor combinations currently being researched, including combining PARP inhibitors with different immunotherapies.
In one area of immunotherapy and PARP inhibitor combination therapy research, physicians have been looking at the efficacy of PARP inhibitors in combination with immune checkpoint inhibitors.
When high-grade serous ovarian carcinoma (HGSOC) tumors deficient in BRCA1 are treated with a PARP inhibitor, the tumor cells will increase their output of PD-L1 – an “immune checkpoint” protein that makes the tumor cells invisible to the immune system. Drugs known as “checkpoint inhibitors” are capable of removing immune checkpoint proteins like PD-L1—which are essentially blinders on the immune system—so that attacks on the tumor cells can resume.
There’s promising preclinical evidence to suggest that the PARP inhibitors and the immune checkpoint inhibitors are synergistic, meaning that—when taken together—they can deliver results greater than the sum of their parts. Trials are currently underway on the efficacy of combining the PARP inhibitor niraparib (Zejula) with the immune checkpoint inhibitor pembrolizumab (Keytruda) in patients with advanced or metastatic triple-negative breast cancer or recurrent ovarian cancer.
We have also tested PARP inhibitors in combination with Phosphoinositide 3-kinase (PI3Ks) inhibitors.
The PI3KS inhibitors inhibit enzymes that are a part of the PI3K/AKT/mTOR pathway—a signaling pathway for a myriad of critical cellular functions including cell growth, proliferation, and survival. The targeted therapy of PI3KS inhibitors helps with tumor suppression, and the combination of PI3K inhibitors with PARP inhibitors opens a whole other area of clinical trial studies.
Learn more about the side effects of PARP inhibitors here.
Learn more about SurvivorNet's rigorous medical review process.
Dr. Ursula Matulonis is the Chief of the Division of Gynecologic Oncology at Susan F. Smith Center for Women's Cancers at the Dana-Farber Cancer Institute. Read More
Will all women with ovarian cancer eventually benefit from poly (ADP-ribose) polymerase (PARP) inhibitors? It’s a great question, and one which offers new hope for many ovarian cancer survivors.
Who do PARP inhibitors help?
Read More While there are several trials underway into the eventual wider-spread efficacy of PARP inhibitors, there are some patients who are obvious candidates to benefit from a PARP inhibitor already: namely, those women who have deleterious underlying BRCA mutations and whose cancers exhibit platinum sensitivity. We know that patients facing those medical conditions are prime candidates because we’ve completed clinical tests that have shown favorable results from that treatment. Once such study was the
groundbreaking SOLO-1 with olaparib, which demonstrated that if the cancer is responding to platinum, a PARP inhibitor is going to
increase the chance for progression-free survival. In the SOLO-1 test, 60% of the patients who had received olaparib remained progression-free three years into the trial, compared to just 27% of the placebo arm of that study.
What happens when a PARP inhibitor stops working?
One of the issues or challenges on which researchers are actively working is what to do when women are on a PARP inhibitor and the inhibitor stops working. At that point the cancer is progressing, and therefore is no longer responsive to a PARP inhibitor.
In those situations, we’re looking at PARP inhibitor combinations—ways to pair the PARP inhibitor with other treatments, bringing about a synergistic effect with the PARP inhibitor’s function.
What are some PARP Inhibitor combinations?
Researchers are investigating several PARP inhibitor combinations.
One potential PARP inhibitor combination that’s undergoing trials brings a PARP inhibitor together with angiogenesis inhibitors, which are drugs that limit blood flow to tumors. These angiogenesis inhibitors work by preventing the growth of new blood cells. In a recent trial, physicians compared treating recurrent platinum-sensitive ovarian cancer with the PARP inhibitor olaparib alone (i.e. monotherapy) versus treating the cancer with a combination of the PARP inhibitor with an oral antiangiogenic inhibitor (cediranib). The median progression-free survival was favorable for the combined therapy, at 17.7 months for the combination versus 9.0 months for the PARP inhibitor by itself.
There are a lot of other PARP inhibitor combinations currently being researched, including combining PARP inhibitors with different immunotherapies.
In one area of immunotherapy and PARP inhibitor combination therapy research, physicians have been looking at the efficacy of PARP inhibitors in combination with immune checkpoint inhibitors.
When high-grade serous ovarian carcinoma (HGSOC) tumors deficient in BRCA1 are treated with a PARP inhibitor, the tumor cells will increase their output of PD-L1 – an “immune checkpoint” protein that makes the tumor cells invisible to the immune system. Drugs known as “checkpoint inhibitors” are capable of removing immune checkpoint proteins like PD-L1—which are essentially blinders on the immune system—so that attacks on the tumor cells can resume.
There’s promising preclinical evidence to suggest that the PARP inhibitors and the immune checkpoint inhibitors are synergistic, meaning that—when taken together—they can deliver results greater than the sum of their parts. Trials are currently underway on the efficacy of combining the PARP inhibitor niraparib (Zejula) with the immune checkpoint inhibitor pembrolizumab (Keytruda) in patients with advanced or metastatic triple-negative breast cancer or recurrent ovarian cancer.
We have also tested PARP inhibitors in combination with Phosphoinositide 3-kinase (PI3Ks) inhibitors.
The PI3KS inhibitors inhibit enzymes that are a part of the PI3K/AKT/mTOR pathway—a signaling pathway for a myriad of critical cellular functions including cell growth, proliferation, and survival. The targeted therapy of PI3KS inhibitors helps with tumor suppression, and the combination of PI3K inhibitors with PARP inhibitors opens a whole other area of clinical trial studies.
Learn more about the side effects of PARP inhibitors here.
Learn more about SurvivorNet's rigorous medical review process.
Dr. Ursula Matulonis is the Chief of the Division of Gynecologic Oncology at Susan F. Smith Center for Women's Cancers at the Dana-Farber Cancer Institute. Read More
