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PARP Maintenance Therapy in Recurrent Ovarian Cancer

Panelists: Bradley J. Monk, MD, FACS, FACOG, Arizona Oncology Practice of US Oncology; Oliver Dorigo, MD, PhD, Stanford University Medical Center; Thomas Herzog, MD, University of Cincinnati Cancer Institute; Kathleen Moore, MD, Stephenson Cancer Center; Leslie M. Randall, MD, MAS, University of California, Irvine
Published: Friday, Sep 14, 2018



Transcript: 

Bradley J. Monk, MD, FACS, FACOG: Now let’s talk about second-line chemotherapy. Leslie told us that bevacizumab has some indications. We have 3 single-agent options in resistant disease—PLD (pegylated liposomal doxorubicin), topotecan, weekly paclitaxel. We have 3 platinum doublets in sensitive disease—carboplatin/gemcitabine, carboplatin/PLD, and carboplatin/paclitaxel.

We are now in an era of maintenance therapy. Maintenance therapy with frontline bevacizumab—we’ve talked about it. Now we consider maintenance therapy with PARP inhibitors in patients who respond to platinum. Katie, why would a patient who responds to platinum also be helped by a maintenance PARP inhibitor?

Kathleen Moore, MD: Or maintenance anything.

Bradley J. Monk, MD, FACS, FACOG: Maintenance anything.

Kathleen Moore, MD: As you know, the standard of care used to be 6 or 8 cycles. If you got them into a remission, for lack of a better word, you would stop. With GOG-0213 and the overall survival advantage, and with the results of ARIEL3, NOVA, and SOLO-2, we have multiple approvals in this maintenance space. The selected population was people who went on a clinical trial. But now, in patients who were selected, you can see, at least in the PARP inhibitor case, by response—and these are people who responded to chemotherapy enough to go on a maintenance therapy—the group that got placebo had a median progression-free survival of 5.5 months. That’s platinum resistance. That’s what you’re setting half of your patients up for. At a minimum, the use of a PARP inhibitor prolongs that.

Bradley J. Monk, MD, FACS, FACOG: How much?

Kathleen Moore, MD: Well, depending on the biomarker group, it could be 5.5 months to 21 months in a BRCA patient; 5 months to 13 months in an HRD patient; 5 months to 8 months in a HRD-negative patient. First of all, you’re prolonging the time to next chemotherapy, which is important. Secondly, you are extending the time away from this dichotomous platinum-resistant category, which doesn’t really exist. You’re reconsidering platinum therapy, which is a really good drug. When we call people platinum resistant, we just stop using it. When patients get it again, they probably respond and do well. So, it has a myriad of benefits. These studies just show us that if you do nothing…again, I say this for the third time—shared decision making. Some patients are done, and they need a break. That’s fine, but I don’t think that should be your standard of care, because you’re setting people up to be resistant.

Bradley J. Monk, MD, FACS, FACOG: PARP inhibitors inhibit single-stranded DNA repairs and unrepaired single-stranded breaks for your double-standard breaks, and BRCA is a double-stranded break enzyme. Platinum also causes DNA damage. If platinum works, it’s kind of a test. If platinum works, then a PARP inhibitor should work. So, there’s a shared biology mechanism of action.

You say, “Oh, a standard of care. Fifteen patients and 3 FDA approvals of PARP inhibitors—olaparib, niraparib, and rucaparib.” What percentage of patients do you think are not treated with a maintenance therapy after a platinum response? In other words, she was pretty dogmatic and definitive, but a patient with platinum-sensitive response in the second line setting should get something—bevacizumab or PARP. What percentage of patients are treated with observation? How common is that?

Leslie M. Randall, MD, MAS: I think it’s very common.

Bradley J. Monk, MD, FACS, FACOG: Is that possible? Dr. Katie Moore says that we shouldn’t do it.

Leslie M. Randall, MD, MAS: What the barriers are? I don’t know if the barriers are knowledge, cost.

