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PARP Inhibitors and Platinum Sensitivity or Resistance

Panelists:Joyce OShaugnessy, MD, Baylor University Medical Center; Tiffany A. Traina, MD, Memorial Sloan Kettering Cancer Center; Nadine M. Tung, MD, Harvard Medical School
Published: Wednesday, Apr 25, 2018



Transcript: 

Joyce O’Shaughnessy, MD: What have we learned so far about the utility of PARP inhibitors in someone who’s had a platinum agent? I think this is going to come up for our patients who are triple-negative, particularly in the metastatic setting. Before olaparib was available to them or, soon to be, talazoparib (we hope), women got some platinum. What do we know from EMBRACA or OlympiAD in terms of timing? If you were to give one immediately upon progression on a platinum, would you get anything? Should we try to separate it out? Is there a difference, a differential benefit, between those who have had a prior platinum and those who haven’t? Didn’t EMBRACA look at that?

Nadine Tung, MD: Yes. First of all, it’s important to say that both of those phase III trials (EMBRACA and OlympiAD) excluded patients who were platinum refractory. You couldn’t have progressed on a platinum. You could have had it in the adjuvant setting, but it had to be a good 12 months before you developed metastatic disease. Or you couldn’t be refractory. Your point is excellent—regarding platinum sensitivity, there are data that demonstrate that it predicts for response to a PARP inhibitor. There are more data in the ovarian cancer population. With platinum-refractory disease, there’s almost no response. In platinum-sensitive disease, where you’re recurring more than 6 months from your last platinum, there are high response rates.

Joyce O’Shaughnessy, MD: Six months in the ovarian cancer population?

Nadine Tung, MD: That’s in ovarian. That’s how they define platinum sensitive. Platinum refractory means that your tumor is growing while you’re being exposed to a platinum. Platinum resistant is in the middle. That’s how the ovarian cancer experts define it. In breast cancer, we have much fewer data. But there is 1 clue, based on the phase II trial with talazoparib. I think the trial is called ABRAZO? I never know whether I’m saying that correctly. They had a cohort of patients who had seen a prior platinum. It’s a small number, but there were 7 patients in that cohort who had a platinum-free interval of less than 8 weeks. I interpret that as platinum refractory. None of them responded to talazoparib. Whereas in those who had been more than 6 months from their platinum, their response rate was about 47%. So I think this is the theme: If you’re platinum refractory, your response is going to be very low; and if you’re platinum sensitive, your response will be higher. It would carry over.

Joyce O’Shaughnessy, MD: Interesting. EMBRACA had 2 separate cohorts, right? One was allowed to have had prior platinum?

Nadine Tung, MD: That’s ABRAZO. That’s the phase II study. EMBRACA, the phase III study, was just like OlympiAD. You could have had prior platinum. You just couldn’t be platinum refractory.

Joyce O’Shaughnessy, MD: OK, yes.

Tiffany Traina, MD: They stratified for it. In OlympiAD, about 30% of the patients had seen prior platinum therapy. In EMBRACA (I can visualize that forest plot), regardless of prior exposure to platinum or not, the PARP inhibitor benefited over treatment of physician’s choice.

Nadine Tung, MD: But these were not platinum refractory.
Joyce O’Shaughnessy, MD: Right. That’s interesting. So it may end up being similar to the platinum, but we need more data. From a practical standpoint, in your practice, if someone’s had platinum but they’re germline BRCA1, and you’d like to give them the opportunity for olaparib, and they had benefited in the past, would you consider coming back?

Tiffany Traina, MD: Sure. I think the scenario is very likely—you would have seen an amazing response if you used a platinum in the neoadjuvant setting, for example. You saw the tumor melt away, clinically. Maybe they even had a pathologic complete response? And yet later, they present with metastatic breast cancer in that germline setting. That patient would be a candidate for a PARP inhibitor, and I’d be enthused about it.

Nadine Tung, MD: I agree.

Joyce O’Shaughnessy, MD: Me too. And even in the metastatic setting, in the OlympiAD trial, you were eligible for platinum. In EMBRACA, as long as you hadn’t progressed, you were eligible.

Tiffany Traina, MD: Correct.

Joyce O’Shaughnessy, MD: But sometimes we do keep going with the platinums until they do progress. They do progress, right? But then, maybe they do well. They’ve done well. Then, later on, you can come back. Maybe you wouldn’t necessarily rule that out, down the road, for someone?

Nadine Tung, MD: I think the patient would be the one who got platinum but stopped because of toxicity. They got a response, and then you went on to something else.

