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PARP Inhibitors in Recurrent 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: I want to spend plenty of time talking about our PARP inhibitors. It’s been my pleasure to participate in the development of PARP inhibitors. Thanks to many of you included, the first PARP inhibitor that was brought to market—in 2014, in ovarian cancer—was olaparib. Tell us about olaparib. Where are we with the current indication in the development of olaparib? Matt?

Matthew Powell, MD: It has been quite a journey and adventure. Let’s start with the maintenance setting. Let’s look at the SOLO2 study. It randomized 295 patients and saw 19 months of progression-free survival in those who got the drug. The placebo was 5 months.

Bradley J. Monk, MD, FACS, FACOG: If they responded to second-line platinum.

Matthew Powell, MD: They had the biomarker. They responded to platinum the first time. They also responded to the platinum the second time. They had either a complete or partial response, and they went on to be maintained with placebo or the drug. The results were quite exciting. Then we coupled that with Study 19, where we have long-term follow-up. Now 10% of the patients on that trial are over 6 years into it. No new safety signals were seen. That’s quite exciting, and there is this kind of overall survival hint. I know because of multiple comparisons that we don’t call it statistical.

Bradley J. Monk, MD, FACS, FACOG: Secondary endpoint, anyway.

Matthew Powell, MD: But it’s kind of exciting.

Bradley J. Monk, MD, FACS, FACOG: Then we have treatment as an option with olaparib.

Matthew Powell, MD: Correct. We know that when patients have bulky disease, they’re going to have good response rates, so it’s an option. The label for olaparib actually includes both a maintenance and treatment setting.

Bradley J. Monk, MD, FACS, FACOG: The treatment is for germline BRCA, with more than 3 lines of therapy?

Matthew Powell, MD: Correct.

Ursula Matulonis, MD: And those data were emanated. As Matt mentioned, another trial really led to the initial approval or olaparib as treatment.

Bradley J. Monk, MD, FACS, FACOG: With BRCA.

Ursula Matulonis, MD: Right.

Bradley J. Monk, MD, FACS, FACOG: Why is platinum sensitivity a biomarker, Ursula? I understand that it works in the BRCA patients, but why does it also work in patients who respond to second-line platinum?

Ursula Matulonis, MD: Well, certainly from a more basic science perspective, there are a lot of common and overlapping resistant mechanisms. There are also sensitivity mechanisms of platinum and PARP inhibitors. So, we looked at retrospective data of germline BRCA patients. The highest response rates are in those patients who are less frequently treated—so, fewer prior regimens and platinum-sensitive. As you treat patients with more regimens—as they become more platinum-resistant—that response rate drops down.

Bradley J. Monk, MD, FACS, FACOG: There are really 3 biomarkers—molecular signature, platinum sensitivity, and number of lines of therapy for PARP inhibition—so you can create an algorithm in that individual patient on what her chance for response is.

Matthew Powell, MD: Also, we need to get away from the months thing, as we said before. Make them prove that they’re not working on platinum anymore, before we give up on platinum. I think platinum is probably underutilized in some ways, because of this whole arbitrary 6-month issue.

Ursula Matulonis, MD: That’s true.

Matthew Powell, MD: Patients had big, bulky disease. You brought them down to nothing, and they happened to recur at 6 months. Then they responded well. The patient is probably going to be platinum-sensitive.

Bradley J. Monk, MD, FACS, FACOG: The wonderful thing about olaparib, because it was first in class, is that now we have a breast indication, right? It’s fantastic.
So, the olaparib formulation today—you said it’s a tablet?

Shannon N. Westin, MD, MPH: That’s right.

Bradley J. Monk, MD, FACS, FACOG: Tell us about the evolution of the tablet…?

