Bradley J. Monk, MD: Let’s pivot to the NCCN [National Comprehensive Cancer Network] guidelines. NCCN guidelines inform reimbursement and are certainly educational on how we treat our patients. As you know, the NCCN guidelines were updated on March 11, 2020. If you think we can’t build consensus, although I think we can, it takes the NCCN 127 pages to tell us how to treat epithelial ovarian cancer. That’s impressive. Page 11 is the most informative to our conversation here about frontline therapy. It’s entitled, “Epithelial Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Cancer, and What to Do Frontline.” They start with this bifurcation of no bevacizumab use during primary therapy or bevacizumab use during primary therapy. They don’t tell us when to do it, there’s no preference. They don’t say, “This is when you should use bevacizumab, this is when you shouldn’t use bevacizumab.” I thought that’s what the NCCN was supposed to do, tell us how to treat our patients. It doesn’t do that. That’s why I have Tom Krivak because I can ask Tom Krivak, since he presented GOG-0218 [Gynecologic Oncology Group 0218 study], when do we use bevacizumab? When should we or when shouldn’t we?

Thomas C. Krivak, MD: You’re absolutely correct. When you look at the NCCN guidelines, you’d like to see who gets bevacizumab and who doesn’t. It’s nebulous, so everybody can say, “I’m right and you’re wrong, look at the NCCN.” How do I use bevacizumab? I use it by the label. Surgical debulking is important, but if you have stage III/IV ovarian cancer, you’re going to get bevacizumab up front and then tailor with maintenance therapy.

Obviously, that’s not what the NCCN says. They have a very nice algorithm where they look at upfront use versus use in the maintenance phase; look at BRCA wild type or not, and germline status; and then go through complete response versus partial response and how you could potentially use bevacizumab—as you said, Brad—as the building block to add a PARP inhibitor to. Or do you use PARP alone? To me, what I like about the NCCN guidelines is that they say you can use bevacizumab however you want to, basically, in upfront ovarian cancer. We really need to be testing these folks, and we should stratify based off of testing. It’s taking all the data that we’ve discussed and allowing us to say that for certain tumors we’re going to use bevacizumab alone for that patient. For other patients, they’re going to get a combination therapy. For other patients, they’re going to get single-agent PARP inhibition. They’ve done a nice job of covering all their bases for how we have our biases with therapy.

Bradley J. Monk, MD: It creates four cells. You have the bifurcation of bevacizumab—yes, no—and then each one of those cells, it has germline or somatic BRCA mutation or not.

Thomas C. Krivak, MD: Right.

Bradley J. Monk, MD: Unknown is in the no-mutation subgroup. All of a sudden you have four cells, and we can work through them. If you don’t have bevacizumab, which is at least 50% or about 50% of the patients, and you have a BRCA mutation, you need the SOLO-1 (NCT01844986) or PRIMA (NCT02655016) regimen. NCCN guidelines give you both of those options. If you get no bevacizumab and have a BRCA mutation, SOLO-1 or PRIMA are category 1. Pretty easy. If you do not receive bevacizumab and you are wild type or unknown, it gives you the option to observe or use PRIMA, which is niraparib. Then there’s a footnote, Footnote F, and Footnote F says that in the absence of a BRCA1 or BRCA2 mutation, HRD [homologous recombination deficiency] status may provide information on the magnitude of the benefit of the PARP inhibitor. But it’s a category 2B recommendation. We’ll see more as the labels become clear and as the reimbursement becomes clear. But they also don’t tell us if we should use the HRD test, yes or no. They don’t tell us when to use it. They just say that if you do use it, it’s a 2B recommendation and it might be helpful. Do you have any comments on that, without bevacizumab? Do you agree with that? We’ve gone through the assay, but do you like this, Tom Krivak? Tom Herzog? How do you work through that? Is this informative or not?

Thomas J. Herzog, MD: It’s been a month or so since I’ve read them, but I thought you summarized them well and I know that it was category 2B in terms of the HRD. I think one of the other things—if I didn’t misread them—was that it also included stage II? Quite interesting, right?

Bradley J. Monk, MD: Brilliant.

Thomas J. Herzog, MD: Because these studies are all stage III/IV. But I think, Brad, you’ve taught us that one decision affects the other decision, right? If you make that first decision, your real first decision is, are you going to operate right away or are you going to give chemotherapy and then operate? If you’re going to operate right away, that takes you to your next decision, if you’re going to use neoadjuvant therapy. Your next decision is bevacizumab or no bevacizumab. Now, with all these new data from PRIMA and PAOLA-1 (NCT02477644), how are we going to incorporate that? Now you’ve really got to make some decisions. Are you going to add to the bevacizumab? Are some people going to, when they get their HRD information back, stop bevacizumab even if the patient is responding well, and then start a PARP inhibitor as maintenance?

It’s going to be very interesting to see what people do with the information because it’s also going to be temporal in terms of when you’re getting this information and when you test. Obviously, the sooner, the better, so that you can make the best decision for the patient. I found the NCCN guidelines to be interesting, and nebulous was a good way of wording it.

Transcript edited for clarity.