The Rationale for Using PARP Inhibitors

A discussion on when to implement bevacizumab into the treatment plan and the rationale for using PARP inhibitors to treat individuals with ovarian cancer.

Maurie Markman, MD: Now we’re going to begin the topic of some of the really incredible advances. We begin with a discussion of bevacizumab. When’s the right time to use bevacizumab, up front, or at the time of progression, or in the resistant setting? Mike, I’ll ask you to try to take that topic on.

Michael Birrer, MD, PhD: That’s a loaded question because we have a lot of data, and everybody interprets it a little differently. So to cut to the chase, we have basically FDA-approved indications in platinum-resistant patient population, platinum-sensitive recurrent population, and now up front. And it sort of developed in that timeline. The AURELIA study was in platinum-resistant patients, and that was the first indication in the United States. And then GOG-213 and OCEANS studies were in the platinum-sensitive recurrence. And just recently within about 9 months, we got approval based on GOG-218 for use of the drug up front. I’m still a fairly big fan of using it in frontline therapy. You have an advantage of PFS [progression-free survival] anywhere between 4 and 6 months, depending on CA-125 [cancer antigen 125]. I find it easy to give. I’ve never had a patient come off based on hypertension or bowel perforation.

But there is an argument to be made. If you look at the hazard ratios, meaning the impact of the drug, they actually get better as you go later in the natural history of the disease. The AURELIA study I think was 0.48. So we’re wrestling with this, and we’re trying to integrate bevacizumab with the use of PARP [poly ADP ribose polymerase] inhibitors, and then we’ll discuss the PAOLA-1, trial which combined the 2. And I think it provides us with a lot of opportunities to tailor the therapy according to the needs of the patient. So patients who have high-risk disease with a lot of ascites, they’d probably get BEV [bevacizumab].

R. Wendel Naumann, MD: So Mike, do you only use it 1 time or do you use it again?

Michael Birrer, MD, PhD: Great question. Just to add to that, the GOG-218 was 15 months, 22 cycles, that I recall. We then had GOG-262 and other trials that suggested maybe treating until progression would make sense. In the BOOST trial, which is in Europe, it should be reading out soon, that’s 15 versus 30 months. To get to the relevant question Wendel asked, I actually think that ovary cancer is a lot like colorectal. I think that after [bevacizumab] works, we have the MITO MANGO study, which actually addressed that question directly. Patients who had already been treated with [bevacizumab], received [bevacizumab] again, and the hazard ratio there in favor of bevacizumab was about 0.57. So I will do it if I can get the insurance to reimburse it.

Maurie Markman, MD: At this point, are they not reimbursing it?

Michael Birrer, MD, PhD: Sometimes you’ll run into difficulties, not in Massachusetts, but in Alabama.

Maurie Markman, MD: It’s an important question because the data would suggest that it is not unreasonable to consider multiple lines of therapy.

Michael Birrer, MD, PhD: Correct.

Maurie Markman, MD: But it doesn’t help if no one is going to pay for it. OK, we’re going to come back to [bevacizumab] because 1 of the critical trials we’re going to talk about, actually several of the trials specifically looked at [bevacizumab] with the PARPs.

Turning our attention to the PARPs, I’m going to ask Wendel: what is the rationale for PARP inhibitors? And we’ve got to keep this short. And then what percentage of your own patients today, this is kind of like high level, are getting PARPs? And what do you think is going to happen in the future?

R. Wendel Naumann, MD: Obviously outside of the SOLO-1 indication, these are not FDA indicated at the current time, but I think they will be shortly. And I think this probably should be offered to everybody as maintenance therapy to keep pressure on the tumor. I think there are going to be questions about whether this is going to lead to a survival advantage. I certainly think that that’s going to be the case in patients with the homologous repair deficiency [HRD]. That is a group that is likely to benefit from them. And there are some data, at least the initial data in the PRIMA trial showed that using a PARP in HRD-negative patients may also not only provide a PFS but there was some hint that there might be an OS [overall survival] benefit. Although those data are not mature.

Maurie Markman, MD: Mike, anything to add to that? We’re going to talk a little bit more, but it’s such a rapidly evolving area and incredibly interesting. And the data are very impressive.

Michael Birrer, MD, PhD: I would agree completely with Wendel. I think if your patient, essentially any ovarian cancer patient who doesn’t see a PARP inhibitor, that’s a problem. The only question is sequence to me, when and where, and do you combine it with other drugs? We can talk about those trials. But this is a whole new class of drugs that has changed, fundamentally, our management of ovarian cancer patients.

R. Wendel Naumann, MD: And the toxicity versus benefit ratio that you get with those drugs.