Shannon N. Westin, MD, MPH: Initially, the olaparib formulation was in capsule form. This involved taking many more pills, and that was 1 of the things we always worried about. Once we had multiple PARP inhibitors in the same indication, how hard would it be for a patient population who may already have gastrointestinal issues and difficulties with swallowing to take 4, 8, 12, or 16 pills at a time? So, they were able to transition to a tablet formulation, which just involves 2 pills per dose. That’s certainly a lot easier for patients to tolerate, and we still are seeing the same efficacy signals and toxicity.

Bradley J. Monk, MD, FACS, FACOG: The interesting thing, though, is that the tablet dose isn’t the same as the capsule dose.

Matthew Powell, MD: Bioavailability.

David O’Malley, MD: That’s a very important point. You cannot cross your prescriptions on that.

Bradley J. Monk, MD, FACS, FACOG: Dave, can you tell us about the second PARP inhibitor, rucaparib?

David O’Malley, MD: We have a germline approval for olaparib.

Bradley J. Monk, MD, FACS, FACOG: In treatment?

David O’Malley, MD: In treatment. Next is rucaparib, for treatment in the second-line or beyond settings, for somatic BRCA and germline BRCA. The ARIEL2 trial was approximately a 350-patient trial. It was a single-arm phase II trial. Platinum-sensitive disease was treated with rucaparib before going back to a platinum doublet. In the BRCA patients, there was a 70% response rate. It persisted for 9.5 months. In the BRCA-like, HRD population—and we can talk about that more in the future—it dropped down to about a 30% response rate. Again, this used a LOH test. In looking at the patients who were biomarker-negative, there was a 13% response rate. Because of the impressiveness of the response rate in ARIEL2 in those somatic and germline BRCA patients, there was an indication created for treatment.

Bradley J. Monk, MD, FACS, FACOG: So, they also have a positive trial for maintenance—just like SOLO2 and Study 19 for rucaparib—called ARIEL3. Is rucaparib FDA approved in the maintenance setting?

David O’Malley, MD: Rucaparib is not yet FDA approved. We expect to hear more in the next week or so. Once again, this was placebo controlled. The trial was a 550-patient randomized phase III trial. There was a 2:1 randomization. The trial looked at all-comers. The biggest impact that we’ve seen in other trials was in those with germline and somatic BRCA, but there’s also benefit in all patients.

Bradley J. Monk, MD, FACS, FACOG: Ursula, you and Dr. Mirza led this wonderful trial, which we call NOVA. What you did is pretty neat. You published it in the New England Journal of Medicine on the same week that it was presented at ESMO. I love the synchronization. That molecule, or PARP inhibitor, is called niraparib. Can you tell us about the indication for niraparib?

Ursula Matulonis, MD: Sure. Niraparib has a maintenance indication. It was the first agent to receive a maintenance indication in the United States. Again, it has a very similar, if not identical, FDA approval as olaparib. The NOVA trial enrolled about 550 patients and placed them into 2 groups. One was a germline BRCA group, and the other was a non-germline BRCA group. All patients had germline testing up front and then were put into 1 of these 2 groups. I should also mention that these were all patients who had high-grade serous carcinoma. All of these patients had received previous platinum-based chemotherapy. They had platinum-sensitive disease, and they had responded and showed that their cancer continued to have a response to platinum.

The trial had a 2:1 randomization—niraparib versus placebo. There were 3 primary subgroups. One was the germline BRCA group. In the results for progression-free survival, which was the primary endpoint of the trial, we saw about 21 months of progression-free survival for the women who received niraparib versus about 5.5 months for those on placebo. The second group was then the non-germline BRCA but HRD-positive group. We saw about a 9-month improvement in progression-free survival. And then, for the last group, which was non-germline BRCA but the whole group, there was about a 6-month improvement in progression-free survival on niraparib versus placebo. And that led to the FDA approval of niraparib in March of 2017.

David O’Malley, MD: We have to be very careful when we’re talking about median progression-free survival. The assessments were different. For example, in the niraparib trial, it was independent radiologic interpretation. The other 2 trials were investigator initiated. We know the independent radiologic always prolongs those evaluations.

