PARP Inhibition in Ovarian Cancer: BRCA-Mutated and Beyond - Episode 4
Bradley J. Monk, MD, FACOG, FACS:Let’s pivot to the second PARP inhibitor trial that was also published in the same issue of theNew England Journal of Medicine. Incidentally, Dr Antonio Gonzalez-Martin is the first author of this other study, called VELIA 3005. These are both GOG [Gynecologic Oncology Group] trials.
Thomas J. Herzog, MD:GOG-3005.
Bradley J. Monk, MD, FACOG, FACS:We enroll our patients on GOG trials. Now, that’s not NRG Oncology. This is GOG, which partners with pharma, so thank you for that. So tell us about VELIA.
Thomas J. Herzog, MD:Well, it was an interesting trial because it looked at using veliparib in over 1100 patients in 3 different arms. So it had a design very similar to GOG-0218.
Bradley J. Monk, MD, FACOG, FACS:The bevacizumab study.
Thomas J. Herzog, MD:Correct, which obviously has implications too, and we’ll talk about that in terms of how we’re using that in frontline therapy. But back to GOG-3005, or VELIA. There were over 1100 patients enrolled, and it was 1-to-1 randomization. The control arm had placebo with chemotherapy followed by placebo and then the 36 cycles, which worked out to about 2 years of maintenance there.
The second arm was veliparib, a fourth PARP inhibitor in this space now, with chemotherapyso concomitant chemotherapy—followed by placebo maintenance. The third arm, of course, is veliparib throughout. We call that veliparib throughout being that it was given with chemotherapy at a lower dosage, 150 mg bid [twice a day], and then there was a run-in phase for maintenance that was done at a lower dose, 300 mg, then they kicked it up to full dose, 400 mg. That went on again for approximately 24 months: 36 cycles, 3 arms.
Bradley J. Monk, MD, FACOG, FACS:We needed to do that because we needed to see if chemotherapy and PARP together was a good idea. And so that’s why this is a 3-arm, right?
Thomas J. Herzog, MD:Yes.
Bradley J. Monk, MD, FACOG, FACS:Is it a good idea?
Thomas J. Herzog, MD:Well, it depends on how you look at it. Again, they very much met their end point. The primary end point on this wasBRCA, and it was a hierarchical design and it was step down.
Bradley J. Monk, MD, FACOG, FACS:BRCAis easy.
Thomas J. Herzog, MD:They hit that, 0.44again, impressive—and they had some differences again. What’s interesting is a lot of these studies allowed primary debulking, of course, but also neoadjuvant therapy in all of them. Which is interesting, right? Because of the dirty little secrets out now that people are using more and more neoadjuvant therapy. You can’t design a trial now with just the primary. It would take too long to enroll.
But the other trials required that you had a PR [partial response] or CR [complete response] to get randomized. Think about the randomization time here, because people like to look at medians and so forth. But the time 0 is different, right? The enrollment, the randomization, occurs up front as you start chemotherapy, because we have to know whether you’re getting veliparib with the chemotherapy or not in 2 of the 3 arms. That was an important component. Your time 0 is actually in front of the chemotherapy, so you have to add on approximately 4.5 months, or add on to the other trials or try to figure it out. But importantly, there are preclinical data that show synergy with PARP inhibition and DNA-damaging drugs, such as platinum.
Bradley J. Monk, MD, FACOG, FACS:That’s why we had to test it. So is it a good idea?
Thomas J. Herzog, MD:That’s why it had to be tested. Again, it hit the primary end point, the intent-to-treat. If you look at the overall patient population, all comers, it was a group of patients who were a little more demanding in that they had patients who also had stable disease, and even a few of those with progressive disease who were eligible for this. There’s all this argument of which patient population is the worst. Nonetheless, it was not the easiest population, and they still hit their end point with a hazard ratio of 0.68.
Bradley J. Monk, MD, FACOG, FACS:Was it a good idea, for the third time?
Thomas J. Herzog, MD:Well, they were able to do so without significantly impairing the relative dose intensity. So they were able to look at that. From a combination standpoint, it was tolerable. We look at the safety data. We look at the relative dose intensity: there was a small decrease but not a significant decrease. And there was a small number of patients who benefited because those SDs [standard deviations] became PRs [progesterone receptors], which would have made them eligible for any other PARP trial. So there’s that in question. But if you look at the curves, part of the curves, there’s not a significant separation.
Bradley J. Monk, MD, FACOG, FACS:But there is an increase; it wasn’t emphasized. There is about a 10% improvement in response rate. Let’s say you’re a bevacizumab person. You don’t need to worry about the debulking and all this. I had someone come up to me, whether or not they are someone you would recognize, I’m not going to use their name.
Thomas J. Herzog, MD:What were the initials?
Bradley J. Monk, MD, FACOG, FACS:And he said, “I like VELIA because I’m not going to have HRD [homologous recombination deficiency] back when I start chemotherapy.” He says, “Look, I get it, maybe, but not really.” I like VELIA because I can start the PARP inhibitor, and if it works, keep it going. If it doesn’t work, then pivot to second-line bevacizumab. Is there an attraction with that message? I think there might be a little bit. And it’s tolerable and it increases a response rate, and even the stable disease you transition seamlessly into the maintenance.
Thomas J. Herzog, MD:No, I think it’s a positive trial, as I said. I think it’s great.
Bradley J. Monk, MD, FACOG, FACS:It got in theNew England Journal of Medicine. I think that’s pretty good.
Thomas J. Herzog, MD:Very impressive, yes. Very impressive data. By the way, Robert Coleman was the PI [primary investigator] on the trial.
Bradley J. Monk, MD, FACOG, FACS:Part of the GOG, that’s right.
Transcript edited for clarity.