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Combination Veliparib and Chemotherapy in Ovarian Cancer

Panelists: Michael J. Birrer, MD, PhD, The University of Alabama at Birmingham; Robert L. Coleman, MD, FACOG, FACS, The University of Texas MD Anderson Cancer Center; Bradley J. Monk, MD, FACS, FACOG, The University of Arizona College of Medicine; Kathleen Moore, MD, The University of Oklahoma Health and Sciences Center; Shannon N. Westin, MD, MPH, The University of Texas MD Anderson Cancer Center
Published: Wednesday, Nov 06, 2019



Transcript:

Bradley J. Monk, MD, FACS, FACOG: Let’s go ahead and pivot now to the second study, which is called VELIA. The beauty of this study is that it introduced a fourth PARP inhibitor into the discussion. We had had olaparib, rucaparib, and niraparib. Shannon, go ahead and tell us about VELIA, which was also published in The New England Journal of Medicine at the same time it was presented by this gentleman from The University of Texas MD Anderson Cancer Center in Houston, Texas, Robert.

Shannon N. Westin, MD, MPH: Robert Coleman, yes.

Bradley J. Monk, MD, FACS, FACOG: We’ll let him give the results. You tell us about the study.

Shannon N. Westin, MD, MPH: Yes, we want to be done in a reasonable amount of time, so I’ll give the design.

Robert L. Coleman, MD, FACOG, FACS: In the beginning.

Shannon N. Westin, MD, MPH: VELIA is a little different from PRIMA because we are making a decision right when we start chemotherapy regarding what we’re going to do. This study incorporates veliparib, which is not a new PARP but is a PARP that does not have an indication yet in ovarian cancer. VELIA is combining it with standard chemotherapy. There were 3 arms to this trial. It was randomized 1-to-1-to-1. There were patients with stage III or IV ovarian cancer, all of them high-grade serous. They collected things like BRCA but, those were not required. They could be any mutation status, and they were randomized to standard paclitaxel and carboplatin; paclitaxel and carboplatin plus veliparib in the treatment phase but then no maintenance; or paclitaxel, carboplatin, and veliparib in the treatment phase followed by a veliparib maintenance.

The dosing of veliparib had to be adjusted. When we were giving veliparib with chemotherapy, it was at 150 mg bid [twice daily]. Once we transitioned to maintenance therapy, we could go up to the maximum tolerated dose of 400 mg bid.

The way this was statistically designed, a progression-free survival endpoint was the primary endpoint, but it was a hierarchical analysis starting with the BRCA-mutant group, then moving to the HRD [homologous recombination deficiency]–positive group, and then moving to the intention-to-treat group. Each of those had to be positive to move on to the next analysis. There were a number of stratification factors, including stage, region, and those types of things. I’m excited to hear about what the results were.

Robert L. Coleman, MD, FACOG, FACS: You don’t know.

Michael J. Birrer, MD, PhD: Rob, can you start with the exploratory endpoints?

Shannon N. Westin, MD, MPH: Yes, we’re going to start with exploratory now.

Robert L. Coleman, MD, FACOG, FACS: It’s great. Just as we heard in the last discussion, we have this HRD group, which is incorporating 2 cohorts, and then the all-comers population. It’s analogous to that design, and you’re right. We started with an all-comers population.

The first 200 patients or so who fit into the BRCA germline—or tissue, because both of those were required. We made that a stratification factor midtrial because of what looked to be an imbalance in 1 of the arms for the BRCA-mutation status, so we pivoted there and made that so we had a balance across the arms.

In those 200 patients we had a PFS [progression-free survival] of around 34 months on the median, compared with around 21 months. That was a hazard ratio of 0.44, so it was quite significant. The next step down was to look at the total HRD-patient population with a hazard ratio of 0.57. Again, there was about a 12-month improvement in the medians between the groups. Then in the all-comers population, we had a hazard ratio of 0.68, which is obviously statistically significant.

