PARP Inhibitors Are Changing the Treatment Landscape for Ovarian Cancer

PARP inhibitors are bringing an exciting shift to the treatment landscape of ovarian cancer, says Kathleen N. Moore, M.D., associate director of Gynecologic Oncology at the Stephenson Oklahoma Cancer Center.

In an interview with CURE at the 2017 Society for Gynecologic Oncology Annual Meeting, Moore discussed the use of PARP inhibitors such as niraparib for the treatment of ovarian cancer — advances that could be practice changing, she says.

Can you give an overview of the randomized, double-blind phase 3 NOVA trial of niraparib maintenance therapy?

It's a study trying to answer the question whether maintenance PARP inhibitor, in this case the PARP inhibitor niraparib, improves progression-free survival (PFS), and then there's a number of other endpoints: overall survival (OS), time to first subsequent therapy, chemotherapy-free interval, and a number of quality of life measures, as well. But the main question is: does the use of niraparib improve survival endpoints in what we call maintenance therapy following chemotherapy for patients with recurrent ovarian cancer who are considered sensitive to platinum?

It's an interesting study in that it allowed really any ovarian cancer patient who had high-grade serous or high-grade endometrioid tumors, irrespective of whether or not they had a germline BRCA mutation. But, within the main study, there were actually two independently powered studies. One study for patients with a known germline BRCA mutation; they were randomized in a two to one fashion to niraparib or a placebo. So, patients could get really any sort of platinum-based chemotherapy that their physician felt was the best choice for them. They had to either be in a complete response (CR) or in a very good partial response (PR), meaning they had less than 2 cm of visual disease on CT scans.

The other independent study was the same design: two to one randomization, for patients without a germline BRCA mutation. Within that group there were a number of exploratory studies done within certain subgroups.

The primary results were presented at ESMO in 2016 and were just remarkably positive for the initial endpoint, which is PFS. So, in the germline BRCA mutation group, there was a hazard ratio of .27 in favor of use of niraparib. And then in the germline BRCA mutation, there was also a very statistically significant hazard ratio as well. The exploratory end points of that trial were to look within that germline-negative group and try to characterize them further. That was presented in the main presentation when they found patients with somatic BRCA mutations, and found small numbers, which we expect. But in that small group of patients, that hazard ratio was almost identical, if not identical, to that of the germline BRCA mutation patients. So, they seem to gain the same degree of benefit from the use of niraparib as did their germline BRCA counterparts.

And then there were subgroups that looked at patients who had something called homologous recombination deficiency, and this was measured by the myriad test. Basically what that means is that there's evidence in the tumor that that tumor at some point in the life cycle of that patient had difficulty repairing double-stranded DNA breaks. It doesn't tell you why that is, or whether or not that status is still present, but it tells you that that tumor at least at some point couldn't fix itself. So, they've divided patients into what we call HRD-positive, excluding those somatic BRCA patients who are certainly HRD-positive, so they were analyzed separately. Really the surprising thing, I think to everyone, was that both groups benefitted significantly. So you wouldn't have really expected the HRD-negative group to benefit, but they had a statistically significant improvement in their PFS by virtue of a hazard ratio.

Questions that investigators still have are: What's the impact on subsequent therapies? Should a patient receive a PARP inhibitor in the maintenance setting? Does it impact OS? If it improves your PFS, but then you can't get subsequent therapies, that would be an important thing to know. At this meeting, some preliminary data on that was presented, at least the data for the treatment chemotherapy-free intervals. The time from completion of chemotherapy to the next needed chemo, and then what's called the time to subsequent therapy, which is the time from the beginning niraparib to the time of beginning subsequent therapy. So there's the same kind of continuum, but those showed equal improvement, as did the PFS, which is to be expected. I think what we're really going to want to see is what happens when you treat someone again, and then how long they survive after that or what their response is there.

For maintenance treatment with niraparib, what ultimately, do these results mean?

I think the other big question is what we do about the HRD-negative group. They seemed, at least by the myriad test, to benefit. Not as much, but the benefitted. And we want things that benefit our patients, so it would be a reasonable thing to offer our patients if it's approved effective. But it raises the question of whether or not we need a better test to really pick patients who truly should or should not get any PARP inhibitor, much less niraparib in this setting. So I think we're still working on that as well. The studies that are resulting now in the maintenance setting, really have the potential to be paradigm-shifting for our patients. And practice patterns differ, some people will give six cycles and stop, some do eight. Some, if they don't have a CR, will just continue it indefinitely. So, either way, if you do six or eight and then stop and watch someone, it should be similar to the placebo arm. Or if you continue someone on chemotherapy indefinitely, at some point patients are going to be re-exposed to chemotherapy again when they recur, they're just going to keep right on being exposed to it until they progress.

So it's chemotherapy, it's infusions, patients have to come in, they have to have pre-medications, there's the physicians visits, travel, you're constantly being reminded that you're a patient and coming in and having a variety of medications infused into your body. Depending on the medications given, there's hair loss or neuropathy or other sorts of toxicities. And so, if we believe that PARP inhibitors have a role here, then if you're someone that treats to complete response, if you know — and the data pretty clearly shows us — even in complete response, that those patients actually recur or can recur relatively quickly. The median time to progression for the whole group is about five to six months for placebo, and probably there are those who had complete response that was longer, but it doesn't look like it's years.

What are some major takeaways from this study?

And so, if we believe in the maintenance strategy, then you can put someone on an oral therapy, which after an initial time of pretty close supervision for all the drugs — for niraparib, we're watching for thrombocytopenia with rucaparib, we're doing some initial tests to just make sure their liver functions. It's not clinically relevant unless it gets too high. With olaparib, we're looking for anemia. So you kind of have to watch people a little closely in those first one or two cycles. Then, once you have someone on a stable kind of regimen, they're tolerating things, not having nausea, then you have someone that can be home and be doing fine, checking labs, and be frequently sent in for physician visits. This is not to say no physician visits, because we do need to keep an eye on our patients, but there's no reason to see someone every three weeks on an oral agent doing well. They don't need to come into the infusion center or come in and wait in your waiting room. Once they're stable and doing well and you're monitoring them from a symptom and lab standpoint, you kind of stretch things out and they can have a little bit of their life back. I think one of the most hopeful things is just that finally we are developing drugs of importance for patients with ovarian cancer -- good drugs with reasonable side effect profiles that may have meaningful prolonged survival for a meaningful amount of time. We're not just talking a couple of months.

Behind this first wave of PARP inhibitors, there's whole pipeline in almost every pharmaceutical company, of different but similar agents that work just in a different way, but then with the same DNA response pathway which may be very effective drugs when PARP inhibitors stop working or drugs that work with the PARP inhibitors so that people get a better response or work in different subtypes.

There's just quite a wave of very exciting new agents coming behind these very effective PARP inhibitors, so clinical trials and clinical trial participation will continue to be really critical. Even though we've had some successes here, we just still have so many questions to answer. We're not curing people yet, we want to cure people, and so there's still a lot of questions to ask. Clinical trials are going to be important in answering these questions, and there's a lot of really exciting agents -- immune agents, DNA agents, targeted chemotherapy, other pathway targeted drugs -- which may have relevance in ovarian cancer. It's a hopeful time for patients to finally have some new, potentially better options with things on the way.