Ahead of SGO, Westin Sheds Light on Treatment Considerations for Recurrent Ovarian Cancer

Shannon Westin, MD

Shannon Westin, MD

Ahead of the SGO 50^thAnnual Meeting on Women's Cancer,Targeted Oncologysharedthe case of a patient with platinum-sensitive epithelial ovarian cancer and a germlineBRCA1mutationin a Twitter case chat. As oncologists looked forward to the meeting ahead, they discussed their treatment decisions for this patient.

After receiving IV/IP paclitaxel/cisplatin treatment, the patient in this case relapsed. The majority of participants in the Twitter discussion agreed they would treat this patient with chemotherapy followed by a PARP inhibitor.

What option would you have suggested for second-line therapy for this patient with platinum-sensitive epithelial ovarian cancer with a germline BRCA1 mutation?

— Targeted Oncology (@TargetedOnc)March 11, 2019

In a Twitter discussion about the poll, experts weighed in on their treatment considerations. Many agreed on the use of a platinum-based chemotherapy combination. Mario M. Leitao, Jr, MD, FACOG, FACS, fellowship director of the gynecology service; director of the minimal access and robotic surgery program in the department of surgery at Memorial Sloan Kettering Cancer Center, said he would assess the patient for possible complete surgical resection.

“Decision for surgery is individualized and requires direct patient assessment and review of imaging by surgeon,” Leitao tweeted. “Goal is complete gross resection. Based on presented info she otherwise would be an excellent candidate with long treatment-free interval…”

In regard to PARP inhibitors, 3 have been approved already for this setting, according to Westin. Bobbie J. Rimel, MD, assistant professor of obstetrics and gynecology at Cedars-Sinai Medical Center, said she would choose olaparib (Lynparza) for this patient, based on data fromthe phase III SOLO-1 trial.

Westin, an associate professor at The University of Texas MD Anderson Center, discussed some of the data for PARP inhibitors, as well as some other data for immunotherapy in this space. At the annual meeting, several abstracts will be presented in regard to both immunotherapy and PARP inhibitor combinations that could potentially impact the way oncologists look at a patient with recurrent ovarian cancer.

In an interview ahead of the meeting, Westin discussed the key takeaways from this case chat and highlighted some data she is looking forward to at the meeting for patients with recurrent ovarian cancer. She also highlighted other data that will play an important part in this treatment landscape and for patients with recurrent cervical cancer.

TARGETED ONCOLOGY:What are some of the most significant takeaways from our case chat discussion?

Westin:In a case like this where you have a clear target, theBRCAmutation, it takes away some of the stress of decision. I feel like that’s where we have our strongest data. We know that when we have aBRCAmutation, that’s where PARP inhibitors definitely shine, so you lose some of the hard decision-making around [if we] should use bevacizumab or not. For me, I think it makes it a much more straightforward case.

The other thing is that for now, platinum-based chemotherapy is still the standard of care for platinum-sensitive recurrent disease. Although there are a number of trials that are exploring non-chemotherapy options in that space, we still don’t know what’s going to be best, so for now, platinum-based chemotherapy is the primary choice.

TARGETED ONCOLOGY:Could you discuss some of the data that support the use of PARP inhibitors in this patient?

Westin:AERIAL2 looked at single-agent PARP inhibitor rucaparib specifically in the platinum-sensitive space and demonstrated response rates that were 75% to 80%. This is essentially equivalent to what we see with platinum-based chemotherapy, so there are data there to potentially consider that in aBRCA-mutant patient.

In addition, there was a study that compared olaparib to olaparib and cediranib in the platinum-sensitive setting, which demonstrated a very high response rate in both arms. Those data are certainly very exciting. Now, there are randomized trials that are comparing PARP combinations to platinum-based chemotherapy combinations to see if they’re equivalent or if one is better than the other.

TARGETED ONCOLOGY:Liposomal doxorubicin plus carboplatin was mentioned during the case chat. What are your thoughts on this combination?

Westin:The primary benefit is with carboplatin. We know that, and we know that carboplatin-based doublets are better than carboplatin on its own. When it comes to the chemotherapy partner, it really comes down to patient preference, existing toxicities, and schedule. It does appear that the use of something like paclitaxel versus pegylated liposomal doxorubicin versus gemcitabine versus docetaxel all appear to give related survival outcomes, but the difference between those agents that you pair with the carboplatin comes in the side effects and the schedule. For example, with pegylated liposomal doxorubicin, there’s no alopecia, the schedule is once a month, so that is something that a lot of patients want; they like that idea. They think they are going to have to go back to the weekly treatments or every 3-week treatments, so it’s nice to know that they don’t have to do that, and they also like not losing their hair. From the standpoint of paclitaxel, if they have existing neuropathy, that might be something that you want to avoid. I think there are different reasons that we make those decisions for the patients.

TARGETED ONCOLOGY:There seemed to be a lot of hesitation when it comes to eliminating chemotherapy in favor of PARP inhibitors. Why do you think this is?

Westin:I think it’s because it is very clear right now what the benefit of chemotherapy is. We’re seeing signals now with the benefit of PARP inhibitors or non-chemotherapy options, but people tend to be [cautious]. They want to see it over and over again. They want to see it multiple times. The studies that have demonstrated these high response rates are encouraging, but I think people want to see a randomized trial that proves it is safe to exchange the platinum-based chemotherapy with a non-chemotherapy arm.

TARGETED ONCOLOGY:DrLeitao said he would consider a complete surgical resection for this patient. Why is this such a controversial idea in this space?

Westin:There is a lot of retrospective data, including retrospective analyses of prospective trials, that demonstrated that in appropriately-selected patients, a secondary cytoreduction, or a resection of full tumor in this setting is appropriate. However, there was a recent randomized control trial that indicated it was better to proceed with chemotherapy in these patients. Now, importantly, that was chemotherapy with bevacizumab compared to going to surgery followed by chemotherapy. They demonstrated a survival benefit of not going to surgery.

