Sequencing Therapies in Ovarian Cancer

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Sequencing Therapies in Ovarian Cancer

Panelists: Bradley J. Monk, MD, FACS, FACOG, University of Arizona, Creighton University, & Arizona Oncology Practice of US Oncology; Ursula Matulonis, MD, Dana-Farber Cancer Institute; David OMalley, MD, The Ohio State University; Matthew Powell, MD, Washington University; Shannon N. Westin, MD, MPH, MD Anderson Cancer Center
Published: Thursday, Apr 26, 2018



Transcript: 

Bradley J. Monk, MD, FACS, FACOG: Let’s talk about sequencing. The decision that this patient is a good candidate for PARP inhibition really means sequencing. I’m going to create some clinical scenarios and bounce them off you. The first clinical scenario is probably the most common clinical scenario. A patient develops a platinum-sensitive relapse. This patient is bevacizumab-naive and is BRCA-negative. That’s the most common because most patients don’t get bevacizumab, upfront. And, most patients don’t have a BRCA mutation. In that group, which is the most common scenario, in the platinum-sensitive space, does that patient need chemotherapy/bevacizumab, or chemotherapy/PARP?

Matthew Powell, MD: The answer is, yes. Again, this is where we hope molecular testing is going to help.

Bradley J. Monk, MD, FACS, FACOG: What test would you use?

Matthew Powell, MD: If I was trying to decide on this, I’d use HRD, potentially. But, I don’t personally order HRD very much. I use their platinum sensitivity as a guide. I may use some of the features of bevacizumab to help guide this, too, especially if it’s somebody who I’m going to give Taxol to. If they’re going to get paclitaxel, again, carboplatin/paclitaxel/bevacizumab would be my go-to regimen.

Bradley J. Monk, MD, FACS, FACOG: Because of the overall survival benefit in GOG-213?

Matthew Powell, MD: That would probably win out in somebody who was really a wild-type person, as you suspected.

Bradley J. Monk, MD, FACS, FACOG: Chemotherapy/bevacizumab. Go ahead.

Ursula Matulonis, MD: I completely concur. I use carboplatin/Taxol/bevacizumab in very certain clinical situations. “Yes, we’re going to use carboplatin/paclitaxel, and I know that patient is going to be able to tolerate the addition of bevacizumab.” I would also bring up considerations in certain circumstances. Maybe the patient has existing hypertension, or she’s got underlying renal dysfunction? Maybe her counts are not so great. You may consider incorporating that platinum doublet—sort of the old-fashioned carboplatin/pegylated liposomal doxorubicin, or carboplatin/gemcitabine without thinking about a PARP inhibitor, and without thinking about bevacizumab. I think it’s important that this decision be very personalized.

Bradley J. Monk, MD, FACS, FACOG: But what bias do you bring to the table? What side of the fence do you sit on?

Ursula Matulonis, MD: If I’m going to use paclitaxel with carboplatin, I would consider bevacizumab because of the overall survival. If I’m going to use carboplatin/gemcitabine, I’m probably not going to use bevacizumab.

Shannon N. Westin MD, MPH: My bias is towards personalized medicine. If I have a patient who’s completely wild-type, I’m going to treat that patient with bevacizumab. I want that patient to live longer and I want to get that overall survival benefit. I know that if I treat them with a bevacizumab-containing combination, they're more likely to get to maintenance. So, we see a higher response rate.

Bradley J. Monk, MD, FACS, FACOG: The response rate goes from about 50% to about 75%.

Shannon N. Westin MD, MPH: Almost 80%.

Bradley J. Monk, MD, FACS, FACOG: It’s 77%. OK.

Shannon N. Westin MD, MPH: Right. For the patients who get bevacizumab, I can get them to maintenance. If I don’t give them that combination, I can’t.

Ursula Matulonis, MD: If you’re following someone and they go from like 10 to 20, and you do a CT scan and it shows some peritoneal nodularity, and she feels fine, I find it hard to expose her to a lot of medications.

Bradley J. Monk, MD, FACS, FACOG: That’s also true. But, I’m trying to simplify things.

