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PARP Inhibitors in the Management of Ovarian Cancer

Predictive Markers in Ovarian Cancer

Robert L. Coleman, MD, offers insight regarding the current knowledge with predictive markers in ovarian cancer.


Robert L. Coleman, MD: Having the option of a PARP inhibitor, at this time, is revolutionary in our field. Many people ask, “What targeted therapy can I go on?” That’s a great question, because we have very, very few targeted therapies. In fact, ovarian cancer is not even a disease defined by a specific targetable mutation. Look at kidney cancer, lung cancer, and GBM (glioblastoma multiforme) in the brain. There are many diseases that have specific targets. Breast cancer has definite specific targets. Even endometrial cancer has definite specific targets. For ovarian cancer, it’s a copy number alteration. There’s too many copies of the genes around and p53, the most dominant mutation, is not a targetable event. So, we don’t have targeted therapies that are reliable—except BRCA. BRCA is the 1 mutation that can actually fit in a targeted sphere. And so, we’re super excited that we have these drugs, now available to us, to approach the aspect of targeted therapy in ovarian cancer.

The prediction of response to a PARP inhibitor is strongest when we know that patients carry the BRCA mutation. But in multiple phase II trials and in 2 of the 3 switch maintenance trials that have been conducted, excluding SOLO-2, which was just in a germline patient population, we’ve seen that the entire ovarian cancer space of patients who have platinum-sensitive recurrent disease, potentially, are candidates for the use of a PARP inhibitor. Now, identifying exactly why that’s the case is still the work of some major ongoing trials. And, it’s actually very important because our next steps into this area will look at using PARP inhibitors in combination. There are multiple potential partners that are already under investigation, that look very promising. Just understanding that there may be a way to interrogate the entire epithelial ovarian cancer, particularly platinum-sensitive ovarian cancer patient population by using the PARP inhibitor, either alone or in combination with something, is going to be a great advance for us as we go forward in trying to identify better therapies for patients.

There are many characteristics that define patients who have recurrent disease. The one that seems to be used most frequently is this issue about platinum sensitivity. Platinum sensitivity was a concept that was generated back in the late 1980s, when there were very few options other than platinum-based therapy. The thought was, if we had a time period for which patients were off chemotherapy and you could reintroduce platinum, they would have a response rate that was better than what we had available. At that time, we had very little available. And so, through a series of retrospective studies, it was defined that somewhere between 6 and 12 months seemed to be a nice discriminator for using a non-platinum therapy, where it would be just as good as giving a platinum-based therapy.

I want to make sure that people don’t misinterpret this. We do use platinum therapy in patients who have short platinum-free intervals. Frequently, we use it with a combination of another drug, because they have drug-drug synergism and it was shown that there is activity in platinum-resistant patients. But as a general rule, after about 6 months, or maybe after 12 months, we actually start to see that the benefit for re-treatment with the platinum therapy is better than the non-platinum alternatives. And the opportunity to receive platinum combinations now becomes even more important. I’ve mentioned that gemcitabine and carboplatin was compared against carboplatin in platinum-sensitive patients. And, it was shown that the combination was better. So, we’ve been able to demonstrate that patients who have longer treatment-free intervals have a better likelihood to respond to chemotherapy and an even better likelihood to respond to platinum-based therapy. And so, that’s the concept around chemotherapy sensitivity or platinum sensitivity.
 
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