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Recurrent Ovarian Cancer; Considerations Beyond the Platinum-Free Interval

Panelists: Bradley J. Monk, MD, University of Arizona and Creighton University School of Medicine at St. Joseph’s Hospital; Robert L. Coleman, MD, MD Anderson Cancer Center; Thomas Herzog, MD, University of Cincinnati; Kathleen N. Moore, MD, Stephenson Cancer Center; Angeles Alvarez Secord, MD, Duke University School of Medicine
Published Online: Tuesday, Feb 14, 2017



Transcript:

Bradley J. Monk, MD:
Let’s transition to recurrent ovarian cancer. Unfortunately, despite all of these changes in surgery, targeted therapy, scheduling, and route of administration, almost all patients recur. They recur somewhere between 10 and 30 months, and the better the prognosis, obviously, the longer the PFS. In considering treatment of recurrent ovarian cancer, it all used to be platinum-resistant, platinum-sensitive, and obviously that’s not true. It’s an important factor. But, Rob, you helped Ronnie Alvarez write a paper about other factors, other than the platinum-free interval, that help determine what the best treatment is. Outline those other factors other than platinum-free interval.

Robert L. Coleman, MD: Obviously, the BRCA status, which we talked a lot about. I think that this whole dynamic actually is continuing to evolve as we know more about the molecular signatures, although that was a very strong prognostic factor in that.

Bradley J. Monk, MD: So, you said you don’t treat your patients differently frontline based on histologic subtype. Do you begin now in the recurrent setting to put your low-grade serous in this trial, or the mucinous or the clear-cell? Does it now begin to have more of an impact on treatment decisions?

Kathleen N. Moore, MD: It actually has an impact on clinical trial consideration. So, if you’re talking about the kind of standard of care—platinum, Doxil—I don’t know that it really impacts those decisions as much. But, from a clinical trial standpoint, we know you have PARP inhibitors that are much more likely to work on patients that have a molecular signature, HRD, so you’re going to be looking for that more in your high-grade serous and your high-grade endometrioid patients, although you’re going to look everywhere for them. You have other targeted agents, targeted chemotherapy, that are targeting a certain protein in clinical trials that are much more likely in high-grade serous and high-grade endometrioid, and that actually defines eligibility for a number of novel agents. P53-targeted agents are only going to be in a certain histology, and so in the recurrent clinical trial world, it’s gotten much, much tighter.

Robert L. Coleman, MD: And I think with the number of prior treatments, it adds to that. So, as you start to build in the eligibility by histology, these prognostic factors we talked about include BRCA, but there’s probably going to be other important ones.

Bradley J. Monk, MD: So, you see a patient with recurrent ovarian cancer. What’s the time from the last platinum? What’s the molecular signature? What’s the histologic subtype? Tom, tell us now what the role of the line of therapy is. Does the line of therapy matter when you’re treating recurrent ovarian cancer? Tell us how.

Thomas Herzog, MD: Absolutely. We know that not only is it important in terms of making decisions individually on patients, it’s probably a new pathway in terms of regulatory approval. We’ve seen that with PARP inhibition in terms of fourth-line and beyond.

Bradley J. Monk, MD: So, Angeles, tell us about these drugs that we have approved. It also depends on the number of lines of therapy, right? They’re restricted.

Angeles Alvarez Secord, MD: Right, they are. Well, olaparib is restricted for fourth-line. That can be very challenging for certain patients by that time to take an oral agent, where their disease or their tumor burden may be difficult for them to tolerate drugs that are taken by mouth compared to IV drugs. So, I always want to move that one up. And then, the other restriction is on bevacizumab. It’s approved not beyond second-line therapy, where I do think that drug has value beyond that line of therapy.

Bradley J. Monk, MD: Let’s talk about that. We had, on December 6, 2016, a second approval in ovarian cancer, platinum-sensitive, and that’s just a second-line approach. But, in platinum-resistant, it’s for second- and third-line. We got platinum-resistant bevacizumab in second- and third-line, platinum-sensitive bevacizumab in second-line, and olaparib in fourth-line and beyond. So, there’s line of therapy, to your point, in all of these treatments. In the old world, paclitaxel, carboplatin, and PLD (pegylated liposomal doxorubicin) that didn’t matter, but today it does.

Robert L. Coleman, MD: But, let’s get back to where we started with this because I think that many clinicians look at the definition of “platinum sensitivity” like a binary variable. And they make a treatment decision about that. I think that what we’re describing here though, as we get more in lines of therapy, is the nuances of the patient characteristics that actually help us to determine what might be the expected outcomes. We still don’t really know how to mix the salad together.

Bradley J. Monk, MD: That’s why Tom says it might be a regulatory approval. We used to think that the regulatory option was in platinum-resistant disease, but by the time you get fourth-line and beyond, that’s not the most important factor anymore.

Thomas Herzog, MD: And it’s a mixture: platinum-sensitive and platinum-resistant.