David O’Malley, MD: I will simplify it for you, Dr. Monk. Even though observation or continuous cytotoxic therapy is a reasonable option, you’re going to make me choose. Eighteen months, you said, of treatment-free interval, platinum-free interval, correct?

Bradley J. Monk, MD, FACS, FACOG: In that range.

David O’Malley, MD: In that instance, the time they’re going to have to be on bevacizumab maintenance may approach 18 months. That’s a lot of cumulative exposure. I worry about the cumulative toxicities of bevacizumab in this scenario. It’s a very reasonable option, but I do think we’re now in the age of biomarker…

Bradley J. Monk, MD, FACS, FACOG: What biomarker?

David O’Malley, MD: I’m going to do a germline and somatic test. You had it—it’s wild-type. If the somatic was also negative—and 40% of these will have something—my only opportunity to give that patient a PARP, right now, is in the platinum-sensitive maintenance setting.

Bradley J. Monk, MD, FACS, FACOG: It is 2 to 3. That’s what I think. I think in the germline normal and somatic normal, bevacizumab-naïve patient, which is who we’re talking about, if she responds to platinum, this is your only chance to use a PARP inhibitor. It’s your only chance. And so, you might as well use that. These patients are going to get all of these drugs. Let’s use it now, and give her bevacizumab later. We agree. But, it’s 2 to 3—just saying.

Shannon N. Westin MD, MPH: I hear what you’re saying. Right now, at this very moment, that’s your only chance. But, you’re looking at a couple months of benefit in progression-free survival. In the exploratory analyses, when you tease out each of these trials and you look at that completely biomarker-negative, completely wild-type patient, you’re looking at a few months of progression-free survival.
So, if you look at Joyce Liu’s beautiful data with the combination of olaparib and cediranib, if you tease out that population that’s completely biomarker-negative, you’re getting a pretty impressive progression-free survival benefit.

Bradley J. Monk, MD, FACS, FACOG: It’s not labeled.

Shannon N. Westin MD, MPH: It’s not labeled, but we’ve got to take it step by step.

Bradley J. Monk, MD, FACS, FACOG: To talk about a biomarker that I don’t have, or an indication that isn’t labeled…

Matthew Powell, MD: I have an issue with you saying that you don’t have it available, because you can do it after a third platinum response, as well. That patient is going to get a response to her second-line, and you have an opportunity to give her…

Bradley J. Monk, MD, FACS, FACOG: But, it gets to be less, and less, and less.

Matthew Powell, MD: It is less, but it’s not...

Bradley J. Monk, MD, FACS, FACOG: Let’s change the scenario. Let’s say the patient is still BRCA-negative, germline, somatic. She got bevacizumab in the frontline setting. You said that GOG-0218 was going to change your practice. Does that now make it easier? Or, are you going to use bevacizumab after bevacizumab and still not use the PARP?

Shannon N. Westin MD, MPH: We don’t know. There are data. Data presented on GOG-213 demonstrated that the patients who had bevacizumab in the frontline setting, a small proportion…

Matthew Powell, MD: Ten percent of them had bevacizumab.

Ursula Matulonis, MD: We don’t know what the results are going to be. It’s going to be even more personalized. Did she respond? How long was she on bevacizumab maintenance?

Bradley J. Monk, MD, FACS, FACOG: For a long time.

Ursula Matulonis, MD: Well, I don’t know. What’s a long time?

Bradley J. Monk, MD, FACS, FACOG: So, the label, assuming it will be 15 months, in total…And when you get 15 months, in total, it’s about 20, 24 months.

Ursula Matulonis, MD: So, if she stays on bevacizumab maintenance in the upfront setting for a long time, meaning a year plus, and she has another platinum-sensitive recurrence, I would definitely consider it in my armamentarium.

David O’Malley, MD: I do want to make a couple of points. The improvement in median progression-free survival in GOG-213 was about the same as in the PARP trials.

Ursula Matulonis, MD: That’s what I’m trying to say.

David O’Malley, MD: You say it’s only 3 months. It’s the same exact thing in GOG-213. Saying that, I do think the NCCN guidelines need to look at this and word it a little bit more carefully. Ten to 12% of ICON7 or GOG-213 patients had prior bevacizumab, with no data to say that it impacted the outcome. We should have the ability to treat our patients, if the personalized decision discussion with the patient goes on.

