Sobering OS Data With Maintenance Niraparib in Recurrent Ovarian Cancer

Niraparib (Zejula) maintenance did not improve overall survival (OS) in patients with platinum-sensitive recurrent ovarian cancer in research presented at the Society of Gynecologic Oncology (SGO) annual meeting. However, the OS analysis was confounded by differences in treatment given after disease progression.

MedPage Today brought together three expert leaders in the field. Moderator Ursula A. Matulonis, MD, chief of the division of gynecologic oncology at Dana-Farber Cancer Institute in Boston, is joined by Kathleen Moore, MD, a gynecologic oncologist at Stephenson Cancer Center at the University of Oklahoma in Oklahoma City, and Krishnansu S. Tewari, MD, a gynecologic oncologist at the University of California Irvine, for a virtual roundtable discussion. This third of four exclusive episodes covers their reactions to the updated data from the phase III ENGOT-OV16/NOVA trial.

Following is a transcript of their remarks:

Matulonis: Hello, everyone. My name is Ursula Matulonis. I’m a medical oncologist from Dana-Farber Cancer Institute in Boston, Massachusetts. And I have the privilege and honor of being here today with two of my wonderful colleagues, Dr. Kathleen Moore from the University of Oklahoma, and Dr. Krish Tewari from the University of California Irvine. And we’re going to be talking about updates that were presented at the Society of Gynecologic Oncology 2023 annual meeting that just took place in Tampa, Florida.

All right, so I’m gonna move on to NOVA. I know, a little bit of a downer, but Krish, your impressions of second iteration of the overall survival data?

Tewari: Yeah, so the thing with NOVA is, we had a PFS2 [progression-free survival 2] analysis, which was very favorable and sustained what was seen in the primary analysis. But, the OS, there’s no benefit. But again, I think it’s very clear that the study was never powered to show OS. And so it’s really not much of, it doesn’t really weigh on me too much because I’m using this frontline now. Particularly in the HRD [homologous recombination deficiency]-positive patients who don’t want to also come in and get an IV infusion of bevacizumab [Avastin] every 3 weeks. So the NOVA data again, wasn’t powered for OS, so I’m not surprised. I like the PFS2 data, but it doesn’t really clinically have an impact on my practice right now.

Matulonis: Right. Yeah. Although every once in a while there’ll be a patient who kinda sneaks in who just didn’t get — just saw this recently, a lady didn’t get upfront PARP inhibitor use, high-grade serous, was germline tested, but did not have somatic testing. Recurred like three years later. And somebody did sequencing on her and yeah, it was a somatic BRCA mutation. And of course got carboplatinum allergy after two cycles, lives up in New Hampshire and she didn’t want to come down to Boston to get desensitized. So I actually recommended that she go on olaparib [Lynparza]. So every once in a while those patients will pop up.

Tewari: Oh, they do. I mean unfortunately, I saw a patient in consultation, she was diagnosed in 2020, BRCA mutated ovarian cancer, and she wasn’t on olaparib. Yeah. Can you believe that?

Matulonis: Yeah.

Tewari: In the United States 2020. Two years after Katie presented her data, a year and four months after it got approved. And she’s recurred.

Matulonis: Yeah, right.

Tewari: I mean, it’s just unbelievable. So yeah, these patients will show up. Heartbreaking. She’s 39 years old.

Matulonis: Oh, that is heartbreaking. That’s totally heartbreaking.

I think the other interesting aspect of NOVA was again, the reiteration of the AML/MDS [acute myeloid leukemia/myelodysplastic syndrome] risk, especially in patients who have underlying germline BRCA mutations and are treated with long-term PARP inhibitor use. And that that risk, again, SOLO-2 showed around 8%. NOVA was just above 7%. So again, more reasons to abandon use in the recurrent setting and focus on the upfront setting. Katie, any thoughts about the NOVA data?