The hypothesis testing went through that segment. The next step will be to do the overall survival [OS]. We preserved all the alpha in the analysis to go into the OS, which we’re waiting for endpoints for, as well.

As Shannon mentioned, the importance here is that this is a decision that’s occurring when you’re going to initiate chemotherapy. It’s a very early time point, so you can use that data to help inform how you’re going to write your prescription on day 1. This trial also allowed neoadjuvant chemotherapy. It allowed for dose-dense versus Q3 [every-3]-week paclitaxel, importantly, because toxicity has always been a concern with combining PARP and chemotherapy. The dose intensity that we were able to maintain throughout the entire chemotherapy phase was essentially standard-of-care dosing.

Bradley J. Monk, MD, FACS, FACOG: Go ahead.

Shannon N. Westin, MD, MPH: I was just going to comment. I think what’s really interesting about this study is that compared with the PRIMA study, a larger proportion of these patients were stage III. It was about 70% or so, and a large proportion of them had surgery to no gross residual disease. It was a good population.

Robert L. Coleman, MD, FACOG, FACS: It was also representative of what we see.

Shannon N. Westin, MD, MPH: Absolutely. It was a little different from what we see with PRIMA, where they favored a lot.

Bradley J. Monk, MD, FACS, FACOG: I wanted to congratulate you, Rob, for the publication and for the practice-changing result. We needed to check off the box. Do we need to give a PARP inhibitor with a DNA-damaging agent, chemotherapy?

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

Bradley J. Monk, MD, FACS, FACOG: We always wondered that. You were right that you would have to do a dose reduction, because there’s some overlapping toxicity. I think we answered that question, and the answer is no.

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

Bradley J. Monk, MD, FACS, FACOG: The opportunity is mostly in maintenance, right?

Robert L. Coleman, MD, FACOG, FACS: Right. We’ve learned since we designed the trial that this idea of treatment and maintenance is probably superimportant. We had hoped that maybe we could increase the efficacy during the chemotherapy phase. I think using progression-free survival is probably not a sensitive enough variable to determine whether we are actually adding anything to it.

Bradley J. Monk, MD, FACS, FACOG: There was an improvement in the response rate.

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

Transcript Edited for Clarity

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Transcript:

Bradley J. Monk, MD, FACS, FACOG: Let’s go ahead and pivot now to the second study, which is called VELIA. The beauty of this study is that it introduced a fourth PARP inhibitor into the discussion. We had had olaparib, rucaparib, and niraparib. Shannon, go ahead and tell us about VELIA, which was also published in The New England Journal of Medicine at the same time it was presented by this gentleman from The University of Texas MD Anderson Cancer Center in Houston, Texas, Robert.

Shannon N. Westin, MD, MPH: Robert Coleman, yes.

Bradley J. Monk, MD, FACS, FACOG: We’ll let him give the results. You tell us about the study.

Shannon N. Westin, MD, MPH: Yes, we want to be done in a reasonable amount of time, so I’ll give the design.

Robert L. Coleman, MD, FACOG, FACS: In the beginning.

Shannon N. Westin, MD, MPH: VELIA is a little different from PRIMA because we are making a decision right when we start chemotherapy regarding what we’re going to do. This study incorporates veliparib, which is not a new PARP but is a PARP that does not have an indication yet in ovarian cancer. VELIA is combining it with standard chemotherapy. There were 3 arms to this trial. It was randomized 1-to-1-to-1. There were patients with stage III or IV ovarian cancer, all of them high-grade serous. They collected things like BRCA but, those were not required. They could be any mutation status, and they were randomized to standard paclitaxel and carboplatin; paclitaxel and carboplatin plus veliparib in the treatment phase but then no maintenance; or paclitaxel, carboplatin, and veliparib in the treatment phase followed by a veliparib maintenance.

