Treating Ovarian Cancer Based on HRD Status

Bradley J. Monk, MD: Tom Krivak, I’m going to call you out on a contradiction. You said, “I’m a biomarker guy. But if the biomarker is negative, I’m going to use niraparib anyway.” I don’t get it.

Thomas C. Krivak, MD: It’s predictive and prognostic. It’s not perfect. BRCA is a great biomarker for risk-reducing surgery, but do all BRCA patients respond to platinum-based chemotherapy? Is that 100%? I don’t think so.

Bradley J. Monk, MD: No, but we use it.

Thomas C. Krivak, MD: It’s a biomarker, there’s no doubt about it. I did read the abstract by Dr Elizabeth Swisher, and here is how I looked at it: you have veliparib, which is not an approved PARP for ovarian cancer, and you have 2 groups that crossed unity. You’re comparing some things. I’d love to see the slides of the presentation. I’m biased. I believe in biomarkers to help me stratify and develop my plan for sequencing, because I don’t think we know how to sequence. That’s what we’re talking about. How do we sequence chemotherapy? Doing this for 25 years as a fellow, it seems like the best way to sequence chemotherapy is when you get in a large group and they tell you that you have to do this. You go through your algorithms. But to me, I’m looking at HRD [homologous recombination deficiency] as a biomarker to help stratify, to help me develop a sequence.

Bradley J. Monk, MD: Tom Herzog, what do you think?

Thomas J. Herzog, MD: You’re seeing the difficulty that the experts have right now, because we don’t have labels yet. We have a lot of new data. We have very different interpretations of these subgroups. As I sit in these different panels, I see that. I believe any information is going to be helpful. I saw the subgroup analysis where there’s benefit; therefore, I do want to use that. For me, the more information, the better, and I think these tests will evolve. They’re not perfect, but they’ll continue to get better. There are a number of tests in the works, and we’ll see if we can do better in terms of being not only prognostic but also predictive as we move forward. I like these subgroup analyses. It’s information we’re otherwise not going to get. On the other hand, I do believe we have to be careful in terms of regulatory status, because if the intent-to-treat population and the primary population are positive, it gets a little dangerous to deny subgroups benefit and label. I have concerns about how these subgroups are being used, not only clinically but also from a regulatory standpoint. The quick answer from me, Brad, is yes. I’m going to continue to use HRD. I’m hoping for a better test. It’s great to have options, but this is an evolving dynamic.

Bradley J. Monk, MD: What’s most provocative is in PAOLA, if you don’t have an HRD signature, the hazard ratio is 1.00. Those 2 therapies together have toxicity, financial and otherwise. I think you’re on thin ice—I would never criticize you, but you’re on thin ice—if you say, “I’ve got a biomarker that says the hazard ratio is 1.00, and I’m going to do both drugs together anyway.” If the label prevents you from using both drugs because of that reason, then it’s going to be simple. I like flexibility too, but I’m really not sure that’s the thing to do.

Sharyn, you and I talk all the time. You like the assay, and so do I. What’s the best treatment for a patient who doesn’t have HRD and doesn’t have somatic BRCA? What’s the best maintenance treatment for that patient? Tom Krivak says I’ve got to use maintenance no matter what.

Sharyn N. Lewin, MD: That’s a great question. When you really look at these papers and think about it, if a patient has HRP [homologous recombination proficiency], that will be someone who I observe or who I consider giving bevacizumab to. But for me right now, with the data we have, I would really not push a PARP in that particular patient.

Bradley J. Monk, MD: What do you think, Tom Krivak?

Thomas C. Krivak, MD: That’s completely reasonable. That’s how I look at it because I do agree, with HRP I give 2 drugs together versus sequencing, and you may get more long-term longevity with having sequencing. I would like to comment on the development of the HRD test because I did read the abstract. How they developed it at Myriad Genetics, Inc was to capture your BRCA patients. In the abstract at SGO [Society of Gynecologic Oncology], if you use 33 as a cutoff, you captured 96% of the BRCA patients. When you use 42 as a cutoff, you captured 92%. The data I looked at when they developed the 42 cutoff were capturing about 95% of BRCA patients. They took their BRCA patients and wanted to make sure that HRD was capturing patients who look like that. When you look at the Foundation Medicine, Inc test, the test was looked at and cutoffs were made based on response. You had the Myriad test that was developed looking at BRCA and then plugged into studies looking at responses, whereas Foundation was developed and a cutoff was based on responses, not necessarily looking at the percentage of patients they missed who had a BRCA mutation. The tests were developed a little differently. That’s my understanding of how they did it and how Myriad has made some of its cutoffs to try to capture those BRCA patients.

Bradley J. Monk, MD: Yes, that’s very insightful.

Transcript edited for clarity.