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PARP Inhibitor Mechanisms of Resistance

Panelists: Bradley Monk, MD, FACOG, FACS, St. Joseph's Hospital and Medical Center; Michael J. Birrer, MD, PhD, O'Neal Comprehensive Cancer Center; Jubilee Brown, MD, Levine Cancer Institute; Thomas Herzog, MD, UC College of Medicine; Krishnansu S. Tewari, MD, University of California, Irvine
Published: Wednesday, Aug 21, 2019



Transcript:

Bradley Monk, MD, FACOG, FACS: All right, so let’s go ahead and talk about 1 last agent in recurrent ovarian cancer, and that’s mirvetuximab soravtansine. Tell us about the FORWARD I study and what it did or didn’t do.

Michael J. Birrer, MD, PhD: Yeah, so MIRV [mirvetuximab soravtansine]—we’ll abbreviate it because it’s a complicated name—is an antibody drug conjugate that targets a folate receptor alpha. It’s been in development now for multiple years. The phase I and phase II trial was completed and demonstrated what looked like about a 40% response rate—40%, 45% response rate in platinum-resistant patients. And that led on to FORWARD I, a randomized phase III trial of approximately 270 patients comparing MIRV as a single agent to dealer’s choice—topotecan, weekly Taxol, or pegylated liposomal doxorubicin.

I’m heavily involved in the study, so I’m somewhat biased. But a lot of us thought this would be strongly positive. It turned out for the primary endpoint it was a negative study. Reanalysis and extensive analysis of it would suggest that the high expressors actually do benefit.

Bradley Monk, MD, FACOG, FACS: Which makes sense for mechanism of action.

Michael J. Birrer, MD, PhD: Yeah, and I think if you look closely at the trial, some of it’s not public, so I can’t go into it, but there were reasons I think that perhaps the primary endpoint was not positive and some of it was related to targeting.

The drug is still alive, and there will probably be an additional phase III trial for single agent, but what was presented here by Dave O’Malley is combinations.

Bradley Monk, MD, FACOG, FACS: Yeah, that’s nice. Combinations with PEMBRO [pembrolizumab], combinations with BEV [bevacizumab], combinations with carboplatin—it all makes sense. I’m struck by this idea that every FDA approval—all 12 of them in 4½ years—has either been single-arm, accelerated approvals or randomized trials that compared 3 drugs with 2. Two drugs with 1, or 1 drug with placebo. And your trial was head-to-head.

Michael J. Birrer, MD, PhD: You’ve said this.

Bradley Monk, MD, FACOG, FACS: When you have a very active comparator, such as weekly paclitaxel, which Jubilee said is a very good agent in platinum—I’m not going to use the word platinum resistant— but where platinum is not an option. I think that’s also part of the challenge. Maybe the combination is the opportunity.

Michael J. Birrer, MD, PhD: Yeah. And they’ve showed a 40% response rate in about 27 patients in the combination. And in the BEV–naïve patients, the response rate was 55%. So it’s active.

Bradley Monk, MD, FACOG, FACS: Another concept I want to talk about is that with all this maintenance therapy, particularly PARP inhibitors, there’s a concern that the mechanism of resistance to a PARP inhibitor may translate into the mechanisms of resistance of future cycles of chemotherapy. So tell me, Jubilee, about how an exploratory analysis in ARIEL3 helped answer that question.

Jubilee Brown, MD: Well, yes, I think there are a couple of things. Actually, you know Dr Robert Coleman presented ARIEL3—an exploratory analysis, as you mentioned, that essentially showed no adverse effect, no new safety signals. But looking at all the secondary endpoints, it showed no worse outcomes for patients who were treated with rucaparib. And this is really important. We saw that with olaparib in SOLO-1, and now we see it again in ARIEL3. We know that maintenance treatment with PARP does not adversely affect future chemotherapy.

Bradley Monk, MD, FACOG, FACS: Yeah. If the next line of therapy works just as well in the placebo arm, then it must not have an impact. That’s an important message, because I don’t want to hear some excuse, “Well I don’t want to use a PARP inhibitor maintenance because I’m afraid it’s going to make her platinum resistant.” What it actually does is make her platinum resistant or platinum sensitive. But it makes them more eligible for platinum because generally, when you give a PARP inhibitor in maintenance—what you said Krish in the ARIEL3, SOLO-2, or NOVA sort of experience—they ultimately almost always have more than 6 months when they recur, and then you give them platinum again.

Thomas Herzog, MD: And if you look at the placebo arms in NOVA and ARIEL3 and SOLO-2, they were all around 5.4, 5.5, to your point.

Bradley Monk, MD, FACOG, FACS: Right.

Thomas Herzog, MD: Which would, in our old paradigm, make them ineligible for platinum. And that’s a big deal. You’re taking out 1 of the most active agents and taking it off the table for that patient.