Moore: No, I agree with everything you’ve said. It is a frontline opportunity now for those that kind of present late. We do have olaparib still as all-comer indication in that second line that we can use, even though we’ve lost rucaparib [Rubraca] and niraparib in BRCA wild-type, otherwise we still have it. So you can still use it. And you know, I think there’s going to be some other data coming out in this space that will be interesting to look at that will give us some context for how to interpret the OS from A3 and NOVA. You have to kind of think about them together a little bit. There is a signal there. I think we have to acknowledge that there’s a little bit of a signal that’s going the wrong direction. So…

Matulonis: Yeah. It’s a consistent signal.

Moore: It’s a consistent signal. And you can make all the excuses, which I have made on a stage, I’ve made those statements on a stage, but it keeps coming out. So now you have to always be like, I’m going to have humble pie. I can make all those excuses, but it may be real. And I do think we have biologic plausibility for why it’s much better to use it in the front line. And certainly the treatment-related myeloid neoplasms syndromes are.

I feel like you guys are, as medical oncologists, are so much better at treating it, or maybe it’s a different subtype. But I feel like I have so many now, they’re living and I can still give them some things for a while and in the past they didn’t live at all. But it’s such a devastating complication that anything you can do to avoid it.

I’m actually not treating indefinitely in the second line, in the third line. I’ll stop them. I make it up, 3 years, but I’m stopping them. With conversation, but I’m not going to treat them for 6 or 7 years.

Matulonis: Yeah, I’ve actually, I have probably between 10 and 20 patients on long-term PARP inhibitor use in the recurrent setting and have had conversations with them, all of them. And I mean, a few have definitely said that they want to stop, but several have wanted to continue on. And maybe because…

Moore: Yeah, if they wanna continue I’m fine with that. That’s the data. That’s the data, and I’m not going to argue with you. But a few of the mine are like, yep, I want off, I’m done.

Matulonis: Yeah.

Moore: Yeah, they just were like 3 years, I’m good.

Tewari: Yeah, I only have a handful of patients on PARP in the second and third line now. Because I think, at least in my practice, once we got the first line indication, the people I had on second and third line, they’ve now progressed. Because remember, PARP’s not curing anyone. And so they’re on to other things and I just haven’t had very many opportunities to use second line PARP. I do have the olaparib indication if needed, but I think I’ve only got a handful of people on second line PARP at this point.

Matulonis: Yeah.

Moore: Hey Ursula, I’m going to ask you a question. I’m sorry to take over. I’m going to ask you a question because you’re in NOVA. So do you think as little as 2 years ago, even a year ago, we were all on the bandwagon of these PARP combinations in the platinum-sensitive recurrent space, like maintenance, like DUET. We were like, literally I was yelling at them that they were closing down DUET <laughter>, like olaparib, ATR must do it. All these combinations. Overcoming PARP resistance. So much preclinical work at your institution, we all have a study. Do you think, if the signals we’re seeing are real in A3, NOVA, A4, almost all of them, do you think that there’s an appetite to continue to develop those strategies in this space?

Matulonis: No, I think with a regular PARP inhibitor like niraparib or olaparib or rucaparib, but no, I think that ship is sailed. And obviously, they’re pole theta inhibitors, the PARP one, so I think there’re going to be other molecules that are indicated that may be different. But I think we need to see.

But I think the studies that have launched a PARP inhibitor combinations, and you’re right, there are a bunch of them. I think especially telling was PARP/IO [immuno-oncology]. At least in the resistance setting where that just hasn’t, or triplets, adding [bevacizumab] in there. Really, you just see additive, there’s nothing synergistic at all about it.

Tewari: Well, I agree, with our JAVELIN 100, JAVELIN 200, IMAGINE 50, all those were bust. But the DUO-O, I think is going to be a problem also because it’s analytic in the HRD population. So DUO-O just basically tells us that PAOLA-1 works, but I don’t think it’s going to be enough to get durvalumab [Imfinzi] a label.

Moore: That’s exactly it, <laughter>, that’s exactly it. Yeah. We’ll just have to see. I want to see the data. We’ll talk about that the next round table.

Tewari: Yeah.

Matulonis: That’s good, at ASCO [American Society of Clinical Oncology], right.

Watch episode one: A Deep Dive Into Two Randomized Trials in Endometrial Cancer

Watch episode two: Choosing a Treatment Regimen for Your Endometrial Cancer Patients