Frontline Approaches Fine-Tuned in Newly Diagnosed Ovarian Cancer

Paul Sabbatini, MD

The decision of whether or not to use frontline bevacizumab (Avastin), intraperitoneal (IP) therapy, and administer chemotherapy as a weekly dose-dense regimen or on a 3-week dosing schedule in patients with newly diagnosed ovarian cancer has been clouded by a series of conflicting clinical trials.

Those questions are now being put to rest, enabling physicians to focus on additive combinations with greater activity, according to Paul Sabbatini, MD.

“We're now exploring PARP inhibitors, antivascular therapies, and anti—PD-1 drugs. We've settled what the optimal doses and schedules are [for these backbones] that we can use in combination with these novel compounds,” said Sabbatini, deputy physician-in-chief for clinical research, Memorial Sloan Kettering Cancer Center.

OncLive: How has the frontline setting of ovarian cancer evolved over the years?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Ovarian Cancer and Soft Tissue Sarcoma, Sabbatini clarified where the field stands regarding the use of these modalities in the frontline setting of newly diagnosed ovarian cancer.Sabbatini: We've looked at several different modalities, including IP therapy, the addition of anti-vascular therapies, as well as changing the dosing schedule of frontline therapy. Based on several randomized studies, we've come to a place where we've decided that there doesn't appear to be an advantage with IP chemotherapy. There was a robust advantage to weekly chemotherapy in the Japanese GOG3016 study, but it appeared to be less so in the subsequent GOG262 study.

What was the rationale for the use of IP chemotherapy in this space?

What has been explored in terms of anti-vascular therapies?

Could you elaborate on the dosing schedules that have been explored?

Is there a certain class of drugs that you are particularly excited about?

In the ICON8 study, there doesn't appear to be an advantage for weekly therapy over 3-week therapy. This tells me that we can choose either a 3-week dosing schedule or a weekly backbone, upon which to add new novel therapies.It's not more easily delivered. The push for IP chemotherapy in ovarian cancer was because the disease is largely confined to the peritoneal cavity. There was also a lot of interest in high-dose therapy. Some investigators also thought IP chemotherapy might work because of its stimulation from an immunotherapeutic standpoint. We’ve shown that IP chemotherapy can deliver similar outcomes. Despite the fact that the National Cancer Institute put out an alert to say that everyone should have [IP chemotherapy] in 2006, the uptake was very low—largely based on the technical expertise required to give it and the added toxicity.The anti-vascular story has been an interesting one in ovarian cancer. Bevacizumab has been approved in Europe for use as frontline therapy and was recently approved in the United States by the FDA. For all comers, it seems to deliver a modest progression-free survival advantage of about 4 months. In certain subsets of patients—those with stage IV disease, suboptimal debulking, or ascites—bevacizumab appears to induce a modest overall survival advantage. Those particular patients might want to consider bevacizumab in the frontline setting. Certainly, there is utility of bevacizumab later in the disease course.In terms of weekly versus 3-weekly dosing, we all wanted the weekly schedule to be markedly better. It seemed like it was heading that way from the Japanese study, but perhaps there are pharmacogenomic differences in those patients that make weekly delivery more effective. Now we have to add drugs to this primary backbone; we need backbones with the least toxicity. The IP backbone makes it very difficult to add additional drugs. We’re looking to add PARP inhibitors and PD-1 drugs to those backbones; those trials are ongoing. We're going to have these answers within the next few years.The therapeutic class that has the most potential but is also one in which we have to learn how to appropriately use it in ovarian cancer [is immunotherapy]. [We may be able to make] ovarian cancer tumors more susceptible to responses with agents in the realm of immunotherapy. [We may have to look beyond] single-agent PD-1 drugs. There's a lot of interest in turning these "cold" tumors into “hot” tumors that are more responsive to immunotherapy. That's an exciting area of research. PARP inhibitors are also exciting, and we're going to have data pretty soon about what they do and in whom they work best. It might be easier to sort [that class of agents out after we have those data].

Where do you feel future research should be focused?

What continues to be an unmet need in this setting?

PD-1 inhibition alone has not been so effective in ovarian cancer. If you give anti—PD-1 agents and take the brakes off the immune system, giving it concomitantly with a vaccine for example, that may direct the immune response. Those are all approaches that are being evaluated now. That's an exciting area, and there’s more to come.In the frontline setting, we are looking at anti-vascular agents and PARP inhibitors. The area to be explored is the realm of immunotherapy. PARP inhibitors may extend outcomes and increase the cure proportion. It's pretty clear that bevacizumab by itself isn't going to dramatically do that. [Testing ways] to enhance immunotherapeutic effects appears to be a beneficial way to go. If I could increase funding and look at that, that's probably the area I would focus on.We pay more attention to the cure proportion and question whether we can cure more patients on the front end with different therapeutic strategies. Many of our gains in ovarian cancer have come because of the effectiveness of therapies for recurrence. That's good, but we don't want patients to have recurrence and require additional treatment. To put a little bit more focus on the things that we can do in the frontline setting to increase the cure proportion would be beneficial to patients.