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Ovarian Cancer: Predictors of PARP Sensitivity

Panelists: Bradley J. Monk, MD, FACOG, FACS, University of Arizona; Creighton University School of Medicine; Arizona Oncology; Kathleen N. Moore, MD, University of Oklahoma; Elena S. Ratner, MD, Yale University School of Medicine; Brian M. Slomovitz, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System
Published: Tuesday, Jun 04, 2019



Transcript: 

Bradley J. Monk, MD, FACOG, FACS: I do love this conversation, Brian, and I’m sure glad that all 3 of you could be with me here today. I’ve kind of learned that there are 3 predictors of PARP [poly (ADP-ribose) polymerase] sensitivity. The first, of course, is BRCA. The second is the number of lines of therapy. I think that we’ve learned that after multiple lines of therapy, PARP inhibitors are less effective. And I would say second line, platinum sensitive, although they’re clearly indicated for multiple lines. And then the third is platinum sensitivity.

Katie, what is the most important predictor of PARP sensitivity if you had to do that: BRCA, molecular signature—that is, the number of lines of therapy—or platinum-sensitivity? What’s the most relevant in predicting PARP activity?

Kathleen N. Moore, MD: Probably sensitivity to platinum, but BRCA would be really close. But if you are BRCA and you are platinum resistant, you’re probably not going to respond.

Bradley J. Monk, MD, FACOG, FACS: Exactly what I think.

Kathleen N. Moore, MD: Some of them will, but platinum sensitivity, in most settings, is a good marker for response.

Bradley J. Monk, MD, FACOG, FACS: If you look at the hazard ratio between SOLO-1 and SOLO2, they’re both 0.3. So they’re both BRCA. But now, all of a sudden, you have changed first line versus second line.  And certainly, platinum sensitivity is there as well. But I think that’s 1 of the reasons why there’s such a great opportunity in the frontline. And if you look at QUADRA, which is 3 prior regimens, niraparib, and treatment, there were BRCA patients. They didn’t do as well as the patients who were platinum sensitive. So platinum resistant—that’s a clear example where even though you’re BRCA, it probably is not going to work if you’re further down the line and are platinum resistant.

Kathleen N. Moore, MD: Right.

Bradley J. Monk, MD, FACOG, FACS: I think there’s a message there that the earlier that you use these medications, the more [effective they are]. We can continue to debate bevacizumab. In fact, you said, “Oh, but if they really have bevacizumab, ascites, improvement in quality of life, I get it.” I could argue otherwise, but what you say makes a lot of sense. I don’t think you can make that argument in PARP inhibitors. But I said I’m going to delay them until later.

Kathleen N. Moore, MD: No, absolutely not.

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

Elena S. Ratner, MD: I think the caveat to what you said is: When are you taking this? As we all know, their BRCA reverts. You can have a BRCA reversion. You might think somebody is BRCA, so I agree with you. I will go with platinum positivity and not BRCA, because you don’t know if this BRCA is actually currently deficient or not.

Kathleen N. Moore, MD: We’re just beginning. I think there are very recent papers out on being able to use, to your point, circulating tumor DNA to detect the BRCA-reversion mutations that predict lack of response to rucaparib. So as we start talking about PARP after PARP, that’s going to be important. Loss of PARP—you still maintain your platinum sensitivity. In fact, it’s a marker of platinum sensitivity, but you’re PARP resistant. So this whole story is going to be complicated. It’s going to be exciting and complicated moving forward.

Bradley J. Monk, MD, FACOG, FACS: I used to think the reversion was a common mechanism of PARP resistance. But if that were true, then platinum wouldn’t work after PARP.

Kathleen N. Moore, MD: Right.

Bradley J. Monk, MD, FACOG, FACS: So there are other complicated factors.

Transcript Edited for Clarity

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Transcript: 

Bradley J. Monk, MD, FACOG, FACS: I do love this conversation, Brian, and I’m sure glad that all 3 of you could be with me here today. I’ve kind of learned that there are 3 predictors of PARP [poly (ADP-ribose) polymerase] sensitivity. The first, of course, is BRCA. The second is the number of lines of therapy. I think that we’ve learned that after multiple lines of therapy, PARP inhibitors are less effective. And I would say second line, platinum sensitive, although they’re clearly indicated for multiple lines. And then the third is platinum sensitivity.

Katie, what is the most important predictor of PARP sensitivity if you had to do that: BRCA, molecular signature—that is, the number of lines of therapy—or platinum-sensitivity? What’s the most relevant in predicting PARP activity?

Kathleen N. Moore, MD: Probably sensitivity to platinum, but BRCA would be really close. But if you are BRCA and you are platinum resistant, you’re probably not going to respond.

Bradley J. Monk, MD, FACOG, FACS: Exactly what I think.

Kathleen N. Moore, MD: Some of them will, but platinum sensitivity, in most settings, is a good marker for response.

Bradley J. Monk, MD, FACOG, FACS: If you look at the hazard ratio between SOLO-1 and SOLO2, they’re both 0.3. So they’re both BRCA. But now, all of a sudden, you have changed first line versus second line.  And certainly, platinum sensitivity is there as well. But I think that’s 1 of the reasons why there’s such a great opportunity in the frontline. And if you look at QUADRA, which is 3 prior regimens, niraparib, and treatment, there were BRCA patients. They didn’t do as well as the patients who were platinum sensitive. So platinum resistant—that’s a clear example where even though you’re BRCA, it probably is not going to work if you’re further down the line and are platinum resistant.

Kathleen N. Moore, MD: Right.

Bradley J. Monk, MD, FACOG, FACS: I think there’s a message there that the earlier that you use these medications, the more [effective they are]. We can continue to debate bevacizumab. In fact, you said, “Oh, but if they really have bevacizumab, ascites, improvement in quality of life, I get it.” I could argue otherwise, but what you say makes a lot of sense. I don’t think you can make that argument in PARP inhibitors. But I said I’m going to delay them until later.

Kathleen N. Moore, MD: No, absolutely not.

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

Elena S. Ratner, MD: I think the caveat to what you said is: When are you taking this? As we all know, their BRCA reverts. You can have a BRCA reversion. You might think somebody is BRCA, so I agree with you. I will go with platinum positivity and not BRCA, because you don’t know if this BRCA is actually currently deficient or not.

Kathleen N. Moore, MD: We’re just beginning. I think there are very recent papers out on being able to use, to your point, circulating tumor DNA to detect the BRCA-reversion mutations that predict lack of response to rucaparib. So as we start talking about PARP after PARP, that’s going to be important. Loss of PARP—you still maintain your platinum sensitivity. In fact, it’s a marker of platinum sensitivity, but you’re PARP resistant. So this whole story is going to be complicated. It’s going to be exciting and complicated moving forward.

Bradley J. Monk, MD, FACOG, FACS: I used to think the reversion was a common mechanism of PARP resistance. But if that were true, then platinum wouldn’t work after PARP.

Kathleen N. Moore, MD: Right.

Bradley J. Monk, MD, FACOG, FACS: So there are other complicated factors.

Transcript Edited for Clarity
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