Leveraging HRD Testing Results in Ovarian Cancer: Clinical Data
Discussion centered around data from the PAOLA-1 trial, highlighting the prevalence of BRCA1/2 mutations and HRD status in ovarian cancer, and how patients with these alterations may benefit from PARP inhibitor treatment.
EP: 1.Opening Remarks from Dr. Herzog, Dr. Krivak, and Dr. Hagemann
EP: 2.Defining HRD and its Role in Ovarian Cancer
EP: 3.Other Causes of HRD: Chromosomal LOH, LST, and TAI
EP: 4.Commercially Available HRD Tests for Ovarian Cancer
EP: 5.Leveraging HRD Testing Results in Ovarian Cancer: Clinical Data
EP: 6.HRD Testing in Ovarian Cancer: Clinical Guidelines Recommendations
Dr. Thomas Herzog: So we're going to talk a little bit about leveraging HRD testing results in ovarian cancer. Tom, can you take us through this a little bit?
Dr. Thomas Krivak: Absolutely. Thanks for asking. Again, looking at HRD and ovarian cancer, to me, we wanted to look at that. Ian did a great job of saying we have BRCA, let's look for a test that may give us that BRCA phenotype and looked at how these companies have gone through and developed these tests. And what does that mean? And how can that actually increase the number of patients who may be exposed to medication? And so what you can see here is this is looking at PAOLA and looking up to, again, 50% of patients with advanced stage ovarian cancer and can be positive for an HRD test without a BRCA mutation. So, we had SOLO come out and it showed excellent responses for patients in an upfront setting. Prolonged PFS, now we have OS data that was very good. And then, how can we expose, how can we identify patients who may best tolerate additional maintenance therapy and have good outcomes? And so looking at HRD positive patients, and again, PAOLA looked at that and saw that upwards of 50% can be HRD positive and increasing the number of patients who may get exposed to maintenance medication from roughly 20% up to 45 to 48%. Not novel by any means, because we knew in NOVA, we saw the HRD, we saw when they did study 19 how they looked at different, going back looking at germline, looking at somatic mutations. ATHENA as well as other trials have showed this. But the bottom line is that you look at- When you look at BRCA mutations and you look at patients who have tumor tested for HRD, it does increase the number of patients who may get exposed to this medication. So you can see here, PAOLA was Olaparib/bevacizumab versus bevacizumab/placebo. And you can see the number of patients who fell out who are HRV positive or BRCA positive with these- With this type of test. And in PAOLA I think it was myriad for these folks. And what does that mean clinically? Go ahead.
Dr. Thomas Herzog: I was just going to say just for our audience SOLO-1 was done in those patients who had BRCA mutations almost exclusively but not completely germline and a few somatic scattered in, And then PAOLA-1 and PRIMA came out looking at a wider group, inclusive but the labels were somewhat different there in terms of how that got labeled when those were presented in 2019.
Dr. Thomas Krivak: And, to me, if we could go on to the next slide which really is trying to say - Ian said it really nicely, what's the outcome? What are we seeing here with these tests? And when you look at BRCA mutation, positive, negative, positive, negative, and then HRD, mutation, negative, negative, positive, positive, really what you're seeing when you look at Olaparib versus bevacizumab versus bevacizumab alone, what you're seeing in those patients if they are HRD positive, and you can see whether they were BRCA mutation status negative or positive. And again, to me, that BRCA negative HRD positive is going to be that score that's an LOH score above 16%, or an HRD genomic instability score above 42, Caris, how they define it. But when you look at that, then you look at the patients who had a BRCA mutation and they were classified as HRD mutation status negative but when you look at positive mutation status and then positive, positive in the HRD group and you look at Olaparib versus bevacizumab, you're seeing that clinical relevance that Ian was talking about. BRCA mutations, hazard ratio by adding Olaparib to bevacizumab of.31. And then you look at the HRD positive, basically BRCA mutated patients again,.33. And then looking at this group that are HRD negative or HRD positive of BRCA wild type, you're still seeing a significant hazard ratio of.43. So in those positive groups you're seeing a really strong reduction of risk of recurrence for those patients. And again, just like we were talking about earlier, PRIMA was similar looking at HRD. So to me, this looks like it's a predictive marker as well as a prognostic marker for these patients. So I think what PAOLA-1 did really was, nicely, was had an enriched population for high grade CRS, high grade endometrioid, showed that you can increase the number of patients who may be exposed to maintenance therapy and then showed in that HRD test positive patients as well as BRCA patients, you really had a decrease in the chance of recurrence. And again, with PAOLA we did see an overall survival benefit. So it's really nice this year to see overall survival benefit in SOLO as well as an overall survival benefit in PAOLA. Again, we need to wait for statistical significance but the trend is there in our HRD positive patients.
