The Importance of HRD Testing in Ovarian Cancer

Transcript:

Bradley J. Monk, MD, FACS, FACOG: Let’s get into it. At 2019 ESMO [European Society for Medical Oncology Congress], the first 3 papers presented at the presidential session were on ovarian cancer. The first paper presented was a study called PRIMA which was published on the same day in the New England Journal of Medicine, and Antonio Gonzalez-Martin, MD, is the first author. I’d like to have a thumbnail sketch of that clinical trial. Katie, tell us about the design of PRIMA.

Kathleen Moore, MD: Of the 3 studies we’re going to discuss, which are all great studies, PRIMA is probably the simplest to interpret and maybe the cleanest trial. It enrolled women who we’d consider the highest risk, so patients with stage IV or with stage III disease who still had residual tumor. They could have partial responses or complete responses. It was a higher-risk group of patients, from a recurrent standpoint.

They were given whatever platinum-based induction chemotherapy that their provider thought appropriate. At the end of that, if they were in a complete or partial response, they could enter PRIMA and were randomized in a 2-to-1 fashion to receive niraparib or placebo. The primary endpoint was progression-free survival [PFS] in what they termed the homologous recombination deficient [HRD] group, as measured by the Myriad Genetics, Inc test. Then for the second primary endpoint, if that was positive, was hierarchical evaluation of the entire cohort, which is called the “intention to treat” cohort.

Bradley J. Monk, MD, FACS, FACOG: That’s interesting. The reason we’re here to talk about it is that we have capitalized on your wonderful discovery and expanded it to be on BRCA, particularly in the HRD subset. The point is that BRCA was great, but now it’s beyond BRCA. And the first analysis is this HRD group, which we’re going to hear about, but maybe it’s relevant for everyone. In platinum-sensitive, relapsed ovarian cancer, all 3 PARP inhibitors are approved in second-line responders. The challenge is that in the frontline, we don’t really have the responses that provide a clinical biomarker.

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

Bradley J. Monk, MD, FACS, FACOG: Maybe we need to rely a little more on a molecular biomarker. Michael, what did PRIMA show, and how was it practice changing?

Michael J. Birrer, MD, PhD: As already mentioned, the primary endpoints include the HRD group. Remember, this is that assay that shows us who has homologous recombination deficiency.

It’s important to know that this assay is still evolving. In fact, the cutoff has been changed from previous studies in which it was 33 and has been moved up to 42. What does that mean? That means theoretically, it should predict for patients who are going to benefit from PARP better than their old assay. The hazard ratio for that group was 0.43, or highly statistically significant, and the median PFS went from 10.4 to 21.9 months. So those data were strongly positive.

Bradley J. Monk, MD, FACS, FACOG: You had told me that we need to take the BRCA patients out of that. That included the BRCA patients, right?

Michael J. Birrer, MD, PhD: That includes the entire group, right.

Bradley J. Monk, MD, FACS, FACOG: I get that that was the primary endpoint, so it counts.

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

Bradley J. Monk, MD, FACS, FACOG: We really didn’t know that this HRD thing was going to work out. I don’t want you to think that this was some bait-and-switch pharmaceutical thing. We really didn’t know, because in second-line maintenance, it really wasn’t that great. OK? Tell us about what would happen if you subtract the BRCA as the HRD opportunity.

Michael J. Birrer, MD, PhD: Obviously, when you take the BRCA out, that’s a group of patients who’d clearly benefit. The HRD group, however, that is basically BRCA wild type, also benefits.

Bradley J. Monk, MD, FACS, FACOG: Right, so a hazard ratio of 0.40.

Michael J. Birrer, MD, PhD: Yes.

Bradley J. Monk, MD, FACS, FACOG: Again, just to put that in perspective, if you have an HRD assay and high-risk patients, who need it the most, you have basically a doubling of the PFS. It’s better than 6 months with bevacizumab. It’s not BRCA but sort of intermediate. I want you to think of HRD as an intermediate between no biomarker and BRCA.

Michael J. Birrer, MD, PhD: Right. Again, I think in PRIMA you’re identifying those patients who benefit a little better than in NOVA because the assay shifted a bit.

Bradley J. Monk, MD, FACS, FACOG: Yes.