Bradley J. Monk, MD, FACS, FACOG: What do you think, Oliver?

Oliver Dorigo, MD, PhD: It’s actually very true. The majority of the patients nationwide do not get maintenance therapy.

Bradley J. Monk, MD, FACS, FACOG: Even though she says they should?

Oliver Dorigo, MD, PhD: Well, Katie knows more than most other people. I don’t think that the message has gotten out there into the community, particularly.

Bradley J. Monk, MD, FACS, FACOG: How do we get the message out there, Tom? How do we get the message out, that there’s a real therapeutic opportunity in treating patients who respond to second-line platinum therapy? You can get a PARP inhibitor, and you can sometimes quadruple the progression-free survival.

Thomas Herzog, MD: Unfortunately, if you look at the patterns of practice in the United States, which I’m most familiar with, you see that there are a number of physicians who treat less than a handful of cases of ovarian cancer per year.

Bradley J. Monk, MD, FACS, FACOG: You’re going to blame it on the medical oncologist?

Thomas Herzog, MD: I’m not blaming it on anyone.

Leslie M. Randall, MD, MAS: Any low-volume provider.

Thomas Herzog, MD: I’m talking volume, not specialty. There are some very, very good medical oncologists in the world.

Bradley J. Monk, MD, FACS, FACOG: OK.

Thomas Herzog, MD: What I am saying is that in the low-volume practice, chances are that these data are not front of mind. It is complicated. There have been all of these approvals. You think of the 3 drugs and a lot of studies—4 different studies—that have affected this approval process. That’s something that makes it difficult. So, in answer to your question, I think education is a very important part of this. If you’re not sure what to do with that patient, get a second opinion.

Bradley J. Monk, MD, FACS, FACOG: Thank you for that. Is there a survival advantage in using maintenance PARP? In GOG-0213, you mentioned that there’s probably a 5-month improvement in overall survival. Is there a survival advantage, Tom, with PARP maintenance?

Thomas Herzog, MD: I don’t know if we know that. Clearly, the progression-free survival data are fantastic, and we need longer-term…

Bradley J. Monk, MD, FACS, FACOG: The only data that we would have are from Study 19. Study 19, interestingly, was a small study, but there was also a 5-month improvement in overall survival. This wasn’t the primary endpoint, but I think that we hope for a survival advantage.

Thomas Herzog, MD: I think we will see it.

Leslie M. Randall, MD, MAS: Regardless of that, what we’re seeing consistently in our PARP trials is that you do have a subset of patients who have very long-term durable responses. That’s not irrelevant. That’s important, and it’s well tolerated. I always say that we need to have something that permits chronic therapy.

Oliver Dorigo, MD, PhD: There are 6- or 7-year data now on olaparib maintenance.

Bradley J. Monk, MD, FACS, FACOG: Right.

Oliver Dorigo, MD, PhD: There’s still about 10%, 11% of patients without disease.

Kathleen Moore, MD: The other thing that I found fascinating and very consistent that surprised me was that when you have a germline-BRCA patient, our belief is that it’s someone who’s going to be really responsive to platinum, and that they’re going to have a really good prognosis. You would think that would translate in the placebo arms to this longer progression-free survival. It was compared with the biomarker-negative group. I was shocked that they did exactly the same.

Bradley J. Monk, MD, FACS, FACOG: Because BRCA is just predictive or a prognostic marker when you treat the patient. It doesn’t change the biology. It changes the sensitivity of chemotherapy.

Kathleen Moore, MD: But you’d think they’d be that much more sensitive to the chemotherapy that you gave them, and they’d go a little bit longer.

Leslie M. Randall, MD, MAS: I think the fact that they’re platinum-sensitive speaks to that, as well. There’s some measure of HRD that we’re not testing for yet, that exists in a platinum-sensitive…

Oliver Dorigo, MD, PhD: Like Katie said, it’s true for first-line treatment.

Kathleen Moore, MD: Yes.

