Bradley J. Monk, MD, FACS, FACOG: One of the most surprising discoveries with this PAOLA-1 trial is the activity, or the lack thereof, in the non-HRD [homologous recombination deficiency] patients. I’ve been hypnotized. I’m really excited about adding anti-VEGF [vascular endothelial growth factor] and PARP inhibition in all comers. I was taught that if you have BRCA, then the PARP inhibitor works. The real opportunity is in the non-BRCA patients. We had a trial conducted by Joyce Liu of Dana-Farber Cancer Institute with olaparib-cediranib, and then we had this AVANOVA trial with niraparib-bevacizumab. It just didn’t…

Robert L. Coleman, MD, FACOG, FACS: It didn’t rattle you.

Bradley J. Monk, MD, FACS, FACOG: It didn’t pass the sniff test, because those end points were not placebo controlled. There was no independent radiology review.

Robert L. Coleman, MD, FACOG, FACS: The results had no direct independency, we didn’t pull out the…

Bradley J. Monk, MD, FACS, FACOG: For example, in AVANOVA, there’s no bevacizumab arm.

Robert L. Coleman, MD, FACOG, FACS: Or in Joyce Liu’s study.

Bradley J. Monk, MD, FACS, FACOG: Or in Joyce Liu’s. There’s no cediranib arm. I was so excited to see the HRD-negative benefit of adding olaparib to bevacizumab. What happened?

Kathleen Moore, MD: There’s no difference.

Bradley J. Monk, MD, FACS, FACOG: There wasn’t one. How is that possible?

Kathleen Moore, MD: You’re comparing with an active comparator, and in the HRD—if it’s truly HRD negative—I don’t think we have the right assay just yet.

Robert L. Coleman, MD, FACOG, FACS: Yes, correct.

Kathleen Moore, MD: If this is a truly representative HRD negative, you could choose either. I think the other studies support the use. You could use either.

Bradley J. Monk, MD, FACS, FACOG: I’d do both.

Kathleen Moore, MD: There’s no additive effect.

Bradley J. Monk, MD, FACS, FACOG: Bevacizumab isn’t dead.

Michael J. Birrer, MD, PhD: But it’s fair to say it’s an odd result.

Bradley J. Monk, MD, FACS, FACOG: It’s not odd. It’s consistent with other people smarter than me and with what they thought.

Michael J. Birrer, MD, PhD: You would expect at least an additive effect, and you don’t see it.

Bradley J. Monk, MD, FACS, FACOG: I would have, but I wasn’t right.

Michael J. Birrer, MD, PhD: I wouldn’t necessarily expect synergism. I’d never buy that, but at least that effect of “Well, niraparib has 3 months up front in PRIMA.” Why don’t we see that when we add olaparib to BEV [bevacizumab]?

Bradley J. Monk, MD, FACS, FACOG: Maybe niraparib is a better PARP inhibitor.

Michael J. Birrer, MD, PhD: That’s exactly what I think is going to be said, and I don’t believe that, sorry.

Kathleen Moore, MD: The other thing is that—and we brought this up earlier—in the platinum-sensitive space, the best predictor of a PARP inhibitor is being platinum sensitive, right?

Robert L. Coleman, MD, FACOG, FACS: Yes.

Kathleen Moore, MD: You can predict that in PAOLA-1 and PRIMA a little because they’ve responded. At least you’ve excluded the patients who have progressed.…However, you don’t know who is going to make it to 6 or 12 months. And they may, but these people may not have ever made it to AVANOVA.

Bradley J. Monk, MD, FACS, FACOG: That’s right.

Robert L. Coleman, MD, FACOG, FACS: That’s exactly right.

Kathleen Moore, MD: Fifty percent of these patients may never have qualified, and they’re a totally different population from the HRD-negative who are still platinum sensitive. This may be different.

Robert L. Coleman, MD, FACOG, FACS: This is the reason why, when we do randomized controlled trials, we are able to control for confounders. We have no way to control for the confounders that you just brought up, which could have explained these data. That’s really the key, and you called for it. Why don’t we do a PARP inhibitor trial in the biomarker negative, however we pick a biomarker? I think it’s a great idea.

Bradley J. Monk, MD, FACS, FACOG: You’re not going to be giving BEV [bevacizumab]. You want to keep it going. It’s tolerable. The HRD comes back negative, and you’re not going to go, “Oh, maybe PAOLA was wrong. I’m going to go ahead and add olaparib just for the heck of it.”

Shannon N. Westin, MD, MPH: No. I’m not doing that.

Bradley J. Monk, MD, FACS, FACOG: It’s not going to happen.

Kathleen Moore, MD: I think there’s still a lot of clinical equipoise in HRD negative, and I think everybody is going to understand that. We’re going to have to guess for a while to do what’s best for our patients.

Bradley J. Monk, MD, FACS, FACOG: Which is half the patients.

Kathleen Moore, MD: I know, but we’re going to have to figure out the next trial for these people, and we’ll put them in it because we want them to do better.

Bradley J. Monk, MD, FACS, FACOG: I think we have those trials. We have those trials—bevacizumab, atezolizumab. We have them with the PARP inhibitors and the I/O [immuno-oncology]. I think the real unmet medical need now is in the HRD-negative space.

Robert L. Coleman, MD, FACOG, FACS: I actually think the real unmet need is to understand who is HRD negative. We talk about the assays as though they’re binary.

Bradley J. Monk, MD, FACS, FACOG: Yes, that’s true.

Robert L. Coleman, MD, FACOG, FACS: It’s not. I think we need to get away from that.

Michael J. Birrer, MD, PhD: Where you see that benefit in the so-called HRD minus. It’s with a cutoff of 0.42, and you know you’re putting patients in there who actually have homologous recombination deficiency, because they’re between 0.42 and 0.33, right?

Robert L. Coleman, MD, FACOG, FACS: Exactly. That’s exactly what I’m talking about.

Michael J. Birrer, MD, PhD: We need to define it better.

Transcript Edited for Clarity