Systemic frontline therapy options are explored through the lens of treating ovarian cancer.
Shannon Westin, MD: This patient had stage IV ovarian cancer, but she was able to have a complete resection of the disease, down to the point where there was no gross residual. That opens up a number of strategies for her. Of course, you can use the option of intravenous [IV] chemotherapy, the combination of paclitaxel and carboplatin given every 3 weeks. That has been a standard of care for some time. What this patient actually was treated with was a combination of IV as well as intraperitoneal [IP] treatment. Specifically, she received IV IP paclitaxel and cisplatin. That is based on a number of randomized phase 3 studies that demonstrated that the use of intraperitoneal chemotherapy offered both progression-free survival as well as overall survival benefits for those patients who had up-front sites of reduction. Specifically, patients who were able to get down to no gross residual disease had significant benefit compared with the IP chemotherapy, compared with patients who were treated with a standard IV every 3 weeks.
As subsequent trials have shown, that may not be the case when you add a drug called bevacizumab. We can add bevacizumab, which is a VEGF inhibitor, to the combination of intravenous paclitaxel and carboplatin. We could, potentially, see a benefit in progression-free survival. These trials did not show a benefit in overall survival in the randomized trials. When the combination of chemotherapy plus bevacizumab was compared with IP chemotherapy, there was not much of difference. The bottom line is, for this patient, you can treat in whatever way you want. You just need to talk her through your recommendations to help her make that decision. For this patient, given that she had a debulking down to no gross residual disease, was really healthy, had a good performance status, and had some peritoneal disease, the decision was easily made to proceed with the IP chemotherapy. There was also an attempt to see if you could get some of that overall survival benefit that was showing in a few of the studies.
No matter what you chose to treat this patient with, once you get that patient to a clinical complete response, once it appears she is at no evidence of disease, then comes the question of what to do next. Hopefully, you are not just talking to the patient about this now. The discussion regarding maintenance strategies really needs to start early because what you do not want to do have is a situation where a patient gets down to 6 cycles and thinks she is done, and then you surprise her with the choice of continuing or discontinuing therapy. Many patients, when given that choice, will hesitate.
I usually start a discussion around maintenance in cycle 2 or 3, although sometimes I start even earlier, if the patient is receptive to getting as much information as possible. The goal of maintenance therapy, at this point, is to improve progression-free survival or the amount of time without recurrence. Ultimately, we are hoping that these maintenance strategies are going to offer overall survival benefit, but we do not know that. That is what we are waiting on those researchers—utilizing their data—to figure out. For this patient, the different maintenance options are based on what you initially did. If you had started her on chemotherapy alone, which she did, then you would have come to a decision-making point and you would have certain options for your maintenance therapy. If you had started this patient on chemotherapy with bevacizumab, then you would be looking at a different set of options for her maintenance therapy.
First, we will talk about this patient who did not have bevacizumab with her chemotherapy. Your treatment options are to give her a PARP inhibitor, specifically niraparib, which has an FDA approval to treat homologous recombination deficient disease after response to therapy. For this patient, this is a good fit. It is a once-a-day treatment; hopefully, she is recovering from her chemotherapy. You want to make sure that the patient recovers, then you can consider that option.
Do you know how often I hear, “Could you use any PARP inhibitor?” Certainly, there are a great deal of data to indicate that PARP inhibitors are very similar in efficacy, but we have not had any FDA approval or clinical trial that supports the use of any other single-agent PARP inhibitor for this patient with homologous recombination deficient disease. Her other option is active surveillance. You could talk with your patient about transitioning to visits every 3 months with no active maintenance strategy. However, based on the potential benefits, when you talk to most patients about the abnormality in their tumor—this is their target, and this is their potential benefit—most patients seem to opt for utilizing the PARP inhibitor as a strategy.
If you had started this patient on chemotherapy with bevacizumab, then you have a couple of options outside active surveillance. You could transition off the bevacizumab and transition to a single-agent like niraparib, or you could add olaparib based on the PAOLA-1 study. PAOLA-1 took patients that had gotten chemotherapy with bevacizumab and randomized them; the patients either continued the bevacizumab alone or added olaparib to the bevacizumab. The researchers found that, for patients with homologous recombination deficient disease, there was a benefit and an improvement in progression-free survival. For this particular case, that was not an option because we did not start the bevacizumab. If you had a different patient in front of you for whom you’re recommending bevacizumab, then it would be a question to consider question once you get that patient to no evidence of disease after chemotherapy.
A question that often comes up—and 1 of the rationales behind active surveillance in these up-front patients—is, should we retain these PARP inhibitors as an option for later lines of therapy? Most of us would agree that we would like to completely cure a patient, or start treatment as soon as possible, so if we can give it all that we have up front and avoid this patient ever having to get treatment again, that would be ideal. Now, this question around sequencing and reserving treatments for later will hopefully be answered once we get more overall survival data from these trials. The thought process behind this is that by giving these targeted therapies as early as possible—before the tumor has had the opportunity to develop—resistance mechanisms are likely going to give us the best outcomes. We are starting to see some of these overall survival results in the second line. In second-line maintenance, it does seem that there is a benefit to getting it early compared with later treatment lines. We still do not have the complete answer, but when you talk to most patients and tell them, “Our goal is to try to keep this cancer from coming back,” they are willing to put in the time and investment to do that in the up-front setting.
Transcript edited for clarity.
Case: A 68-Year-Old Woman With Recurrent Ovarian Cancer