Oliver Dorigo, MD, PhD: But when it comes to recurrent disease…

Kathleen Moore, MD: It doesn’t hold anymore. There can be a much longer progression-free survival in the frontline setting, but then you lose it.

Transcript Edited for Clarity 

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Transcript: 

Bradley J. Monk, MD, FACS, FACOG: Now let’s talk about second-line chemotherapy. Leslie told us that bevacizumab has some indications. We have 3 single-agent options in resistant disease—PLD (pegylated liposomal doxorubicin), topotecan, weekly paclitaxel. We have 3 platinum doublets in sensitive disease—carboplatin/gemcitabine, carboplatin/PLD, and carboplatin/paclitaxel.

We are now in an era of maintenance therapy. Maintenance therapy with frontline bevacizumab—we’ve talked about it. Now we consider maintenance therapy with PARP inhibitors in patients who respond to platinum. Katie, why would a patient who responds to platinum also be helped by a maintenance PARP inhibitor?

Kathleen Moore, MD: Or maintenance anything.

Bradley J. Monk, MD, FACS, FACOG: Maintenance anything.

Kathleen Moore, MD: As you know, the standard of care used to be 6 or 8 cycles. If you got them into a remission, for lack of a better word, you would stop. With GOG-0213 and the overall survival advantage, and with the results of ARIEL3, NOVA, and SOLO-2, we have multiple approvals in this maintenance space. The selected population was people who went on a clinical trial. But now, in patients who were selected, you can see, at least in the PARP inhibitor case, by response—and these are people who responded to chemotherapy enough to go on a maintenance therapy—the group that got placebo had a median progression-free survival of 5.5 months. That’s platinum resistance. That’s what you’re setting half of your patients up for. At a minimum, the use of a PARP inhibitor prolongs that.

Bradley J. Monk, MD, FACS, FACOG: How much?

Kathleen Moore, MD: Well, depending on the biomarker group, it could be 5.5 months to 21 months in a BRCA patient; 5 months to 13 months in an HRD patient; 5 months to 8 months in a HRD-negative patient. First of all, you’re prolonging the time to next chemotherapy, which is important. Secondly, you are extending the time away from this dichotomous platinum-resistant category, which doesn’t really exist. You’re reconsidering platinum therapy, which is a really good drug. When we call people platinum resistant, we just stop using it. When patients get it again, they probably respond and do well. So, it has a myriad of benefits. These studies just show us that if you do nothing…again, I say this for the third time—shared decision making. Some patients are done, and they need a break. That’s fine, but I don’t think that should be your standard of care, because you’re setting people up to be resistant.

Bradley J. Monk, MD, FACS, FACOG: PARP inhibitors inhibit single-stranded DNA repairs and unrepaired single-stranded breaks for your double-standard breaks, and BRCA is a double-stranded break enzyme. Platinum also causes DNA damage. If platinum works, it’s kind of a test. If platinum works, then a PARP inhibitor should work. So, there’s a shared biology mechanism of action.

You say, “Oh, a standard of care. Fifteen patients and 3 FDA approvals of PARP inhibitors—olaparib, niraparib, and rucaparib.” What percentage of patients do you think are not treated with a maintenance therapy after a platinum response? In other words, she was pretty dogmatic and definitive, but a patient with platinum-sensitive response in the second line setting should get something—bevacizumab or PARP. What percentage of patients are treated with observation? How common is that?

Leslie M. Randall, MD, MAS: I think it’s very common.

Bradley J. Monk, MD, FACS, FACOG: Is that possible? Dr. Katie Moore says that we shouldn’t do it.

Leslie M. Randall, MD, MAS: What the barriers are? I don’t know if the barriers are knowledge, cost.

Bradley J. Monk, MD, FACS, FACOG: What do you think, Oliver?

Oliver Dorigo, MD, PhD: It’s actually very true. The majority of the patients nationwide do not get maintenance therapy.

Bradley J. Monk, MD, FACS, FACOG: Even though she says they should?