Bradley Monk, MD, FACOG, FACS: Thank you for that, Tom. Michael, what are the mechanisms of resistance for PARP inhibitors?

Michael J. Birrer, MD, PhD: Well, it’s a timely question. We’re very enthusiastic about SOLO-1. We may have potentially cured some patients. The truth is that most of the patients who are on PARP or received PARP will eventually recur, and we’re going to have substantial numbers of ladies whose tumors are PARP resistant. We need to understand that. The simple answer is that it’s clearly complex.

Thomas Herzog, MD: That’s not simple.

Michael J. Birrer, MD, PhD: It’s as if you’re understanding a twist, OK? You know, I think the mechanisms of resistance we love to talk about are the reversion mutations, and that’d be well documented—and these are what we call secondary mutations that put the BRCA gene back in frame—and so it makes a functional protein. What we’re arguing about is how frequent that is. I think I’ve seen numbers anywhere from 5% to 30%.

Bradley Monk, MD, FACOG, FACS: But it’s not the predominant mechanism of resistance.

Michael J. Birrer, MD, PhD: No.

Krishnansu S. Tewari, MD: That’s small trials with 30%, so 6 patients.

Michael J. Birrer, MD, PhD: That’s right. There are other mechanisms. And we revisit our old friend p-glycoprotein. 

Bradley Monk, MD, FACOG, FACS: Drug transport.

Michael J. Birrer, MD, PhD: Right, drug transport is certainly in there. Upregulation of the PARP gene itself, activating mutations of the PARP gene have been described. Cyclin E is a bad prognostic feature in ovarian cancer itself.

Bradley Monk, MD, FACOG, FACS: I’ve heard 30% too.

Michael J. Birrer, MD, PhD: Yeah. So what that says to me is that what we will evolve to—and I think the field’s been doing this anyway, but this will accelerate it—is that when our ladies recur from having been treated with a PARP inhibitor, they’re going to probably demand clinically a biopsy. We can understand what the mechanism is. And maybe that’s a scope with a biopsy, maybe it’s just a skinny needle within some extensive sort of a list of assays, where we can then stratify patients and say, “You know, you’ve got a reversion mutation, we’re not going to give you PARP again. But maybe, if you’ve got stabilization of a replication fork, maybe you can get an ATR inhibitor. It’s going to get complicated.

Bradley Monk, MD, FACOG, FACS: There you go. Thank you very much. So these are exciting times: 3 indications for BEV, 6 indications for PARP, 9 FDA approvals of targeted therapies in ovarian cancer, and more to come. Stay tuned. We’ll have more for you after ASCO [the American Society of Clinical Oncology] Annual Meeting. Thank you, again, to my panelists.

Transcript Edited for Clarity

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Transcript:

Bradley Monk, MD, FACOG, FACS: All right, so let’s go ahead and talk about 1 last agent in recurrent ovarian cancer, and that’s mirvetuximab soravtansine. Tell us about the FORWARD I study and what it did or didn’t do.

Michael J. Birrer, MD, PhD: Yeah, so MIRV [mirvetuximab soravtansine]—we’ll abbreviate it because it’s a complicated name—is an antibody drug conjugate that targets a folate receptor alpha. It’s been in development now for multiple years. The phase I and phase II trial was completed and demonstrated what looked like about a 40% response rate—40%, 45% response rate in platinum-resistant patients. And that led on to FORWARD I, a randomized phase III trial of approximately 270 patients comparing MIRV as a single agent to dealer’s choice—topotecan, weekly Taxol, or pegylated liposomal doxorubicin.

I’m heavily involved in the study, so I’m somewhat biased. But a lot of us thought this would be strongly positive. It turned out for the primary endpoint it was a negative study. Reanalysis and extensive analysis of it would suggest that the high expressors actually do benefit.

Bradley Monk, MD, FACOG, FACS: Which makes sense for mechanism of action.

Michael J. Birrer, MD, PhD: Yeah, and I think if you look closely at the trial, some of it’s not public, so I can’t go into it, but there were reasons I think that perhaps the primary endpoint was not positive and some of it was related to targeting.

The drug is still alive, and there will probably be an additional phase III trial for single agent, but what was presented here by Dave O’Malley is combinations.

Bradley Monk, MD, FACOG, FACS: Yeah, that’s nice. Combinations with PEMBRO [pembrolizumab], combinations with BEV [bevacizumab], combinations with carboplatin—it all makes sense. I’m struck by this idea that every FDA approval—all 12 of them in 4½ years—has either been single-arm, accelerated approvals or randomized trials that compared 3 drugs with 2. Two drugs with 1, or 1 drug with placebo. And your trial was head-to-head.

Michael J. Birrer, MD, PhD: You’ve said this.

Bradley Monk, MD, FACOG, FACS: When you have a very active comparator, such as weekly paclitaxel, which Jubilee said is a very good agent in platinum—I’m not going to use the word platinum resistant— but where platinum is not an option. I think that’s also part of the challenge. Maybe the combination is the opportunity.