There are some concerns around that trial. It was a very well-designed trial, but the way patients were selected for surgery was based on surgeon choice. There weren’t very clear criteria such as how many tumors were there, CD125 levels, things like that. There’s a study completed now that we are waiting for results from called DESKTOP III, where they had more specific criteria to decide who went to surgery and who didn’t. It will be interesting to see if they are able to demonstrate different results indicating that maybe if we are better at selecting patients then surgery could be a benefit.

I will say, though, that every sub-analysis that has been done on the GOG-0213 data showed no benefit to surgery, and they looked at 1 site of disease, only nodes, they did a lot of working the data to see if there was any population that would benefit from surgery, and they found no population that benefited. That, in our institution, has definitely made us pause when we are considering surgery whereas previously we were very supportive of secondary cytoreduction. We are definitely more cautious with offering that now.

TARGETED ONCOLOGY:Have we seen the results yet for these trials?

Westin:The GOG-0213 was presented in total at ASCO last year. I believe the surgical data hasn’t been officially published yet. For DESKTOP III, they presented the progression-free survival (PFS) data previously, but that’s not what you need. You need overall survival (OS) data because of course PFS has been improved because you resected all of the tumor. It takes longer to grow back, so that was presented, and we are just waiting for the OS which has not yet been presented.

TARGETED ONCOLOGY:You mentioned in the case chat that immunotherapy doesn’t quite have a role yet in this setting. Are there any trials at SGO that might show encouragement in this space?

Westin:There are a number of studies that are both in platinum-sensitive and platinum-resistant disease with combination, like immunotherapy with PARP inhibitors or immunotherapy with anti-angiogenics like bevacizumab. Those show improved response rates and PFS over the checkpoint inhibitors alone. That’s certainly very exciting, but the majority of the data that has been presented to date has been small studies, phase I and phase II studies. It’ll be interesting over the next year or so as we have a number of randomized trials coming down the pike looking at immunotherapy plus chemotherapy, immunotherapy plus anti-angiogenics, all in that recurrent setting to see if it has benefit. The response rates have been very intriguing, though.

TARGETED ONCOLOGY:We’re also expecting to see results for a phase II trial of pembrolizumab with bevacizumab and cyclophosphamide. Do you think those results can sway how we think about immunotherapy in this setting?

Westin:I’m interested, but I don’t have knowledge yet on those results. I’m assuming it’s going to be positive because the preclinical data has been so great. However, I think regardless, if they are positive, to me, one of the big questions to me would be right now we are looking at a bunch of these combinations in the upfront setting. There are 5 or 6 major randomized controlled trials, around 1000 patients each, that are putting patients on PARP, PARP and checkpoint, PARP and bevacizumab, bevacizumab and checkpoint. So if we are utilizing all of those combinations in the upfront, will we be able to go back to the well in the recurrent setting? Granted, hopefully we will be curing more patients, so we won’t need to go to the well, but for those patients that do recur after receiving that intensive combination therapy, do those things help anymore or will we have some resistance?

TARGETED ONCOLOGY:The results for the phase III JAVELIN Ovarian 200 trial will also be presented. Do you think these results might dull your excitement with immunotherapy?

Westin:This was immunotherapy plus chemotherapy, so there certainly were some data to indicate that it would be a successful combination. They did not meet their endpoint, and we know that from a press release that was put out. Certainly, it does dull the enthusiasm to some degree, but we are still trying to figure out the sweet spot in regard to combination therapy. There may still be some benefit to chemotherapy plus a checkpoint inhibitor, just maybe not this specific type of chemotherapy or maybe the full combination of 3 drugs, which I think there are a lot of different studies looking at these broad combinations. I think we were certainly disappointed, but we are still trying to figure out exactly the right way to combine these things for ovarian cancer.

TARGETED ONCOLOGY:Are there any other abstracts at the meeting that might impact the way we treat ovarian cancer in the recurrent setting?

Westin:In the first plenary PARP session, there is going to be some interesting look at some of the already-presented randomized controlled trials, specifically looking at the way we dose certain PARP inhibitors based on platelets, bodyweight, overall looking at tolerability and things like that. I think those things will be interesting.

I’m particularly interested in a couple of studies that are looking at should we be doing tumor testing for BRCA versus germline testing, or both at the same time. I’m interested to see what those results are because this is something we have been discussing at our institution. Which one should we do first, or should we do both at the same time? I’m very interested in that.

Finally, there is going to be a talk on PARP after PARP, which I don’t know how big that study is, but that is a big question for us, if there is any activity for PARP inhibitors after progression. Doing a different combination or if someone progresses on maintenance, then restarting PARP inhibitors at some point. Those are the things I’m particularly excited about from the PARP standpoint.

We already mentioned the JAVELIN Ovarian 200 data. It’ll be good to really look at that and see if there is any biomarker data that indicates certain populations that benefit from the immunotherapy and chemotherapy. I also think the one study of pembrolizumab, bevacizumab, and cyclophosphamide will be interesting, although I was kind of surprised that they combined it with cyclophosphamide. It’s not something we generally use in practice that often, so I was surprised by that choice. It’ll be interesting to see what the results there are.

TARGETED ONCOLOGY:Are there any other abstracts you are particularly interested in general at this meeting?

Westin:The other abstract I’m excited to see is tisotumab vedotin. This is for recurrent cervical cancer. We had a few patients on that in our institution, and they did really well. I’m really interested to see the data around that because recurrent cervical cancer has almost nothing. If this is a positive study, it would be an incredible [opportunity] for the patient.

See updates from the 50th Annual SGO Meeting.