The Role of PARP Inhibitors in Ovarian Cancer - Episode 12

Platinum-Sensitive vs Platinum-Resistant Recurrence

Maurie Markman, MD, leads a discussion on defining platinum-sensitive versus platinum-resistant recurrent disease, and the role of immunotherapy in managing ovarian cancer.

Maurie Markman, MD: Now we are going to turn to the question of use of PARPs [poly ADP ribose polymerase inhibitors] but in the recurrent setting. Before we do that, it’s important to try to tackle once again this definition of platinum-sensitive versus platinum-resistant recurrence. Mike, I’ll turn that over to you.

Michael Birrer, MD, PhD: I cannot believe you’re going to ask me that question. You’re the father of platinum sensitivity.

Maurie Markman, MD: It was easy in those days.

Michael Birrer, MD, PhD: You did the hard work at the right time to pretty much define what we’ve used in the field for years, which is a 6-month cutoff for recurrence, defining patients earlier than that as resistant, and patients after that as sensitive. What’s changed the equation is the fact that we now have maintenance therapy. So if a patient is on bevacizumab or a PARP inhibitor, and now recurs at 9 months, is that equivalent to the old definition of patients who are platinum sensitive, or has the biology changed?

And my suspicion is that if it’s BEV [bevacizumab], it probably doesn’t make a difference because it works in a different mechanism.

But PARP I’m not so sure of because it’s affecting DNA repair. But we don’t know the answer to that. And then add on to that, now a lot of our patients have 7, 8, 9 regimens. So if they’re out at 8 regimens, and they recur at 8 months, is that still the platinum-sensitive patient we used to talk about? These things are complicated. The truth is I think practically in the clinic, a lot of us are still using the 6-month cutoff. So Maurie, you live on. And in clinical trials, most of the time it’s defined that way.

Wendel Naumann, MD: But, Mike, to your point, I think it’s a spectrum. I don’t think that we should automatically rule out platinum or platinum combinations in patients who might recur right at 6 months. And it’s a somewhat arbitrary cutoff, but it does again help with our counseling of patients in terms of the toxicity of our regimen versus the benefit.

Maurie Markman, MD: Since this has been such an informative panel, I thought I would just throw out to my colleagues for a couple of comments on the potential role and the future of immunotherapy [I/O], checkpoint inhibitors, in the management of ovarian cancer. Trials are ongoing. There have been some negatives. Any thoughts? And then we’ll talk about recurrent disease.

Michael Birrer, MD, PhD: So far, single agents have been disappointing. Response rates have been between 9% and 12% or 13%. That clearly has not stopped the field though because the last time I summarized this on a slide, I couldn’t fit all the trials on the slide. It was over 45. I think the most interesting thing that I’ve seen is this combination of I/O with PARPs, like the TOPACIO study. The idea that a tumor that has a DNA repair problem might have more neoantigens is very interesting. I don’t know if I’d buy that, but there’s certainly pretty good data that these tumors activate the STING [stimulator of interferon genes] pathway. The STING pathway produces interferon, and that can activate T-cells, so combining these drugs I think has a rationale.

Wendel Naumann, MD: And even in the platinum-resistant patients in TOPACIO, you had about a 25% response rate across the board, which is impressive in that patient population.

Michael Birrer, MD, PhD: I think there were even a few refractory in there.

Wendel Naumann, MD: But then we had the failure of the 2 JAVELIN trials. We’ll have IMagyn50 out with ATEZO [atezolizumab] combination. We have ATHENA coming out probably in about 4 years, and we have 2 trials, the first in the DUO-O trial, that are going to throw everything at the tumor. So we’ll have a lot of data, we just don’t have it now. So I think it’s to be determined.

Michael Birrer, MD, PhD: The interesting thing is I think I/O demonstrates how much oncology has evolved. In our days, there was actually a lot of hemming and hawing about what’s the science behind whatever, so on and so forth. But the JAVELIN trials were designed very quickly. These were $100 million experiments, basically. I think that’s bad news for drug development. I think it’s, in some ways, good for patients though because the field is moving so fast, we get answers.


  • The Specialty Pharmacy Program
  • New PARP Inhibitor: The VELIA Regimen