Ursula Matulonis, MD: But I would actually counter that. When you look at ARIEL3, SOLO2, and at NOVA, and that progression-free survival benefit—specifically, in the germline patient population—the numbers are almost overlapping.

Bradley J. Monk, MD, FACS, FACOG: Can you tell me about the dose of niraparib?

Ursula Matulonis, MD: The phase I publication that was published in Lancet Oncology a number of years ago looked at achieving the maximally tolerated, recommended phase II dose of 300 mg a day. When that was translated into NOVA, there was a definite toxicity. That drug has a different toxicity profile versus the other PARP inhibitors.

Bradley J. Monk, MD, FACS, FACOG: At that dose?

Ursula Matulonis, MD: At least at these doses, that’s right. At these doses, that’s correct. So, the 300-mg dose.

Bradley J. Monk, MD, FACS, FACOG: Once a day, which is different because you guys are talking about a BID dose.

Ursula Matulonis, MD: Right. It has about a 33% risk of grade 3/4 thrombocytopenia and also some more neutropenia. At this Society of Gynecologic Oncology meeting, data that tried to determine predictive factors were presented. For example: “This individual may be at higher risk of developing significant thrombocytopenia” and “Those 2 factors happen to be a weight that is less than 77 kg and a baseline platelet count that is less than 150.” So, there is this discussion about, “Well, should you start those patients at 200 mg?” Because there hasn’t been a prospective trial looking at the 200-mg dose, one should consider very carefully monitoring the platelet count during the first month. That’s on the label. It suggests checking platelet counts weekly and doing a rapid dose reduction down to 200 if that starts to occur.

David O’Malley, MD: Rapid dose interruption and then reduction.

Bradley J. Monk, MD, FACS, FACOG: Stop and recover.

Ursula Matulonis, MD: Absolutely.

David O’Malley, MD: This is very important. A big drop in the platelets, even at normal levels, needs to be monitored very closely, and you need to recommend a dose interruption.

Transcript Edited for Clarity 

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Transcript: 

Bradley J. Monk, MD, FACS, FACOG: I want to spend plenty of time talking about our PARP inhibitors. It’s been my pleasure to participate in the development of PARP inhibitors. Thanks to many of you included, the first PARP inhibitor that was brought to market—in 2014, in ovarian cancer—was olaparib. Tell us about olaparib. Where are we with the current indication in the development of olaparib? Matt?

Matthew Powell, MD: It has been quite a journey and adventure. Let’s start with the maintenance setting. Let’s look at the SOLO2 study. It randomized 295 patients and saw 19 months of progression-free survival in those who got the drug. The placebo was 5 months.

Bradley J. Monk, MD, FACS, FACOG: If they responded to second-line platinum.

Matthew Powell, MD: They had the biomarker. They responded to platinum the first time. They also responded to the platinum the second time. They had either a complete or partial response, and they went on to be maintained with placebo or the drug. The results were quite exciting. Then we coupled that with Study 19, where we have long-term follow-up. Now 10% of the patients on that trial are over 6 years into it. No new safety signals were seen. That’s quite exciting, and there is this kind of overall survival hint. I know because of multiple comparisons that we don’t call it statistical.

Bradley J. Monk, MD, FACS, FACOG: Secondary endpoint, anyway.

Matthew Powell, MD: But it’s kind of exciting.

Bradley J. Monk, MD, FACS, FACOG: Then we have treatment as an option with olaparib.

Matthew Powell, MD: Correct. We know that when patients have bulky disease, they’re going to have good response rates, so it’s an option. The label for olaparib actually includes both a maintenance and treatment setting.

Bradley J. Monk, MD, FACS, FACOG: The treatment is for germline BRCA, with more than 3 lines of therapy?

Matthew Powell, MD: Correct.

Ursula Matulonis, MD: And those data were emanated. As Matt mentioned, another trial really led to the initial approval or olaparib as treatment.

Bradley J. Monk, MD, FACS, FACOG: With BRCA.