Joyce O’Shaughnessy, MD: That’s where the data really speak to not becoming refractory to it.

Transcript Edited for Clarity 
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Transcript: 

Joyce O’Shaughnessy, MD: What have we learned so far about the utility of PARP inhibitors in someone who’s had a platinum agent? I think this is going to come up for our patients who are triple-negative, particularly in the metastatic setting. Before olaparib was available to them or, soon to be, talazoparib (we hope), women got some platinum. What do we know from EMBRACA or OlympiAD in terms of timing? If you were to give one immediately upon progression on a platinum, would you get anything? Should we try to separate it out? Is there a difference, a differential benefit, between those who have had a prior platinum and those who haven’t? Didn’t EMBRACA look at that?

Nadine Tung, MD: Yes. First of all, it’s important to say that both of those phase III trials (EMBRACA and OlympiAD) excluded patients who were platinum refractory. You couldn’t have progressed on a platinum. You could have had it in the adjuvant setting, but it had to be a good 12 months before you developed metastatic disease. Or you couldn’t be refractory. Your point is excellent—regarding platinum sensitivity, there are data that demonstrate that it predicts for response to a PARP inhibitor. There are more data in the ovarian cancer population. With platinum-refractory disease, there’s almost no response. In platinum-sensitive disease, where you’re recurring more than 6 months from your last platinum, there are high response rates.

Joyce O’Shaughnessy, MD: Six months in the ovarian cancer population?

Nadine Tung, MD: That’s in ovarian. That’s how they define platinum sensitive. Platinum refractory means that your tumor is growing while you’re being exposed to a platinum. Platinum resistant is in the middle. That’s how the ovarian cancer experts define it. In breast cancer, we have much fewer data. But there is 1 clue, based on the phase II trial with talazoparib. I think the trial is called ABRAZO? I never know whether I’m saying that correctly. They had a cohort of patients who had seen a prior platinum. It’s a small number, but there were 7 patients in that cohort who had a platinum-free interval of less than 8 weeks. I interpret that as platinum refractory. None of them responded to talazoparib. Whereas in those who had been more than 6 months from their platinum, their response rate was about 47%. So I think this is the theme: If you’re platinum refractory, your response is going to be very low; and if you’re platinum sensitive, your response will be higher. It would carry over.

Joyce O’Shaughnessy, MD: Interesting. EMBRACA had 2 separate cohorts, right? One was allowed to have had prior platinum?

Nadine Tung, MD: That’s ABRAZO. That’s the phase II study. EMBRACA, the phase III study, was just like OlympiAD. You could have had prior platinum. You just couldn’t be platinum refractory.

Joyce O’Shaughnessy, MD: OK, yes.

Tiffany Traina, MD: They stratified for it. In OlympiAD, about 30% of the patients had seen prior platinum therapy. In EMBRACA (I can visualize that forest plot), regardless of prior exposure to platinum or not, the PARP inhibitor benefited over treatment of physician’s choice.

Nadine Tung, MD: But these were not platinum refractory.
Joyce O’Shaughnessy, MD: Right. That’s interesting. So it may end up being similar to the platinum, but we need more data. From a practical standpoint, in your practice, if someone’s had platinum but they’re germline BRCA1, and you’d like to give them the opportunity for olaparib, and they had benefited in the past, would you consider coming back?

Tiffany Traina, MD: Sure. I think the scenario is very likely—you would have seen an amazing response if you used a platinum in the neoadjuvant setting, for example. You saw the tumor melt away, clinically. Maybe they even had a pathologic complete response? And yet later, they present with metastatic breast cancer in that germline setting. That patient would be a candidate for a PARP inhibitor, and I’d be enthused about it.

Nadine Tung, MD: I agree.

Joyce O’Shaughnessy, MD: Me too. And even in the metastatic setting, in the OlympiAD trial, you were eligible for platinum. In EMBRACA, as long as you hadn’t progressed, you were eligible.

Tiffany Traina, MD: Correct.

Joyce O’Shaughnessy, MD: But sometimes we do keep going with the platinums until they do progress. They do progress, right? But then, maybe they do well. They’ve done well. Then, later on, you can come back. Maybe you wouldn’t necessarily rule that out, down the road, for someone?

Nadine Tung, MD: I think the patient would be the one who got platinum but stopped because of toxicity. They got a response, and then you went on to something else.

Joyce O’Shaughnessy, MD: That’s where the data really speak to not becoming refractory to it.

Transcript Edited for Clarity 
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