Bradley J. Monk, MD: SOLO-1, I think is an unprecedented study of frontline treatment using olaparib. So, tell me more about SOLO-1 and what it is.
Ursula A. Matulonis, MD: SOLO-1 is a trial that has been based upon a lot of the results of other trials in the recurrent setting, making use of this drug called a PARP inhibitor, which exploits cancer’s underlying inability to repair DNA properly. It was a 2-to-1 randomization of olaparib versus placebo—a physical placebo study so it makes it even, and the results more exciting. Patients received olaparib and the dose is 300 mg twice daily using the tablet formation. Patients had to have advanced cancer with a BRCA-mutation associated with that cancer—a deleterious BRCA-mutation. Most of those patients had germline [mutations], but there are occasional somatic mutations that are found to be deleterious. And patients received chemotherapy, evaluation by a gynecologic surgeon, and that was another point I wanted to make—you talked about getting evaluated by surgeons.
Bradley J. Monk, MD: Thirty percent of patients in SOLO-1 had neoadjuvant chemotherapy.
Ursula A. Matulonis, MD: Right. But it’s important to get evaluated by a gynecological oncology surgeon.
Bradley J. Monk, MD: That’s right.
Ursula A. Matulonis, MD: Patients with a response to chemotherapy, and are using the olaparib versus placebo as maintenance therapy.
Bradley J. Monk, MD: So importantly, this was for BRCA-mutated patients, either somatic or germline. You had to get that tested really to make the decision not to use bevacizumab, to your point.
Ursula A. Matulonis, MD: Yes.
Bradley J. Monk, MD: The hazard ratio is 0.30. It’s interesting that the hazard ratio in SOLO-1—meaning first-line, and SOLO-2, meaning second-line—was the same, 0.30. Tell us about the differences in the medians and maybe, although the hazard ratios are the same, maybe the medians are so disparate that it’s better to use a PARP inhibitor frontline rather than second-line.
Michael J. Birrer, MD, PhD: Well, it’s certainly remarkable. So, if you sit back and look at SOLO-1, I don’t think there’s anybody in the field, anybody at this meeting, that [is] terribly shocked by the SOLO-1 results. We all anticipated it was going to be positive. Because it is remarkable how the hazard ratios are so impressive and relatively uniform from SOLO-1, SOLO-2, NOVA, ARIEL3. So that’s one take-home message. You could really be comfortable, at least in the BRCA patient population. You just have a tremendous activity for this drug. I think you bring up a very interesting point. What SOLO-1 will do is bring PARP [inhibitors] now into the first-line. There’s just no issue about that. And I think it’ll do that partly because of just the impact in the hazard ratio. But you’re implying that you may have to get a bigger bang for your buck earlier on.
Bradley J. Monk, MD: Right.
Michael J. Birrer, MD, PhD: I mean I have to add vis-a-vis Ursula’s comment that the data for bevacizumab may be the opposite, where if you look at the ARIEL3 study, you get a better hazard ratio than GOG-0218; that’s a separate issue.
Bradley J. Monk, MD: Yes. So think about it, if the control arm in SOLO-2, second-line, is about 5 months, you do a hazard ratio of 0.3, so that’s really good; 5 to 19 months. That’s really good. But if the control arm is 14 months then in frontline, and you get a hazard ratio of 0.3, now all of a sudden you’re 50 months. So, 14 versus 50, 36 months; versus 5 versus 19, basically 14-15 months. So that’s 36 months of PFS [progression-free survival]; unprecedented.
Ursula A. Matulonis, MD: That is impressive.
Bradley J. Monk, MD: Is it practice changing?
Ursula A. Matulonis, MD: I do think it’s practice changing. I think based upon really the enormity of the results, I do think it’s practice changing.
Bradley J. Monk, MD: You’re right; 36 months of PFS.
Ursula A. Matulonis, MD: And I think, and the other considerations to think about are, a) it’s for 2 years, so 2 years of duration. The question is going to be, and again that’s just going to be nagging me 2 years from now, what are patients going to do, continue on, yes or no? I don’t know about that.
Bradley J. Monk, MD: But the clinical benefit persisted even when they [stopped] the olaparib.
Ursula A. Matulonis, MD: I know, exactly, that’s correct.
Michael J. Birrer, MD, PhD: Right.
Ursula A. Matulonis, MD: And the other issue is, and you just don’t know this moving forward, but there are some women who even with advanced cancer who have underlying BRCA-mutations associated with their cancer, they will be cured.
Michael J. Birrer, MD, PhD: Well, it’s certainly possible.
Ursula A. Matulonis, MD: They can be cured without the use of olaparib, just with the chemotherapy.
Ursula A. Matulonis, MD: So, you may be treating, but that’s where I think you’ve got that sort of stopgap measure of having the 2 years in there.
Bradley J. Monk, MD: But do you think we’re curing more with olaparib?
Ursula A. Matulonis, MD: Well, I don’t know that; we’re going to see.
Michael J. Birrer, MD, PhD: Could be, I don’t know. As you know, in Study 19, which we’ll get to later, there are still patients.
Bradley J. Monk, MD: Eleven percent, and that’s second-line; 11% now at a follow-up of 7 years are still disease-free. So, I like these landmark analyses that kind of put it in perspective. So, you get 2 years of olaparib, and then you keep watching, and so at 3 years, a year later, 60% on the olaparib are progression-free, versus 27% on the placebo. So, you’ve doubled the amount of patients that are progression-free, a year after they stopped it. It’s not like you stopped it and the cancer came back, right?
Ursula A. Matulonis, MD: It’s really amazing, incredible. They’re amazing results.
Bradley J. Monk, MD: They’re amazing results. Interesting. So, the toxicity, there was only [an] 11% discontinuation rate. The [adverse] effect profile was like SOLO-2 and olaparib—generally marrow suppression, ischemia, and gastrointestinal toxicity; and only 11% discontinuation rate. But there were three MDSs [myelodysplastic syndromes]. And all 3 of those patients died and all 3 of those patients had been on olaparib at least for a year. Does that concern you?
Ursula A. Matulonis, MD: As you both know, one of the initial impediments to getting FDA approval for a PARP inhibitor back in the ODAC [Oncologic Drugs Advisory Committee] meeting in 2014, was this underlying potential risk for AML [acute myeloid leukemia] or MDS. And I think what’s been interesting is that in the subsequent 3 randomized phase III studies for maintenance and recurrence—you mentioned SOLO-2, the NOVA study, as well as ARIEL3, and you look at PARP versus placebo—there really wasn’t much difference in terms of patients with MDS or AML on one. It was pretty equal between both.
Bradley J. Monk, MD: Yes, 0/3 versus 0.
Ursula A. Matulonis, MD: But now you’ve got the upfront trial, and so it’s 3 patients; it’s never good, but these patients all have underlying BRCA mutations. So they are probably going to be at higher risk just by the fact that they have that BRCA mutation, of having an underlying secondary leukemia. They’ve all had chemotherapy.
Bradley J. Monk, MD: But it was 0 in the placebo arm.
Ursula A. Matulonis, MD: No, I know, I know. So, it will always have to be a discussion with the patients, and it would be interesting to understand in those 3 patients what their counts were during [chemotherapy]; was this something that was predicted during the chemotherapy?
Transcript Edited for Clarity