Michael J. Birrer, MD, PhD: More importantly, the other primary endpoint is the entire group: “intention to treat.” The hazard ratio there was 0.62.

Bradley J. Monk, MD, FACS, FACOG: Which, interestingly, is the same as bevacizumab, right?

Michael J. Birrer, MD, PhD: In addition to an 8.2-month control arm meeting PFS to approximately 13. Both primary endpoints were hit and were strongly statically significant, so it’s a very exciting study. There are exploratory endpoints, which I think are important. Rob will say, “Hey, you’re using exploratory endpoints. Please leave the room.” But we need to talk about this.

We talked about the BRCA-mutated a little. That’s a hazard ratio of 0.4. To me, that’s actually the most comparable across the 3 studies we’re going to talk about because it’s very well defined. In this case, it’s 0.4. You could argue a bit that that’s not on the level of SOLO-1, but I’m going to argue that PRIMA was actually a very high-risk group of patients and they were sicker.

Bradley J. Monk, MD, FACS, FACOG: Katie, compare the high-risk group in SOLO-1, because 0.3 was all comers. If you take the high-risk patients in SOLO-1, what are the hazard ratios? I get that we’re doing cross-drug comparisons across subsets, but I’m trying to make this into a clinical opportunity.

Kathleen Moore, MD: It was very similar. I will emphasize that, just like this other discussion, this is an exploratory endpoint that was never meant to be compared. The group of patients in SOLO-1 who had neoadjuvant chemotherapy or were stage IV—which is most comparable with PRIMA—or had residual disease at the time of surgery, had a hazard ratio of 0.44.

Bradley J. Monk, MD, FACS, FACOG: There are no direct comparisons, but would it be difficult to say that 1 was better than the other in the BRCA patients?

Kathleen Moore, MD: Just as I say in the platinum-sensitive recurrent setting, the BRCA patients all performed similarly, regardless of the PARP inhibitors. There are subtle differences between PARP inhibitors and PARP trapping, and we can argue that, but that’s a whole separate session. They function the same. The hazard ratios are almost identical, so I don’t know why they would be different in the frontline in a biomarker-selected group like BRCA.

Bradley J. Monk, MD, FACS, FACOG: Rob, go ahead. I know you have some comments.

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

Bradley J. Monk, MD, FACS, FACOG: I could tell. I can hear you breathing down my neck.

Robert L. Coleman, MD, FACOG, FACS: Yes, we call it ready to launch.

Bradley J. Monk, MD, FACS, FACOG: Here and in the field.

Robert L. Coleman, MD, FACOG, FACS: The point is, you want to at least inform what it is that you’re trying to get out of that information, right?

If there’s a hypothesis that understanding the isolated benefit of the testing is there, then what it should make you want to do is get that information so that you can then prospectively validate whether that’s the case. The value of carving out the BRCA and looking at just the HRD, or carving out those 2 groups and looking at just the wild type, is to raise the hypothesis that maybe the knowledge of those biomarkers has informed it. If you don’t have the biomarkers, you can’t make an informative type of decision. It still needs to be validated.

Bradley J. Monk, MD, FACS, FACOG: Right.

Robert L. Coleman, MD, FACOG, FACS: What you’re trying to do is educate our audience surrounding what information is necessary so that you can put these trials into context, and I think that’s really valuable.

Bradley J. Monk, MD, FACS, FACOG: I would say that these are experiments. It’s not relevant to every patient. We have to take the information and translate it into clinical practice—assuming this leads to a full FDA approval, no matter what the biomarkers or whether it works in the non-HRD.

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

Bradley J. Monk, MD, FACS, FACOG: How would HRD and BRCA affect your practice, Shannon?

Shannon N. Westin, MD, MPH: It’s going to depend on the person in front of you, right?

Bradley J. Monk, MD, FACS, FACOG: Of course.

Shannon N. Westin, MD, MPH: You have to make a decision pretty early on about what you’re going to do. I don’t want to jump ahead too much, because we have 2 other trials to discuss that are very exciting, but you’re going to be deciding right when you finish surgery or when you’re determining your neoadjuvant chemotherapy, “Am I going to go down a BEV [bevacizumab] route? Am I going to go down a PARP route? What do I think this patient in front of me is going to respond best to?”