Transcript Edited for Clarity

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Transcript: 

Bradley J. Monk, MD, FACS, FACOG: Let’s talk about sequencing. The decision that this patient is a good candidate for PARP inhibition really means sequencing. I’m going to create some clinical scenarios and bounce them off you. The first clinical scenario is probably the most common clinical scenario. A patient develops a platinum-sensitive relapse. This patient is bevacizumab-naive and is BRCA-negative. That’s the most common because most patients don’t get bevacizumab, upfront. And, most patients don’t have a BRCA mutation. In that group, which is the most common scenario, in the platinum-sensitive space, does that patient need chemotherapy/bevacizumab, or chemotherapy/PARP?

Matthew Powell, MD: The answer is, yes. Again, this is where we hope molecular testing is going to help.

Bradley J. Monk, MD, FACS, FACOG: What test would you use?

Matthew Powell, MD: If I was trying to decide on this, I’d use HRD, potentially. But, I don’t personally order HRD very much. I use their platinum sensitivity as a guide. I may use some of the features of bevacizumab to help guide this, too, especially if it’s somebody who I’m going to give Taxol to. If they’re going to get paclitaxel, again, carboplatin/paclitaxel/bevacizumab would be my go-to regimen.

Bradley J. Monk, MD, FACS, FACOG: Because of the overall survival benefit in GOG-213?

Matthew Powell, MD: That would probably win out in somebody who was really a wild-type person, as you suspected.

Bradley J. Monk, MD, FACS, FACOG: Chemotherapy/bevacizumab. Go ahead.

Ursula Matulonis, MD: I completely concur. I use carboplatin/Taxol/bevacizumab in very certain clinical situations. “Yes, we’re going to use carboplatin/paclitaxel, and I know that patient is going to be able to tolerate the addition of bevacizumab.” I would also bring up considerations in certain circumstances. Maybe the patient has existing hypertension, or she’s got underlying renal dysfunction? Maybe her counts are not so great. You may consider incorporating that platinum doublet—sort of the old-fashioned carboplatin/pegylated liposomal doxorubicin, or carboplatin/gemcitabine without thinking about a PARP inhibitor, and without thinking about bevacizumab. I think it’s important that this decision be very personalized.

Bradley J. Monk, MD, FACS, FACOG: But what bias do you bring to the table? What side of the fence do you sit on?

Ursula Matulonis, MD: If I’m going to use paclitaxel with carboplatin, I would consider bevacizumab because of the overall survival. If I’m going to use carboplatin/gemcitabine, I’m probably not going to use bevacizumab.

Shannon N. Westin MD, MPH: My bias is towards personalized medicine. If I have a patient who’s completely wild-type, I’m going to treat that patient with bevacizumab. I want that patient to live longer and I want to get that overall survival benefit. I know that if I treat them with a bevacizumab-containing combination, they're more likely to get to maintenance. So, we see a higher response rate.

Bradley J. Monk, MD, FACS, FACOG: The response rate goes from about 50% to about 75%.

Shannon N. Westin MD, MPH: Almost 80%.

Bradley J. Monk, MD, FACS, FACOG: It’s 77%. OK.

Shannon N. Westin MD, MPH: Right. For the patients who get bevacizumab, I can get them to maintenance. If I don’t give them that combination, I can’t.

Ursula Matulonis, MD: If you’re following someone and they go from like 10 to 20, and you do a CT scan and it shows some peritoneal nodularity, and she feels fine, I find it hard to expose her to a lot of medications.

Bradley J. Monk, MD, FACS, FACOG: That’s also true. But, I’m trying to simplify things.

David O’Malley, MD: I will simplify it for you, Dr. Monk. Even though observation or continuous cytotoxic therapy is a reasonable option, you’re going to make me choose. Eighteen months, you said, of treatment-free interval, platinum-free interval, correct?

Bradley J. Monk, MD, FACS, FACOG: In that range.

