Expanding Role of PARP Inhibitors in Advanced Ovarian Cancer - Episode 7
Michael Birrer, MD: The rationale behind maintenance therapy is essentially to prevent relapse. Maintenance therapy is nothing new to medical oncologists. We have treated a variety of our oncology patients, including patients with breast cancer, for years with maintenance therapy. Because the nature of maintenance therapy is the use of a drug over a long period of time, it does require some slightly different approaches. It cannot be agents that are cytotoxic, toxic to the bone marrow, or having a lot of GI [gastrointestinal] adverse events, or other adverse events for that matter. So maintenance therapy has been in the lingo for medical oncologists for a long time, and we’re used to it. And now with the discovery and validation of antiangiogenic agents and PARP [poly (ADP-ribose) polymerase] inhibitors, it is used in ovarian cancer treatments.
I think for gynecologic oncologists, it’s a newer phenomenon, and it’s something that is going to take a while to get used to in terms of its importance and how it is different, if you will, than typical treatment regimens, which are more aggressive and more toxic.
Kathleen Moore, MD: The concept of maintenance therapy has really become mainstream in the last 5 years, or a little bit less, with the rapid FDA approvals of a number of agents—3 PARP inhibitors and bevacizumab—first in the platinum-sensitive recurrent setting as maintenance, and then most recently based on the SOLO-1 data, with olaparib as frontline maintenance only among BRCA-positive patients. And so we’ve already talked about why maintenance therapy makes sense. So the next question is, when do you use maintenance? And you really have 3 options, actually.
You have frontline maintenance either with a PARP inhibitor, olaparib currently, or bevacizumab. You have second-line maintenance. Or, some patients are going to get maintenance in both lines of therapy. There’s nothing to say that you can’t do that. The options are that you’re using maintenance in each of those lines of therapy or discussing with patients whether or not they would rather proceed with observation and careful monitoring. I’ve heard this term watch and wait, which I really don’t like because it just sounds very passive, like I’m just waiting for someone to recur. So I prefer the term close observation for patients who don’t want to proceed with therapy.
But, we really have multiple options now. In the frontline, for patients who have an identified BRCA mutation, I really feel very strongly that they all should be offered maintenance therapy. Right now, olaparib is the 1 that’s approved. So olaparib maintenance therapy. If they have had a complete or partial response to their induction chemotherapy, the progression-free survival benefit for that over placebo is truly unprecedented. We’ve never seen anything like that in ovarian cancer, and to not offer that to a patient is wrong. Now, she may decline, but she needs to be offered it as part of the standard of care. And I’m going to be pretty blunt there. I do not think that observation for a BRCA patient is an equivalent option at all. She may elect that, and if she does, that’s fine. But the recommendation should be for PARP maintenance for that patient.
For patients who are BRCA wild-type currently, the options would include close observation following chemotherapy, and fortunately the vast majority of patients are in what we call a clinical complete remission at the end of chemotherapy. So they do have the opportunity to come off all therapy, and we can closely monitor them for a period of time. The unfortunate truth is that the majority of them will recur, and they’ll recur within 2 years. We do have the 15% who have long-term disease-free survival, and we’d like to bottle that and somehow replicate it, but the vast majority of patients recur, and they do so relatively soon. And so that’s where the concept of maintenance comes in.
So the other option for a non-BRCA patient is bevacizumab. That’s not quite the same maintenance strategy as olaparib because there you’re starting the bevacizumab with chemotherapy, which does optimize your response to chemotherapy, and then continuing it following chemotherapy. And that’s inclusive of patients who maybe had stable disease at the end of their chemotherapy. So it’s a different population of patients than those who were enrolled in SOLO-1. But that’s your other option. It does not have an overall survival advantage, but it does have a statistically significant and clinically relevant improvement in progression-free survival. Some subset analyses, not prespecified, from ICON7 would suggest there’s an overall survival benefit to the high-risk patient with stage IV disease or suboptimal disease. And so that is how some practitioners choose to select their candidates for bevacizumab. And while I don’t think that’s wrong, they’ve defined all advanced ovarian cancer as high-risk, and it feels like just making up categories. They’re all high risk; there’s not a cured group other than that 15%. So I think if you’re going to use bevacizumab, you just should offer it to really anyone. So that’s the frontline option.
Then if you have folks who recur and are still considered eligible for platinum and they respond to platinum again, you can use PARP inhibitors regardless of BRCA mutation in that setting if patients have a complete or partial response. And why is that? While the studies that were done showed a benefit in all subgroups—certainly the BRCA patients benefited the most with very significant hazard ratios—those patients who had evidence of some inability of their tumors to fix DNA outside BRCA benefited second as much. But then what followed were those who patients who had nothing identifiable: no BRCA mutation, and as far as we can tell, no obvious deficits in how their DNA fixes itself. That’s a limitation of the assays. It may not be truly reflective of what they had, but they benefited modestly, as well. So it’s indicated regardless of biomarker.
And you have bevacizumab as well delivered that same way with chemotherapy, which maximizes your response, and then to follow with bevacizumab maintenance. And in that setting you do have an overall survival advantage as well. So maintenance in the second line or third line, if you’re still responding to platinum, is an option along with close observation. We do know you can use bevacizumab in the front line, and you can use bevacizumab in the second-line and it’s just as effective. We know from ASCO [the American Society of Clinical Oncology 2018 Annual Meeting] last year; and from AGO-OVAR 2.21, which was presented at ESMO [the European Society of Medical Oncology 2018 Congress] last year, that repeat use of bevacizumab still has benefit. So repeat maintenance is well indicated. We don’t know that for PARP inhibitors yet, so for all those patients getting PARPs in the front line, we’re going to have to study it. They probably should get it again in some cases, but we don’t know that for sure yet.
Transcript Edited for Clarity.