Ursula Matulonis, MD: Right.

Bradley J. Monk, MD, FACS, FACOG: Why is platinum sensitivity a biomarker, Ursula? I understand that it works in the BRCA patients, but why does it also work in patients who respond to second-line platinum?

Ursula Matulonis, MD: Well, certainly from a more basic science perspective, there are a lot of common and overlapping resistant mechanisms. There are also sensitivity mechanisms of platinum and PARP inhibitors. So, we looked at retrospective data of germline BRCA patients. The highest response rates are in those patients who are less frequently treated—so, fewer prior regimens and platinum-sensitive. As you treat patients with more regimens—as they become more platinum-resistant—that response rate drops down.

Bradley J. Monk, MD, FACS, FACOG: There are really 3 biomarkers—molecular signature, platinum sensitivity, and number of lines of therapy for PARP inhibition—so you can create an algorithm in that individual patient on what her chance for response is.

Matthew Powell, MD: Also, we need to get away from the months thing, as we said before. Make them prove that they’re not working on platinum anymore, before we give up on platinum. I think platinum is probably underutilized in some ways, because of this whole arbitrary 6-month issue.

Ursula Matulonis, MD: That’s true.

Matthew Powell, MD: Patients had big, bulky disease. You brought them down to nothing, and they happened to recur at 6 months. Then they responded well. The patient is probably going to be platinum-sensitive.

Bradley J. Monk, MD, FACS, FACOG: The wonderful thing about olaparib, because it was first in class, is that now we have a breast indication, right? It’s fantastic.
So, the olaparib formulation today—you said it’s a tablet?

Shannon N. Westin, MD, MPH: That’s right.

Bradley J. Monk, MD, FACS, FACOG: Tell us about the evolution of the tablet…?

Shannon N. Westin, MD, MPH: Initially, the olaparib formulation was in capsule form. This involved taking many more pills, and that was 1 of the things we always worried about. Once we had multiple PARP inhibitors in the same indication, how hard would it be for a patient population who may already have gastrointestinal issues and difficulties with swallowing to take 4, 8, 12, or 16 pills at a time? So, they were able to transition to a tablet formulation, which just involves 2 pills per dose. That’s certainly a lot easier for patients to tolerate, and we still are seeing the same efficacy signals and toxicity.

Bradley J. Monk, MD, FACS, FACOG: The interesting thing, though, is that the tablet dose isn’t the same as the capsule dose.

Matthew Powell, MD: Bioavailability.

David O’Malley, MD: That’s a very important point. You cannot cross your prescriptions on that.

Bradley J. Monk, MD, FACS, FACOG: Dave, can you tell us about the second PARP inhibitor, rucaparib?

David O’Malley, MD: We have a germline approval for olaparib.

Bradley J. Monk, MD, FACS, FACOG: In treatment?

David O’Malley, MD: In treatment. Next is rucaparib, for treatment in the second-line or beyond settings, for somatic BRCA and germline BRCA. The ARIEL2 trial was approximately a 350-patient trial. It was a single-arm phase II trial. Platinum-sensitive disease was treated with rucaparib before going back to a platinum doublet. In the BRCA patients, there was a 70% response rate. It persisted for 9.5 months. In the BRCA-like, HRD population—and we can talk about that more in the future—it dropped down to about a 30% response rate. Again, this used a LOH test. In looking at the patients who were biomarker-negative, there was a 13% response rate. Because of the impressiveness of the response rate in ARIEL2 in those somatic and germline BRCA patients, there was an indication created for treatment.

Bradley J. Monk, MD, FACS, FACOG: So, they also have a positive trial for maintenance—just like SOLO2 and Study 19 for rucaparib—called ARIEL3. Is rucaparib FDA approved in the maintenance setting?

David O’Malley, MD: Rucaparib is not yet FDA approved. We expect to hear more in the next week or so. Once again, this was placebo controlled. The trial was a 550-patient randomized phase III trial. There was a 2:1 randomization. The trial looked at all-comers. The biggest impact that we’ve seen in other trials was in those with germline and somatic BRCA, but there’s also benefit in all patients.