Michael J. Birrer, MD, PhD: Yeah. And they’ve showed a 40% response rate in about 27 patients in the combination. And in the BEV–naïve patients, the response rate was 55%. So it’s active.

Bradley Monk, MD, FACOG, FACS: Another concept I want to talk about is that with all this maintenance therapy, particularly PARP inhibitors, there’s a concern that the mechanism of resistance to a PARP inhibitor may translate into the mechanisms of resistance of future cycles of chemotherapy. So tell me, Jubilee, about how an exploratory analysis in ARIEL3 helped answer that question.

Jubilee Brown, MD: Well, yes, I think there are a couple of things. Actually, you know Dr Robert Coleman presented ARIEL3—an exploratory analysis, as you mentioned, that essentially showed no adverse effect, no new safety signals. But looking at all the secondary endpoints, it showed no worse outcomes for patients who were treated with rucaparib. And this is really important. We saw that with olaparib in SOLO-1, and now we see it again in ARIEL3. We know that maintenance treatment with PARP does not adversely affect future chemotherapy.

Bradley Monk, MD, FACOG, FACS: Yeah. If the next line of therapy works just as well in the placebo arm, then it must not have an impact. That’s an important message, because I don’t want to hear some excuse, “Well I don’t want to use a PARP inhibitor maintenance because I’m afraid it’s going to make her platinum resistant.” What it actually does is make her platinum resistant or platinum sensitive. But it makes them more eligible for platinum because generally, when you give a PARP inhibitor in maintenance—what you said Krish in the ARIEL3, SOLO-2, or NOVA sort of experience—they ultimately almost always have more than 6 months when they recur, and then you give them platinum again.

Thomas Herzog, MD: And if you look at the placebo arms in NOVA and ARIEL3 and SOLO-2, they were all around 5.4, 5.5, to your point.

Bradley Monk, MD, FACOG, FACS: Right.

Thomas Herzog, MD: Which would, in our old paradigm, make them ineligible for platinum. And that’s a big deal. You’re taking out 1 of the most active agents and taking it off the table for that patient.

Bradley Monk, MD, FACOG, FACS: Thank you for that, Tom. Michael, what are the mechanisms of resistance for PARP inhibitors?

Michael J. Birrer, MD, PhD: Well, it’s a timely question. We’re very enthusiastic about SOLO-1. We may have potentially cured some patients. The truth is that most of the patients who are on PARP or received PARP will eventually recur, and we’re going to have substantial numbers of ladies whose tumors are PARP resistant. We need to understand that. The simple answer is that it’s clearly complex.

Thomas Herzog, MD: That’s not simple.

Michael J. Birrer, MD, PhD: It’s as if you’re understanding a twist, OK? You know, I think the mechanisms of resistance we love to talk about are the reversion mutations, and that’d be well documented—and these are what we call secondary mutations that put the BRCA gene back in frame—and so it makes a functional protein. What we’re arguing about is how frequent that is. I think I’ve seen numbers anywhere from 5% to 30%.

Bradley Monk, MD, FACOG, FACS: But it’s not the predominant mechanism of resistance.

Michael J. Birrer, MD, PhD: No.

Krishnansu S. Tewari, MD: That’s small trials with 30%, so 6 patients.

Michael J. Birrer, MD, PhD: That’s right. There are other mechanisms. And we revisit our old friend p-glycoprotein. 

Bradley Monk, MD, FACOG, FACS: Drug transport.

Michael J. Birrer, MD, PhD: Right, drug transport is certainly in there. Upregulation of the PARP gene itself, activating mutations of the PARP gene have been described. Cyclin E is a bad prognostic feature in ovarian cancer itself.

Bradley Monk, MD, FACOG, FACS: I’ve heard 30% too.

Michael J. Birrer, MD, PhD: Yeah. So what that says to me is that what we will evolve to—and I think the field’s been doing this anyway, but this will accelerate it—is that when our ladies recur from having been treated with a PARP inhibitor, they’re going to probably demand clinically a biopsy. We can understand what the mechanism is. And maybe that’s a scope with a biopsy, maybe it’s just a skinny needle within some extensive sort of a list of assays, where we can then stratify patients and say, “You know, you’ve got a reversion mutation, we’re not going to give you PARP again. But maybe, if you’ve got stabilization of a replication fork, maybe you can get an ATR inhibitor. It’s going to get complicated.

Bradley Monk, MD, FACOG, FACS: There you go. Thank you very much. So these are exciting times: 3 indications for BEV, 6 indications for PARP, 9 FDA approvals of targeted therapies in ovarian cancer, and more to come. Stay tuned. We’ll have more for you after ASCO [the American Society of Clinical Oncology] Annual Meeting. Thank you, again, to my panelists.

Transcript Edited for Clarity
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