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

Shannon N. Westin, MD, MPH: Those exploratory analyses are helpful, right?

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

Shannon N. Westin, MD, MPH: If you know that the biggest bang for your buck is in BRCA with single agent, great. That HRD-positive may act a little differently. And certainly that biomarker-negative group, while getting benefit, doesn’t get as much benefit. You’re going to tell your patient that and help them decide how many drugs you’re going to give them in the up-front setting.

Michael J. Birrer, MD, PhD: Let’s be honest. The exploratory endpoints are very important because they give us more of these panel discussions.

Shannon N. Westin, MD, MPH: Check!

Robert L. Coleman, MD, FACOG, FACS: Again, it’s about making declarative statements. That’s what I’m concerned about.

Bradley J. Monk, MD, FACS, FACOG: I have no intention of that. The primary endpoint of PRIMA was HRD, which included BRCA, and I can stand on that. It was prospectively validated and placebo controlled. In fact, you said PRIMA has a blind and independent central review.

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

Bradley J. Monk, MD, FACS, FACOG: I can interpret that result and the next step down was all comers. I’m personally confident that the FDA will approve it in all comers because there’s a benefit in all subgroups.

Robert L. Coleman, MD, FACOG, FACS: I guess I’m not sure why you need to carve it out.

Bradley J. Monk, MD, FACS, FACOG: Because I want to use the best treatment for my patients. For example, if a patient has an HRD, non-BRCA, do you agree that the best treatment for that patient would be a PARP, or would you say, “Oh, no, I want to give BEV [bevacizumab]”?

Michael J. Birrer, MD, PhD: I think, based on PRIMA, I would go with the PARP.

Kathleen Moore, MD: Even without separating out the BRCA, I think I know that it’s the best treatment out there.

Robert L. Coleman, MD, FACOG, FACS: Yes. You already have the answer, so I’m not really sure.

Bradley J. Monk, MD, FACS, FACOG: I just think it becomes an easier decision. I respect that. Even if you don’t have the HRD, it’s going to be OK.

Michael J. Birrer, MD, PhD: Let me muddy the waters a little more since you touched on it. We ought to let the audience know the numbers. For the HR [homologous recombinant]—proficient, who are the ones for whom the HRD assay was normal, the hazard ratio was 0.68. There’s the benefit. Not quite 0.58 from NOVA, but it’s still statistically significant, and it’s a 3-month prolongation.

Shannon N. Westin, MD, MPH: Right.

Michael J. Birrer, MD, PhD: I think the debate will be whether that’s better in BEV [bevacizumab], or should that be the group that gets BEV [bevacizumab]?

Shannon N. Westin, MD, MPH: Right.

Bradley J. Monk, MD, FACS, FACOG: I think the take-home message is, if you don’t have HRD in that patient, she is not going to do very well. In fact, if you look at The New England Journal of Medicine paper, although the overall survival is not yet mature, it’s close to mature in the HRD-negative group because they’re doing so poorly.

Kathleen Moore, MD: That’s important information. I think it’s very much hypothesis generating, but when we think about what’s next, and maybe we’ll have time to get to the so-what of all this, this is a great day. It’s going to impact our patients, but we have not cured people. And 50% of our patients are HRD-negative. However, we want to interpret this, whether we want to use PARP or BEV [bevacizumab], we can all discuss that, but the HRD-negative group…

Bradley J. Monk, MD, FACS, FACOG: It’s all about incremental benefit. We had BEV [bevacizumab], and it was pretty good. We had BRCA; it was great. Now we have HRD, and it’s still pretty good, but there’s that half of the patients who are HRD-negative.

Kathleen Moore, MD: They need something better.

Bradley J. Monk, MD, FACS, FACOG: Maybe that’s the best opportunity for I/O [immuno-oncology], right?

Robert L. Coleman, MD, FACOG, FACS: I love it. It’s all maybe, so it’s exactly right. You’re doing exactly what I had hoped you’d do: raise a bunch of hypotheses.

Bradley J. Monk, MD, FACS, FACOG: Thank you, and you’re welcome, because unless you have a hypothesis, you can’t do an experiment.

Transcript Edited for Clarity