Expert Explains Evolving Options in Frontline Ovarian Cancer

Joyce F. Liu, MD, MPH

With the emergence of new frontline regimens in ovarian cancer, Joyce F. Liu, MD, MPH, explained that the key for future research is for broader groups of patients to benefit and eventually be cured with systemic therapies.

In 2018, there were 2 key first-line approvals in ovarian cancer. In June, the FDA approved bevacizumab (Avastin) in combination with carboplatin and paclitaxel, followed by bevacizumab monotherapy, for the treatment of patients with advanced disease after initial surgical resection.

The PARP inhibitor olaparib (Lynparza) was approved in December as a maintenance treatment for patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to frontline platinum-based chemotherapy.

Next steps are to build upon chemotherapy backbones and combine PARP inhibitors, checkpoint inhibitors, and antiangiogenics together in an effort to improve survival for more patient subgroups.

“The key takeaways about newly diagnosed ovarian cancer and how we treat it with chemotherapy nowadays is that there are a number of options,” said Liu. “We still think about carboplatin and paclitaxel as our backbone, but there are a number of considerations that we now give as we meet women with newly diagnosed cancer.”

OncLive: What are the key considerations in the newly diagnosed ovarian cancer space?

In an interview during the 2018 OncLive^® State of the Summit^TM on Ovarian Cancer, Liu, director of Clinical Research, Division of Gynecologic Oncology, assistant professor of Medicine at Dana-Farber Cancer Institute, highlighted the recent changes in the newly diagnosed ovarian cancer space and what the oncology field could see by the end of 2019.Liu: One [consideration] is when to give chemotherapy. Is it after surgery? Do we start chemotherapy before we do surgery, or do surgery and then give chemotherapy?

The second [takeaway] is, do we consider intraperitoneal chemotherapy? This is something that, in 2006, was considered to be potentially a standard of care that we should think about. However, new studies have brought into question whether this is as effective as we thought it once was.

The third is, how do we give this chemotherapy? Do we give it on a weekly basis or do we give it every 3 weeks? New studies have given us a better understanding of this. Then, what can we add to chemotherapy to make it more effective? Should we add bevacizumab? Should we think about maintenance therapy? PARP inhibitors are of very large interest right now, and there are very promising and interesting data in BRCA-mutation carriers with maintenance PARP inhibitors.

You brought up bevacizumab. Could you discuss the 2018 FDA approval of bevacizumab in the upfront setting and what impact it has had thus far?

Looking beyond where we are today to where the clinical trials are taking us, [we need] to understand with the addition of antiangiogenic agents, the addition of PARP inhibitors, and immunotherapies, can we make our backbone therapy better than what it has been?Bevacizumab in upfront treatment of patients with ovarian cancer is an interesting question. The initial studies with bevacizumab were published in 2011, and consistently in the studies, we have seen somewhere between the 2- to 4-month progression-free survival (PFS) benefit but no overall survival (OS) benefit in the overall study populations. When we think about whether we are benefitting our patients, we give bevacizumab with chemotherapy and then maintenance bevacizumab for another year. Trading potential toxicities for a potential 2- to 4- month PFS benefit in everybody may not be the best decision. The question is, “Are there patients who benefit more [from bevacizumab]?”

[There are] subset analyses, but the caution with them is that these are subset analyses. The ICON7 and GOG-0218 study suggest that patients with high-risk disease or stage IV cancer may benefit from bevacizumab, but I don’t think we know that for certain. As we have been looking further into these studies, we have been looking for molecular markers that will tell us whether patients will benefit more. There are potential biomarkers, but nothing that has been validated.

What about PARP inhibitors in the frontline maintenance setting? Could you highlight the data from the SOLO-1 trial?

While the FDA has approved bevacizumab in the upfront setting, what that really says to us is that it’s available, but we have to use our judgement. It’s probably not right for every patient. In fact, it might not be right for most patients, but there are a select number of patients for whom bevacizumab with chemotherapy may be something we consider.Maintenance PARP inhibitors are something that we have looked at in the recurrent, platinum-sensitive settings. These are approved now, they have definitely showed benefit across all women with ovarian cancer. The effect is more pronounced in women with BRCA-mutated ovarian cancer, but we see increased PFS in all women who have platinum-sensitive disease.

In the upfront setting, we only have one study that has given us results: SOLO-1. This was presented at the 2018 ESMO Congress and simultaneously published in the New England Journal of Medicine. We saw a very profound PFS benefit with women with BRCA-mutated ovarian cancer going on a maintenance PARP inhibitor, which was olaparib. Interestingly, the study truncated olaparib treatment at 2 years unless patients still had evidence of active disease, but that benefit looks like it may be persisting.

What could we have learned in this space by the end of 2019?

One thing to know about SOLO-1 is that we need to wait for those data to mature more. When we saw the 3-year landmark study, it showed that the number of women who have not progressed is almost 60%; we have to follow that further in time. One thing that is very intriguing is whether or not we could be actually not just prolonging time to recurrence, but maybe we could be curing some of those women. That would make a huge impact on OS, but we don’t know those data yet.There are a number of very interesting trials that are anticipated to potentially come out this year. We have heard rumors that the PRIMA study will report out; that is of PARP inhibitor maintenance not just in women with BRCA mutations, but across all women with high-grade serous cancer. That may give us an idea about how much effect we'll see across patients, not just the population selected—to be highly sensitive to PARP inhibitors. We expect the PAOLA-1 study will also potentially read out; that is a combination of bevacizumab and olaparib in women with advanced ovarian cancer. This might give us some insight into whether combining an antiangiogenic agent and a PARP inhibitor gives us an extra effect, again, across the whole patient population.

There are intriguing studies that continue to enroll. Another study with a PARP inhibitor is the GOG-3005 study, which is veliparib plus platinum-based therapy and paclitaxel upfront. That is anticipated potentially [in 2019].

What would you identify as the biggest challenges that remain in this setting?

The other thing that’s intriguing is, as we look at the spectrum of things being prepared in the near future and in the coming trials, we are starting to look at the combination of antiangiogenics plus immunotherapy plus PARP inhibitors. As these trials develop, we’re going to start seeing how we can combine these agents to potentially give better effects across a spectrum of women.One of the biggest challenges for us, still, is to understand who are the women who will respond best to any particular therapy? When we think about antiangiogenics, molecular markers for response to antiangiogenics have proven to be extremely elusive over the years. We are still looking.

Is there anything else you would like to add?

With immunotherapy trials in women with recurrent ovarian cancer, one of the things we have seen is that there is a small percentage of women with relapsed ovarian cancer who will respond, but we don’t have a great way of knowing who those are. More importantly, we have few ways of identifying who won’t respond at all. [We] recognize that all these therapies have toxicities, so we are trying to balance who were going to expose those toxicities for how much of a benefit.The important thing to keep in mind when we are thinking about a patient with newly diagnosed ovarian cancer patient is that we certainly have effective options for treatment. It is really important they get a platinum-based agent and a taxane and that, as the landscape develops, they are going to have additional options that may be dependent upon what is in their cancer—molecular markers or BRCA mutation status. Ten percent to 15% of women will have germline mutations, and another 5% will have somatic mutations. It becomes very important to start thinking about molecularly classifying these cancers earlier to really understand which women are going to benefit from which therapies.