Frontline Treatment in Ovarian Cancer Could Undergo Transformation

Heather Dalton, MD

The frontline setting patients with ovarian cancer has potential to change in the near future, with targeted and immunotherapy strategies showing promising signals of activity.

Such combination approaches in the first-line setting include chemotherapy plus the PD-1 inhibitor pembrolizumab (Keytruda) followed by pembrolizumab maintenance. This appeared to be safe and feasible for patients with advanced ovarian cancer, according to preliminary data from a small clinical trial that were presented at the 2018 Society for Gynecologic Oncology Annual Meeting.

In the study, 6 of 10 patients exhibited no evidence of disease during follow-up for as long as 14 months after debulking surgery, including 1 patient who had suboptimal results. No new or unexpected adverse events (AEs) occurred.

However, further data need to be collected before knowing what role immunotherapy should have in the frontline setting, Heather Dalton, MD, says. Other strategies being explored include PARP inhibitors, checkpoint inhibitor monotherapy, and bevacizumab (Avastin). In October 2017, the FDA accepted a supplemental biologics license application for bevacizumab, in combination with carboplatin and paclitaxel, followed by bevacizumab alone, for the first-line treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. The FDA is expected to make a decision on the application by June 25, 2018.

OncLive: What is the standard first-line treatment option for patients with ovarian cancer?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Ovarian Cancer, Dalton, a gynecologic oncologist at Arizona Oncology, discussed the developing standard of care for the frontline treatment of patients with ovarian cancer.Dalton: This is a controversial subject. There were many times where we thought we had it all figured out. With every trial, the water seems to get muddier regarding the standard of care. With the initial dose-dense regimen, we were excited about the improvement in overall survival that we saw that rivaled intraperitoneal (IP) chemotherapy. Everyone was understandably embracing of that regimen, but the results of the GOG 252 trial complicated that significantly as there was no difference in survival between the regimens.

Are there emerging strategies that could be looked at as a frontline option?

I would say, for suboptimally debulked patients, most would agree that the dose-dense regimen or an appropriate clinical trial are good choices. For patients who are not the most robust, consideration of fractionated treatments, such as dose-dense carboplatin and paclitaxel, are good options. For patients with a good performance status, IP chemotherapy is still a reasonable option, although there is no true standard of care. There are lots of controversies there.A lot of exciting things are going on right now in ovarian cancer. There are 6 new FDA appointment dates for potential approvals for drugs in the frontline setting. The addition of PARP inhibitors in the frontline setting [could be] exciting. We are seeing that in multiple clinical trials and it will be exciting to see the results.

Are there any concerns or unanswered questions that we have with PARP inhibitors or immunotherapy in the frontline setting?

Additionally, we are seeing the introduction of checkpoint inhibitors in the frontline setting. Those are all very exciting, so it will be interesting to see what comes out of those trials because there are [encouraging] data in the second-line setting.We are learning more about these medications and the class-specific AEs associated with them. With regimens such as PARP inhibitors, some patients have more hematologic or gastrointestinal-related toxicities, but those are generally manageable. We are getting better at making appropriate adjustments to dosing as we become familiar with these regimens.

What are your thoughts on pembrolizumab (Keytruda) being combined with chemotherapy in the frontline setting?

Have we defined the role of adding bevacizumab (Avastin) to the treatment landscape?

If we get to a point where PARP inhibitors are looked at in the frontline setting, will we run into sequencing challenges?

With checkpoint inhibitors, we are at a time where there is potential with modulating the immune system, but these also have anticipated AEs. Those are often serious, but are usually manageable and can be recognized earlier. As time goes on, we can learn more about these medications so that we can handle things more effectively.I do not think that there are enough data with that combination to say that patients shouldn’t get the standard of care, which is cytotoxic chemotherapy. As we learn more about these trials with checkpoint inhibitors and PARP inhibitors, we will have more data on how efficacious those can be in the frontline setting. It is too early to abandon the treatments that we know work without definitive evidence. Certainly, in some cancer types, we are moving to immunotherapy as a frontline setting and hopefully for patients with ovarian cancer that will be an option—but we are not there yet.There is definitely a benefit in patients who are suboptimally debulked, which has been supported by numerous data. As far as its addition in the frontline setting, there are new data coming out demonstrating the potential benefit of it in the frontline setting. Although those studies have been criticized, there is a pending FDA evaluation of the regimen in the frontline setting. We will see how the indication changes, but many people are using it.As more patients are exposed to PARP inhibitors, it will be interesting to see the data that have come out on the efficacy of these agents. Hopefully, depending on how long it has been since the patient received a PARP inhibitor, it could be given to them again, but those data are forthcoming.

Uyar D, Bishop EA, Bradley WH, Rader JS. Preliminary data on the use of combination carboplatin, paclitaxel and pembrolizumab therapy for ovarian cancer. In: Proceedings from the 2018 SGO Annual Meeting; March 24-27, 2018; New Orleans, LA. Abstract 100.