David O’Malley, MD: In that instance, the time they’re going to have to be on bevacizumab maintenance may approach 18 months. That’s a lot of cumulative exposure. I worry about the cumulative toxicities of bevacizumab in this scenario. It’s a very reasonable option, but I do think we’re now in the age of biomarker…

Bradley J. Monk, MD, FACS, FACOG: What biomarker?

David O’Malley, MD: I’m going to do a germline and somatic test. You had it—it’s wild-type. If the somatic was also negative—and 40% of these will have something—my only opportunity to give that patient a PARP, right now, is in the platinum-sensitive maintenance setting.

Bradley J. Monk, MD, FACS, FACOG: It is 2 to 3. That’s what I think. I think in the germline normal and somatic normal, bevacizumab-naïve patient, which is who we’re talking about, if she responds to platinum, this is your only chance to use a PARP inhibitor. It’s your only chance. And so, you might as well use that. These patients are going to get all of these drugs. Let’s use it now, and give her bevacizumab later. We agree. But, it’s 2 to 3—just saying.

Shannon N. Westin MD, MPH: I hear what you’re saying. Right now, at this very moment, that’s your only chance. But, you’re looking at a couple months of benefit in progression-free survival. In the exploratory analyses, when you tease out each of these trials and you look at that completely biomarker-negative, completely wild-type patient, you’re looking at a few months of progression-free survival.
So, if you look at Joyce Liu’s beautiful data with the combination of olaparib and cediranib, if you tease out that population that’s completely biomarker-negative, you’re getting a pretty impressive progression-free survival benefit.

Bradley J. Monk, MD, FACS, FACOG: It’s not labeled.

Shannon N. Westin MD, MPH: It’s not labeled, but we’ve got to take it step by step.

Bradley J. Monk, MD, FACS, FACOG: To talk about a biomarker that I don’t have, or an indication that isn’t labeled…

Matthew Powell, MD: I have an issue with you saying that you don’t have it available, because you can do it after a third platinum response, as well. That patient is going to get a response to her second-line, and you have an opportunity to give her…

Bradley J. Monk, MD, FACS, FACOG: But, it gets to be less, and less, and less.

Matthew Powell, MD: It is less, but it’s not...

Bradley J. Monk, MD, FACS, FACOG: Let’s change the scenario. Let’s say the patient is still BRCA-negative, germline, somatic. She got bevacizumab in the frontline setting. You said that GOG-0218 was going to change your practice. Does that now make it easier? Or, are you going to use bevacizumab after bevacizumab and still not use the PARP?

Shannon N. Westin MD, MPH: We don’t know. There are data. Data presented on GOG-213 demonstrated that the patients who had bevacizumab in the frontline setting, a small proportion…

Matthew Powell, MD: Ten percent of them had bevacizumab.

Ursula Matulonis, MD: We don’t know what the results are going to be. It’s going to be even more personalized. Did she respond? How long was she on bevacizumab maintenance?

Bradley J. Monk, MD, FACS, FACOG: For a long time.

Ursula Matulonis, MD: Well, I don’t know. What’s a long time?

Bradley J. Monk, MD, FACS, FACOG: So, the label, assuming it will be 15 months, in total…And when you get 15 months, in total, it’s about 20, 24 months.

Ursula Matulonis, MD: So, if she stays on bevacizumab maintenance in the upfront setting for a long time, meaning a year plus, and she has another platinum-sensitive recurrence, I would definitely consider it in my armamentarium.

David O’Malley, MD: I do want to make a couple of points. The improvement in median progression-free survival in GOG-213 was about the same as in the PARP trials.

Ursula Matulonis, MD: That’s what I’m trying to say.

David O’Malley, MD: You say it’s only 3 months. It’s the same exact thing in GOG-213. Saying that, I do think the NCCN guidelines need to look at this and word it a little bit more carefully. Ten to 12% of ICON7 or GOG-213 patients had prior bevacizumab, with no data to say that it impacted the outcome. We should have the ability to treat our patients, if the personalized decision discussion with the patient goes on.

Transcript Edited for Clarity
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TitleExpiration DateCME Credits
Oncology Best Practice™: Expert Perspectives to Incorporate Evidence on PARP Inhibitors into Practice and Optimize the Medical Management of Ovarian CancerOct 31, 20181.0
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