Robert L. Coleman, MD: What I was getting at though is that you get the phone calls all the time and they’re saying, “I have this patient who has this disease, and those factors are being ticked off in that description.” Part of that platinum-free interval in the past was used as guidance for therapy, and so how do we incorporate these things? It’s not for regulatory influence, although that’s going to be important for clinical trial purposes, but how do we guide the clinician as to what they’re going to do?

Transcript Edited for Clarity

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Transcript:

Bradley J. Monk, MD:
Let’s transition to recurrent ovarian cancer. Unfortunately, despite all of these changes in surgery, targeted therapy, scheduling, and route of administration, almost all patients recur. They recur somewhere between 10 and 30 months, and the better the prognosis, obviously, the longer the PFS. In considering treatment of recurrent ovarian cancer, it all used to be platinum-resistant, platinum-sensitive, and obviously that’s not true. It’s an important factor. But, Rob, you helped Ronnie Alvarez write a paper about other factors, other than the platinum-free interval, that help determine what the best treatment is. Outline those other factors other than platinum-free interval.

Robert L. Coleman, MD: Obviously, the BRCA status, which we talked a lot about. I think that this whole dynamic actually is continuing to evolve as we know more about the molecular signatures, although that was a very strong prognostic factor in that.

Bradley J. Monk, MD: So, you said you don’t treat your patients differently frontline based on histologic subtype. Do you begin now in the recurrent setting to put your low-grade serous in this trial, or the mucinous or the clear-cell? Does it now begin to have more of an impact on treatment decisions?

Kathleen N. Moore, MD: It actually has an impact on clinical trial consideration. So, if you’re talking about the kind of standard of care—platinum, Doxil—I don’t know that it really impacts those decisions as much. But, from a clinical trial standpoint, we know you have PARP inhibitors that are much more likely to work on patients that have a molecular signature, HRD, so you’re going to be looking for that more in your high-grade serous and your high-grade endometrioid patients, although you’re going to look everywhere for them. You have other targeted agents, targeted chemotherapy, that are targeting a certain protein in clinical trials that are much more likely in high-grade serous and high-grade endometrioid, and that actually defines eligibility for a number of novel agents. P53-targeted agents are only going to be in a certain histology, and so in the recurrent clinical trial world, it’s gotten much, much tighter.

Robert L. Coleman, MD: And I think with the number of prior treatments, it adds to that. So, as you start to build in the eligibility by histology, these prognostic factors we talked about include BRCA, but there’s probably going to be other important ones.

Bradley J. Monk, MD: So, you see a patient with recurrent ovarian cancer. What’s the time from the last platinum? What’s the molecular signature? What’s the histologic subtype? Tom, tell us now what the role of the line of therapy is. Does the line of therapy matter when you’re treating recurrent ovarian cancer? Tell us how.

Thomas Herzog, MD: Absolutely. We know that not only is it important in terms of making decisions individually on patients, it’s probably a new pathway in terms of regulatory approval. We’ve seen that with PARP inhibition in terms of fourth-line and beyond.

Bradley J. Monk, MD: So, Angeles, tell us about these drugs that we have approved. It also depends on the number of lines of therapy, right? They’re restricted.

Angeles Alvarez Secord, MD: Right, they are. Well, olaparib is restricted for fourth-line. That can be very challenging for certain patients by that time to take an oral agent, where their disease or their tumor burden may be difficult for them to tolerate drugs that are taken by mouth compared to IV drugs. So, I always want to move that one up. And then, the other restriction is on bevacizumab. It’s approved not beyond second-line therapy, where I do think that drug has value beyond that line of therapy.

Bradley J. Monk, MD: Let’s talk about that. We had, on December 6, 2016, a second approval in ovarian cancer, platinum-sensitive, and that’s just a second-line approach. But, in platinum-resistant, it’s for second- and third-line. We got platinum-resistant bevacizumab in second- and third-line, platinum-sensitive bevacizumab in second-line, and olaparib in fourth-line and beyond. So, there’s line of therapy, to your point, in all of these treatments. In the old world, paclitaxel, carboplatin, and PLD (pegylated liposomal doxorubicin) that didn’t matter, but today it does.

Robert L. Coleman, MD: But, let’s get back to where we started with this because I think that many clinicians look at the definition of “platinum sensitivity” like a binary variable. And they make a treatment decision about that. I think that what we’re describing here though, as we get more in lines of therapy, is the nuances of the patient characteristics that actually help us to determine what might be the expected outcomes. We still don’t really know how to mix the salad together.

Bradley J. Monk, MD: That’s why Tom says it might be a regulatory approval. We used to think that the regulatory option was in platinum-resistant disease, but by the time you get fourth-line and beyond, that’s not the most important factor anymore.

Thomas Herzog, MD: And it’s a mixture: platinum-sensitive and platinum-resistant.

Robert L. Coleman, MD: What I was getting at though is that you get the phone calls all the time and they’re saying, “I have this patient who has this disease, and those factors are being ticked off in that description.” Part of that platinum-free interval in the past was used as guidance for therapy, and so how do we incorporate these things? It’s not for regulatory influence, although that’s going to be important for clinical trial purposes, but how do we guide the clinician as to what they’re going to do?

Transcript Edited for Clarity
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