Oliver Dorigo, MD, PhD: Well, Katie knows more than most other people. I don’t think that the message has gotten out there into the community, particularly.

Bradley J. Monk, MD, FACS, FACOG: How do we get the message out there, Tom? How do we get the message out, that there’s a real therapeutic opportunity in treating patients who respond to second-line platinum therapy? You can get a PARP inhibitor, and you can sometimes quadruple the progression-free survival.

Thomas Herzog, MD: Unfortunately, if you look at the patterns of practice in the United States, which I’m most familiar with, you see that there are a number of physicians who treat less than a handful of cases of ovarian cancer per year.

Bradley J. Monk, MD, FACS, FACOG: You’re going to blame it on the medical oncologist?

Thomas Herzog, MD: I’m not blaming it on anyone.

Leslie M. Randall, MD, MAS: Any low-volume provider.

Thomas Herzog, MD: I’m talking volume, not specialty. There are some very, very good medical oncologists in the world.

Bradley J. Monk, MD, FACS, FACOG: OK.

Thomas Herzog, MD: What I am saying is that in the low-volume practice, chances are that these data are not front of mind. It is complicated. There have been all of these approvals. You think of the 3 drugs and a lot of studies—4 different studies—that have affected this approval process. That’s something that makes it difficult. So, in answer to your question, I think education is a very important part of this. If you’re not sure what to do with that patient, get a second opinion.

Bradley J. Monk, MD, FACS, FACOG: Thank you for that. Is there a survival advantage in using maintenance PARP? In GOG-0213, you mentioned that there’s probably a 5-month improvement in overall survival. Is there a survival advantage, Tom, with PARP maintenance?

Thomas Herzog, MD: I don’t know if we know that. Clearly, the progression-free survival data are fantastic, and we need longer-term…

Bradley J. Monk, MD, FACS, FACOG: The only data that we would have are from Study 19. Study 19, interestingly, was a small study, but there was also a 5-month improvement in overall survival. This wasn’t the primary endpoint, but I think that we hope for a survival advantage.

Thomas Herzog, MD: I think we will see it.

Leslie M. Randall, MD, MAS: Regardless of that, what we’re seeing consistently in our PARP trials is that you do have a subset of patients who have very long-term durable responses. That’s not irrelevant. That’s important, and it’s well tolerated. I always say that we need to have something that permits chronic therapy.

Oliver Dorigo, MD, PhD: There are 6- or 7-year data now on olaparib maintenance.

Bradley J. Monk, MD, FACS, FACOG: Right.

Oliver Dorigo, MD, PhD: There’s still about 10%, 11% of patients without disease.

Kathleen Moore, MD: The other thing that I found fascinating and very consistent that surprised me was that when you have a germline-BRCA patient, our belief is that it’s someone who’s going to be really responsive to platinum, and that they’re going to have a really good prognosis. You would think that would translate in the placebo arms to this longer progression-free survival. It was compared with the biomarker-negative group. I was shocked that they did exactly the same.

Bradley J. Monk, MD, FACS, FACOG: Because BRCA is just predictive or a prognostic marker when you treat the patient. It doesn’t change the biology. It changes the sensitivity of chemotherapy.

Kathleen Moore, MD: But you’d think they’d be that much more sensitive to the chemotherapy that you gave them, and they’d go a little bit longer.

Leslie M. Randall, MD, MAS: I think the fact that they’re platinum-sensitive speaks to that, as well. There’s some measure of HRD that we’re not testing for yet, that exists in a platinum-sensitive…

Oliver Dorigo, MD, PhD: Like Katie said, it’s true for first-line treatment.

Kathleen Moore, MD: Yes.

Oliver Dorigo, MD, PhD: But when it comes to recurrent disease…

Kathleen Moore, MD: It doesn’t hold anymore. There can be a much longer progression-free survival in the frontline setting, but then you lose it.

Transcript Edited for Clarity 
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