The Role of PARP Inhibitors in Ovarian Cancer - Episode 10
New PARP Inhibitor: The VELIA Regimen
Expert oncologists discuss the VELIA study and the new frontline PARP inhibitor treatment valiparib.
Maurie Markman, MD: As complicated as all of this is with actually 3 PARPs [poly ADP ribose polymerase inhibitors] that are now approved in the management of ovarian cancer, and we just talked about 2 PARPs specifically in the frontline setting, we add a new PARP that is examined in the frontline setting. We had it recently published in the New England Journal of Medicine, regarding veliparib. And so Wendel, take us through. What is this trial all about?
Wendel Naumann, MD: Veliparib was combined with chemotherapy. It was a design very similar to the GOG-218 with bevacizumab, they had 3 groups. The first group, the control group, was chemotherapy alone; the second group, chemotherapy with veliparib during the chemotherapy, with the idea that veliparib might make the chemotherapy more effective; and then the third group was the veliparib with chemotherapy followed by maintenance therapy. I think the HRD [homologous recombination deficiency] issue was looked at, but I think it’s important to understand that the HRD cutoff, the LOH [loss of heterozygosity] score was actually lower than it was in the PAOLA and PRIMA trials. So again, some subtleties of these trials that are very difficult to look at. The HRD-positive group in the VELIA trial may not have been as HRD-positive as it was in the PRIMA and PAOLA trial. That’s an important distinction.
I think the overall intent-to-treat population was positive, the BRCA patient population was positive, but when we separated out the BRCA wild type, HRD-positive in a subgroup analysis, that didn’t show a statistical benefit. There was a benefit, but it was not statistically significant. And I think a lot of people discounted that trial because of that, although I don’t know that that’s a fair comparison because it really wasn’t designed to do that. This was actually a pretty good prognosis group. About 70% of the patients in this trial actually had debulking down to no visible disease, and if you look at the absolute magnitude of benefit, it was actually the largest of the 3 trials over 6 months.
So again, how do we incorporate this in our decision making? I really don't know.
Michael Birrer, MD, PhD: We could spend the entire time talking about this particular trial and what it means. I think a couple points I would add is that Wendel brought up the HRD cutoff, which is interesting because of its impact on this trial. But it has also an impact on the other trial, which in PRIMA there are probably HRD-like patients in what’s called HR [homologous recombination] proficient because the cutoff was so high. It just gets complex. I think the relevant issue here is, and we all mumbled about this, is will the company file for this drug, and if so, will the FDA approve it and in what indication? The reason I say that is you’re coming to the dance a little bit late. There are a lot of companies already here with known drugs. That’s going to be a very expensive proposition, so it will be interesting to see how it plays out. I always think another drug is helpful for our patients.
Annette Hood, PharmD, BCACP: Another thing I wanted to point out is what’s different with this trial than with the other 2 trials is that the veliparib was given along with the chemotherapy, and the rate of myelosuppression was very high in this trial, so thrombocytopenias, anemias. And so it might lead to potential dose reductions of our curative chemotherapy. I think that’s something to keep in mind as well.
Wendel Naumann, MD: There was a reduction, although not statistically significant. There was a reduction, particularly in the platinum dose in the experimental arms, and I do have some concern about that. I think that’s a very valid point.
Michael Birrer, MD, PhD: And it’s a good point to bring up because if you try to use the other drugs with chemotherapy, we simply can’t. They’re really toxic. So we’ve all had a suspicion that this PARP works a little differently. Maybe, I hate to use the W word, weaker, but again there’s good news and bad news. The good news is you can combine it with chemotherapy, the bad news is it may be a little bit weaker, I don’t know.
Wendel Naumann, MD: Although we're not supposed to do cross-trial comparisons.
Maurie Markman, MD: We do it all the time.
Wendel Naumann, MD: We are cross-trial comparing. The important thing, when you look at the numbers in this trial, remember, these patients were randomized at the initial treatment, and the other trials were after chemotherapy. So it’s a very important distinction in terms of looking at the absolute benefit or the absolute PFS [progression-free survival] in these different trials.