The dosing of veliparib had to be adjusted. When we were giving veliparib with chemotherapy, it was at 150 mg bid [twice daily]. Once we transitioned to maintenance therapy, we could go up to the maximum tolerated dose of 400 mg bid.

The way this was statistically designed, a progression-free survival endpoint was the primary endpoint, but it was a hierarchical analysis starting with the BRCA-mutant group, then moving to the HRD [homologous recombination deficiency]–positive group, and then moving to the intention-to-treat group. Each of those had to be positive to move on to the next analysis. There were a number of stratification factors, including stage, region, and those types of things. I’m excited to hear about what the results were.

Robert L. Coleman, MD, FACOG, FACS: You don’t know.

Michael J. Birrer, MD, PhD: Rob, can you start with the exploratory endpoints?

Shannon N. Westin, MD, MPH: Yes, we’re going to start with exploratory now.

Robert L. Coleman, MD, FACOG, FACS: It’s great. Just as we heard in the last discussion, we have this HRD group, which is incorporating 2 cohorts, and then the all-comers population. It’s analogous to that design, and you’re right. We started with an all-comers population.

The first 200 patients or so who fit into the BRCA germline—or tissue, because both of those were required. We made that a stratification factor midtrial because of what looked to be an imbalance in 1 of the arms for the BRCA-mutation status, so we pivoted there and made that so we had a balance across the arms.

In those 200 patients we had a PFS [progression-free survival] of around 34 months on the median, compared with around 21 months. That was a hazard ratio of 0.44, so it was quite significant. The next step down was to look at the total HRD-patient population with a hazard ratio of 0.57. Again, there was about a 12-month improvement in the medians between the groups. Then in the all-comers population, we had a hazard ratio of 0.68, which is obviously statistically significant.

The hypothesis testing went through that segment. The next step will be to do the overall survival [OS]. We preserved all the alpha in the analysis to go into the OS, which we’re waiting for endpoints for, as well.

As Shannon mentioned, the importance here is that this is a decision that’s occurring when you’re going to initiate chemotherapy. It’s a very early time point, so you can use that data to help inform how you’re going to write your prescription on day 1. This trial also allowed neoadjuvant chemotherapy. It allowed for dose-dense versus Q3 [every-3]-week paclitaxel, importantly, because toxicity has always been a concern with combining PARP and chemotherapy. The dose intensity that we were able to maintain throughout the entire chemotherapy phase was essentially standard-of-care dosing.

Bradley J. Monk, MD, FACS, FACOG: Go ahead.

Shannon N. Westin, MD, MPH: I was just going to comment. I think what’s really interesting about this study is that compared with the PRIMA study, a larger proportion of these patients were stage III. It was about 70% or so, and a large proportion of them had surgery to no gross residual disease. It was a good population.

Robert L. Coleman, MD, FACOG, FACS: It was also representative of what we see.

Shannon N. Westin, MD, MPH: Absolutely. It was a little different from what we see with PRIMA, where they favored a lot.

Bradley J. Monk, MD, FACS, FACOG: I wanted to congratulate you, Rob, for the publication and for the practice-changing result. We needed to check off the box. Do we need to give a PARP inhibitor with a DNA-damaging agent, chemotherapy?

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

Bradley J. Monk, MD, FACS, FACOG: We always wondered that. You were right that you would have to do a dose reduction, because there’s some overlapping toxicity. I think we answered that question, and the answer is no.

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

Bradley J. Monk, MD, FACS, FACOG: The opportunity is mostly in maintenance, right?

Robert L. Coleman, MD, FACOG, FACS: Right. We’ve learned since we designed the trial that this idea of treatment and maintenance is probably superimportant. We had hoped that maybe we could increase the efficacy during the chemotherapy phase. I think using progression-free survival is probably not a sensitive enough variable to determine whether we are actually adding anything to it.

Bradley J. Monk, MD, FACS, FACOG: There was an improvement in the response rate.

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

Transcript Edited for Clarity
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