PARP Inhibitors for Ovarian Cancer: Use of Olaparib

Transcript:Bradley J. Monk, MD: Let’s move on to PARP inhibitors. It’s so exciting that we have new targeted therapies. We’re going to talk about 3 of them, and it’s a competitive landscape. It’s exciting for us as doctors because we have clinical trials that we can talk about and compare. We have plenty of time to do this. Katie, why don’t you tell us a little bit about the current approval of the only FDA-approved PARP inhibitor? Go ahead.

Kathleen N. Moore, MD: The current FDA-approved drug is olaparib, or Lynparza is the commercial name. It is approved for patients who have a germline BRCA1 or BRCA2 mutation, so it does not include a somatic mutation in the label. It is actually based on a phase II basket trial plus some additional patients that had received treatment-level doses of olaparib and had a germline PRC mutation—because they’re all folded into this application—that got them FDA approval. And they looked specifically at patients who had received at least 3 lines of chemotherapy. And so, it included mostly patients who would be deemed “platinum-resistant” in the old terminology. “Platinum inappropriate” is what they called it. So, about 20% of that group was platinum-sensitive. But they showed in fourth-line and beyond that the response rate was 33% and the median progression-free survival was about 7.1 months with a confidence interval around it, which, in this classification of high unmet need indication, is actually a pretty nice outcome. It got accelerated approval, and that’s how it is currently labeled in the United States: fourth-line and beyond, germline BRCA1 and BRCA2. And then, the confirmatory trial is SOLO-2, which is a maintenance trial of a different formulation of olaparib—tablets instead of capsules—in patients with platinum-sensitive recurrent disease who had a complete or partial response to their platinum, and then they’re randomized to olaparib or to placebo. That study has been reported to be positive in a press release, but without any accompanying hazard ratio as of yet. So, we’re waiting for the actual data.

Bradley J. Monk, MD: That sounds great. So, fourth-line and beyond, expected deleterious germline mutation, 34% response rate, 7.9% duration, but there’s toxicity. Tom, tell us about the challenges. She mentioned capsules, tablets. Tell us about the toxicity of olaparib.

Thomas Herzog, MD: Certainly, some class effects that you see with PARP inhibition, nothing that was overwhelming. The biggest thing is really fatigue and anemia. You had about 20% grade 3/4 anemia, about 6% in terms of fatigue, and then there were GI issues, but how much of that is due to the pill burden?

Bradley J. Monk, MD: How many pills?

Thomas Herzog, MD: It’s 16, so it’s a lot.

Angeles Alvarez Secord, MD: But the new formulation will drop that requirement down.

Thomas Herzog, MD: Exactly, and so I think you have to separate those out. And then, you saw the usual increased creatinine due to OCT2 (organic cation transporter 2) interference, which is a transporter—a lot of things that you normally see. There’s the concern of myelodysplasia with these compounds, but nothing that was really, in my opinion, very much above what you see with the baseline disease of ovarian cancer with lots of pretreatment.

Bradley J. Monk, MD: So, the approval is in germline. We started our discussion with HRD and somatic. Are you guys able to get it reimbursed and use it in somatic or germline?

Angeles Alvarez Secord, MD: I am so fortunate in that we have all these clinical trials with PARP inhibitors. We haven’t had to push that, so the patients that we’ve gotten olaparib for have been the patients for whom the indication is present.

Bradley J. Monk, MD: How about you, Rob?

Robert L. Coleman, MD: I would say that given somatic testing, since we do so much of it—mostly, as with Katie’s situation, too, for clinical trials—somatic assessment, looking across not just BRCA but across the board, is not hard, and we do it frequently.

Bradley J. Monk, MD: And how there’s a commercially available test.

Robert L. Coleman, MD: We just sent our first patient yesterday on the commercially available test.

Bradley J. Monk, MD: I was part of the beta testing. And I saw a patient yesterday who’s on olaparib who’s HRD-positive, and she thinks I’m the smartest doctor ever. But, it’s great.

