PARP Inhibitors in the Management of Ovarian Cancer - Episode 4
Robert L. Coleman, MD: Ovarian cancer, as I mentioned, is an uncommon disease. Fortunately, the drugs that we have for primary therapy are active. We know this because in trials, patients who have had bulky disease left after surgery will end up at the end of their chemotherapy with no visible tumor, by CAT scan, and with a negative exam for CA-125. So, we know this is a chemotherapy-sensitive disease. And, since most patients in the United States are now getting good surgery as well as good chemotherapy, the 75% or more of those patients, at the time of completion of their frontline therapy, end up with no disease. At that point, what can we do to maintain that? So, the issue of maintenance therapy was really born out of that primary situation. You finish your frontline therapy, we know there’s a high risk of recurrence, but we don’t know what to do about it. We’ve done maybe 15, 20 randomized trials in that situation. We’ve been able to show that we can delay progression in a couple of these trials, but we haven’t been able to show that we’ve been able to cure more patients with induction maintenance.
So, at that time, when patients are finished with frontline therapy, many patients will go into what’s called “observation.” There’s some benefit for that kind of clinical plan. Patients usually have toxicity from their frontline therapy, and they need some time to recover. Also, we really don’t know that we can influence outcomes, but we do want to make sure that we maintain close surveillance. There are options for patients, if they recur. A lot of patients and physicians will ask, “What’s the risk of recurrence for advanced ovarian cancer?” It’s high.
In most of our frontline trials, we can measure out the time to first progression pretty easily. Most patients will progress. In fact, if you look at the tail of the progression-free survival curves from frontline therapy, you see that only about 20%, 25% of patients, depending on what types of patients you start with, are actually disease-free past 5 years. Those patients are probably at a very low risk to recur at that point. So, that means that 70%, 75% of patients who finish therapy and look good are going to recur. And, even if we operate on those patients at the completion of their frontline treatment and find no disease, half of those patients are going to recur. So, it’s really a major health burden once the patients are diagnosed with the disease. Our close surveillance protocol, which happens at the time of a maintenance time period, is looking for recurrence so we can enact more therapies. It’s a stressful time for patients. They generally will get the white coat syndrome right around the time they come in for their 3-month visit, which is what we frequently will do.
At this time, we’re not able to actually pick or predict which patients are going to recur or not recur. But we have some inference as to how long it will be until they recur. At around 1.5, 2 years, we start to think about what the options will be for a patient who would recur at that time period. Maybe 25% of patients will recur in under a year. Those patients do not have as much sensitivity as we would have anticipated when they first started their disease. We call those patients “chemotherapy-resistant.” Sometimes, you hear the term “platinum-resistant.” The definition of a platinum-resistant patient is not well described. I can tell you that we frequently use the term “6 months,” but it’s completely arbitrary and really represents a continuum. In other words, the point in time that a patient recurs actually describes a continuous improvement in their ability to respond to the next line of therapy. So, short intervals: short likelihood for response. Long intervals: long or big opportunity for response.
In so many people, we use this 6-month characteristic to define platinum-sensitive and platinum-resistant patients. Some of us will use “12 months,” because that represents a more sensitive population that would be potentially amenable to a platinum-based, re-induction therapy. And, that’s really what this is all about. What do you do when the patient recurs? If they’re under 6 or 12 months, patients will frequently receive a nonplatinum agent. If they recur after 12 months, or after 6 months, they’re often re-treated with a platinum-based doublet. The reason this is important, in this discussion about PARP inhibitors, is that most patients who carry a BRCA mutation are going to have very long treatment-free intervals. They are going to be amenable to platinum reinduction therapy. And, now that we have PARPs available, there’s an opportunity to treat these patients with a PARP inhibitor.
As I mentioned before, some of that has been with the concept that we can possibly revisit the maintenance question all over again. Like I mentioned before, with primary maintenance, we’re talking about secondary or switch maintenance. This is a concept that was really born out of the fact that if we treat a patient who is considered platinum-sensitive and they respond to treatment, maybe the machinery is messed up and maybe we can actually impact those patients, again, by using a PARP inhibitor.