Bradley J. Monk, MD, FACS, FACOG: Ursula, you and Dr. Mirza led this wonderful trial, which we call NOVA. What you did is pretty neat. You published it in the New England Journal of Medicine on the same week that it was presented at ESMO. I love the synchronization. That molecule, or PARP inhibitor, is called niraparib. Can you tell us about the indication for niraparib?

Ursula Matulonis, MD: Sure. Niraparib has a maintenance indication. It was the first agent to receive a maintenance indication in the United States. Again, it has a very similar, if not identical, FDA approval as olaparib. The NOVA trial enrolled about 550 patients and placed them into 2 groups. One was a germline BRCA group, and the other was a non-germline BRCA group. All patients had germline testing up front and then were put into 1 of these 2 groups. I should also mention that these were all patients who had high-grade serous carcinoma. All of these patients had received previous platinum-based chemotherapy. They had platinum-sensitive disease, and they had responded and showed that their cancer continued to have a response to platinum.

The trial had a 2:1 randomization—niraparib versus placebo. There were 3 primary subgroups. One was the germline BRCA group. In the results for progression-free survival, which was the primary endpoint of the trial, we saw about 21 months of progression-free survival for the women who received niraparib versus about 5.5 months for those on placebo. The second group was then the non-germline BRCA but HRD-positive group. We saw about a 9-month improvement in progression-free survival. And then, for the last group, which was non-germline BRCA but the whole group, there was about a 6-month improvement in progression-free survival on niraparib versus placebo. And that led to the FDA approval of niraparib in March of 2017.

David O’Malley, MD: We have to be very careful when we’re talking about median progression-free survival. The assessments were different. For example, in the niraparib trial, it was independent radiologic interpretation. The other 2 trials were investigator initiated. We know the independent radiologic always prolongs those evaluations.

Ursula Matulonis, MD: But I would actually counter that. When you look at ARIEL3, SOLO2, and at NOVA, and that progression-free survival benefit—specifically, in the germline patient population—the numbers are almost overlapping.

Bradley J. Monk, MD, FACS, FACOG: Can you tell me about the dose of niraparib?

Ursula Matulonis, MD: The phase I publication that was published in Lancet Oncology a number of years ago looked at achieving the maximally tolerated, recommended phase II dose of 300 mg a day. When that was translated into NOVA, there was a definite toxicity. That drug has a different toxicity profile versus the other PARP inhibitors.

Bradley J. Monk, MD, FACS, FACOG: At that dose?

Ursula Matulonis, MD: At least at these doses, that’s right. At these doses, that’s correct. So, the 300-mg dose.

Bradley J. Monk, MD, FACS, FACOG: Once a day, which is different because you guys are talking about a BID dose.

Ursula Matulonis, MD: Right. It has about a 33% risk of grade 3/4 thrombocytopenia and also some more neutropenia. At this Society of Gynecologic Oncology meeting, data that tried to determine predictive factors were presented. For example: “This individual may be at higher risk of developing significant thrombocytopenia” and “Those 2 factors happen to be a weight that is less than 77 kg and a baseline platelet count that is less than 150.” So, there is this discussion about, “Well, should you start those patients at 200 mg?” Because there hasn’t been a prospective trial looking at the 200-mg dose, one should consider very carefully monitoring the platelet count during the first month. That’s on the label. It suggests checking platelet counts weekly and doing a rapid dose reduction down to 200 if that starts to occur.

David O’Malley, MD: Rapid dose interruption and then reduction.

Bradley J. Monk, MD, FACS, FACOG: Stop and recover.

Ursula Matulonis, MD: Absolutely.

David O’Malley, MD: This is very important. A big drop in the platelets, even at normal levels, needs to be monitored very closely, and you need to recommend a dose interruption.

Transcript Edited for Clarity 
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