Robert L. Coleman, MD: Yes. In the ARIEL2 program that we’ve seen this week, we had a number of patients on that study as well who were BRCA-negative, both somatic and germline, who were positive for HRD. But before we move on to that, I wanted to put the context back on olaparib’s approval because it was a little unusual. They went and they compared it to historical data on all-comers who received chemotherapy in that same line and beyond.

Bradley J. Monk, MD: In a molecularly restricted population?

Robert L. Coleman, MD: Yes. Not to diminish the efficacy that was seen there, but it should be noteworthy that the response rate in this molecularly identified patient population, despite that fact that in this line of therapy, there’s about 4 standard deviations above what the expectation is for chemotherapy. So, it’s not trivial. It’s good that they were able to do this, but it’s in a select patient population.

Thomas Herzog, MD: Rob, it shows a shifting in the regulatory perspective, right?

Robert L. Coleman, MD: Yes, that’s the key.

Thomas Herzog, MD: The fact that we have 193 ovarian patients in this umbrella trial, essentially, and the fact that you’re able to really do this off of overall response rate is phenomenal. Nobody would have predicted that several years ago; although the FDA says they were welcoming it, but the word on the street was not.

Bradley J. Monk, MD: Right. For platinum-sensitive relapse, BRCA-positive patients, SOLO-2 has been announced to be positive. It’s likely that this will be one of the next approvals, and it’s going to be a different formulation, not all these silly capsules. And maybe the toxicity will be different. It should be because it’s a different dose, it’s a different formulation. But that’s going to be one of the exciting things that we’re going to be able to continue to talk about, what I call “the new olaparib.”

Angeles Alvarez Secord, MD: Right. Well, we’re focusing on the United States and FDA approval, but it has been approved in Europe.

Thomas Herzog, MD: Yes, with a different indication.

Angeles Alvarez Secord, MD: For patients who have platinum-sensitive disease in maintenance therapy.

Thomas Herzog, MD: Yes, off of Study 19.

Angeles Alvarez Secord, MD: They have both approvals in Europe.

Thomas Herzog, MD: Right. That shows the difference, and we already said that bevacizumab is approved frontline in Europe when it’s not approved frontline here. So, there are some differences. In addition to SOLO-2, which is platinum-sensitive relapse, BRCA-positive. There is SOLO-1, which is the same frontline maintenance. Tell us, anybody, about SOLO-3 and then we’ll move on to our next drug.

Angeles Alvarez Secord, MD: Well, SOLO-3 is in the recurrent setting comparing olaparib versus the standard-of-care, physician-choice chemotherapy.

Bradley J. Monk, MD: Because that’s the question. That’s what you said, Rob, is that we got this off of a single-agent response rate. How does that compare to chemotherapy? We need to show it.

Robert L. Coleman, MD: Right. But in my opinion though, what if that trial shows equipoise? To me, that’s huge. That’s still a benefit. Angeles Alvarez Secord, MD: Yes.

Bradley J. Monk, MD: How can it be a benefit if it’s the same? That sounds like IP.

Robert L. Coleman, MD: Because of what we just talked about.

Kathleen N. Moore, MD: As long as it has quality of life or age-reported outcome improvement with this versus chemotherapy.

Angeles Alvarez Secord, MD: Yes, toxicity profile inconvenience.

Robert L. Coleman, MD: So, all of our data so far, when we look at these trials that have chemotherapy in symptomatic patients, I think that reducing the symptom burden is going to be very, very important and may even be more important than activity. But if we have another drug that falls in line with something we can offer those patients, I can tell you from the patients I’ve had on study, they don’t want to go back to chemotherapy.

Bradley J. Monk, MD: Yes, right. It is chemotherapy, but I get it, it’s not the same sort of chemotherapy as we think.

Robert L. Coleman, MD: Cytotoxic.

Bradley J. Monk, MD: A PARP inhibitor is cytotoxic, too. So, that’s olaparib. It’s currently FDA-approved under the accelerated approval mechanism. The confirmatory trial, SOLO-2, is press release-positive, and that full approval is likely to be coming.

Transcript Edited for Clarity