PARP Inhibitors's Role as Maintenance Therapy in EOC
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
Whitney S. Graybill, MD, MS: Following treatment with chemotherapy, physicians and patients have the option of delaying any further treatment until the time of disease progression or recurrence. In this setting, after a partial or complete response, a patient would then enter a treatment-free period, also referred to as watch-and-wait. When we talk about maintenance treatments, it would be putting a patient on a therapy after completing their treatment chemotherapy. The goal of this would be to try to lengthen the time between the end of treatment and their next recurrence.
In the NOVA trial, a PARP inhibitor was not given in the chemotherapy phase. It was only given after completion of chemotherapy following a PR or CR. This is really more appropriately described as switch maintenance treatment. Now given that, approximately 50% of patients who go on to a PARP inhibitor maintenance trial have disease at the time that they go on the PARP inhibitor. They’ve had a partial response, so the lines between maintenance and switch maintenance become blurred.
When trying to decide whether to put a patient on PARP inhibitor maintenance, I think it’s important to consider a few things. It’s important to consider the clinical benefit, the side effect profile, and quality of life. Currently, there are 2 PARP inhibitors, niraparib and olaparib, that are FDA approved in the maintenance setting for patients with platinum-sensitive recurrent disease. In order to have this drug covered, it really should be in the setting of platinum-sensitive recurrent disease after first recurrence. The patient population where the maintenance therapy should really be considered is in patients with platinum-sensitive recurrent disease, given that this is where it’s FDA-approved.
In the PARP inhibitor trials in the maintenance setting, quality of life was similar between the PARP inhibitor group and the placebo group. But it’s important to individualize the treatment to every patient sitting in front of you. We know that niraparib tends to have an effect on platelets, and thrombocytopenia is a common adverse event seen. So, it’s important to know how to manage that in those patients who are receiving this drug. With olaparib, you see increases in creatine, which we need to be aware of when looking at what patient populations to treat with this drug.
Matthew Powell, MD: I’m often asked about using a maintenance-type strategy versus a watch-and-wait strategy for our patients with recurrent ovarian cancer if they achieved either complete or partial response after platinum therapy. There is some evidence that platinum is damaging to DNA, and it’s actually good to couple that with immediate use of the PARP inhibitor. The scientific and the in vitro rationale is to capitalize on use of the PARP inhibitor when maybe it will work best. So, the immediate maintenance strategy has been employed by many of the manufacturers with a logical design, to see if we can best capitalize on the damage done by the platinum and then use the maintenance PARP inhibitor to get the best results.
When we think about sequencing of agents for the treatment of ovarian cancer, using these agents early makes some sense, especially if we’re following the use of a platinum. Hopefully that damage done by the platinum could be capitalized on by the use of the PARP inhibitor, so giving these, usually after second or third-line therapy, makes sense to do for most of these patients.
When people ask me about the standard of care for the management of these patients, is a PARP inhibitor a part of that standard of care? It certainly is. It’s part of the NCCN guidelines. This is what I would like to say within the standard of care. The 1 thing we know is that no single ovarian cancer patient is always created the same. They have differences in response to their platinum, differences in toxicity, and differences in goals of whether they want to travel. So, any 1 clinical scenario doesn’t always fit, but this option is certainly a very good option for our patients who meet criteria for use.
Oliver Dorigo, MD, PhD: PARP inhibition has been shown to provide some very valuable benefit for patients, particularly for those who have recurrent ovarian cancer that is platinum-sensitive. I personally do not believe that PARP inhibitors are quite yet the standard of care, because we still have to define those patients who truly benefit from PARP inhibition. I think that we need to gain more experience with PARP inhibition. I think we need to identify those patients who truly benefit from PARP inhibition better.
Those trials are all ongoing. The material that we have from clinical trials is extremely valuable to ask questions like this. Who are the patients who, based on the molecular profile of the tumor, are having the greatest benefit from PARP inhibition? The other thing we have to consider is that PARP inhibitors are expensive, with an average cost of about $10,000 a month. Given that those patients are on maintenance therapy for many months and years to come, we have to be very careful evaluating PARP inhibitors in the context of cost.