Transcript:Adam M. Brufsky, MD: All right. So now that we’ve talked about early disease for about half an hour, we can now switch to really the topic of metastatic disease. And I think the first thing to talk about is a drug that we all use a lot of. But I think, hopefully, we’re gaining a little bit more knowledge about how to use it properly, and that’s fulvestrant. And so, Sara, you can kind of fill us in a little bit about some of the latest stuff on fulvestrant?

Sara A. Hurvitz, MD: This is a drug that in the last five, six years we’ve begun to use more and more, and that’s because data is now emerging that’s telling us the proper dose that we should probably be using. The early studies looking at fulvestrant were done in the aromatase inhibitor refractory setting, head-to-head, with a different aromatase inhibitor and then up front compared to an aromatase inhibitor. But always dosed at 250 mg, one shot in the gluteus, monthly. So it was taking three, four months for patients to achieve like levels that were effective, of the drug in their blood. And during that time, the patients are progressing and having to switch therapy.

So more recently, the CONFIRM study was done looking at 500 mg monthly, with a loading dose given on the first month at day 14. And in that regimen, compared to the 250 mg, there was a significant improvement in outcomes for patients in the metastatic setting. This more recent study, the FIRST trial came out. Robertson presented the data that compared the 500-mg dose of fulvestrant with the loading regimen compared to anastrozole in the first-line, metastatic, ER-positive, postmenopausal breast cancer setting. And in that study, the FIRST data showed that the time to progression was significantly improved with fulvestrant compared to front-line aromatase inhibitor and that was kind of interesting. It was the first time fulvestrant really beat an aromatase inhibitor. And then more recently, last year at San Antonio in 2014, the overall survival was shown to be improved with fulvestrant.

So this has given us another option in the first-line setting. The thing is, is it came right sort of on the heels of the PALOMA data, the palbociclib data, that also showed benefit in terms of progression-free survival in a phase II study, just like the FIRST study, phase II, in the frontline setting in combination with letrozole. And because that combination was approved in February of 2015, we now have two regimens—and we don’t have any way of comparing their relative efficacy—both based on phase II data, not on phase III. So in terms of phase III, first-line fulvestrant data, we’re waiting for the phase III FALCON study to report out, and hopefully that’ll inform kind of better what the time-to-progression and overall survival will be with this drug. But I don’t know whether it’s going to replace palbociclib in this setting.

Hope S. Rugo, MD: You know, it’s interesting, because in the FIRST Trial, the primary endpoint was clinical benefit rate, which wasn’t different.

Sara A. Hurvitz, MD: Right, exactly.

Hope S. Rugo, MD: And then they said, ‘Well, we’ll PFS our secondary endpoints.’ So then they showed this benefit in PFS. They’re like, ‘Oh, maybe we should look for overall survival.’ And they had to go back and consent everybody and find them, so they lost some people. Right? And so they looked at death records, but there were some people who really were lost in both arms. Relatively equal number, but you just don’t know when it was your tertiary added-on endpoint whether it’s really true.

So what they’ve done with FALCON is take a group of patients who were endocrine therapy—naïve, never had any endocrine therapy early stage or whatever. So they will all be de novo metastatic patients. So it’s going to be fascinating because it’s hard to know. I think it’s given me a better appreciation for fulvestrant, and I certainly will use it a lot and in combination with targeted therapies. But I don’t know that even those results will change everything. Because most of the people we see at least have had endocrine therapy before.

Adam M. Brufsky, MD: And have also had aromatase inhibitors in the adjuvant setting.

Sara A. Hurvitz, MD: Right, right.

Joyce A. O’Shaughnessy, MD: I think that’s going to be the interesting thing if FALCON is positive. Being in a population, of course, we do see a fair amount of de novo metastatic.

Adam M. Brufsky, MD: How big is FALCON?

Hope S. Rugo, MD: 600 patients.

Adam M. Brufsky, MD: 600. So it’s not huge.

Joyce A. O’Shaughnessy, MD: Yeah. But if fulvestrant is the winner, does that mean it’ll replace the PALOMA1 population? Instead of using letrozole we’ll use fulvestrant? It’ll be tempting. Because you’re thinking the best endocrine agent plus the CDK4/6 inhibitor.

Adam M. Brufsky, MD: But that’s in the untreated. I mean, the average person who walks in the door likely has been on an aromatase inhibitor and has progressed, right? Has high-risk disease, you put her on aromatase inhibitor. It’s very rare to have a de novo patient come in the door, right?

Hope S. Rugo, MD: Well, it seems to be about 50% of our trial populations now; 50% of PALOMA1 and 50% in several other trials, including the SWOG trial, that looked at combination settings.

Joyce A. O’Shaughnessy, MD: Yeah, we’ve seen the same thing in our trials, too.

Adam M. Brufsky, MD: You’re US because you’re US Oncology.

Joyce A. O’Shaughnessy, MD: Yeah.

Adam M. Brufsky, MD: So you’re North America. But I would think that was because of Europe. But really?

Joyce A. O’Shaughnessy, MD: No, no. PALOMA1 wasn’t a trial that was being done ex-US, and also.

Adam M. Brufsky, MD: Oh, PALOMA1. I’m talking about PALOMA2.

Hope S. Rugo, MD: The other trials, the SWOG trial, which was all US where 50% of the patients had de novo.

Adam M. Brufsky, MD: Disease.

Hope S. Rugo, MD: 48% had de novo metastatic disease.

Sara A. Hurvitz, MD: And I think the first-line trials, it’s selection bias. So it may not be what we’re seeing outside of trials. Because the first-line trials require patients haven’t had an AI in more than 12 months. And so you’re kind of selecting out those patients who recurred in their first 5 years.

Christy A. Russell, MD: See, the other thing that always bothered me, though, is the comparative trial of fulvestrant with 250 versus 500 mg. Even though it met its statistical endpoint, the difference in those two groups was one month.

Adam M. Brufsky, MD: Right.

Sara A. Hurvitz, MD: It was quite small.

Christy A. Russell, MD: Just to see the FIRST trial to be so strikingly positive just worries me and just makes me step back and say, ‘You know, it’s still a lot easier to use an oral endocrine therapy here than committing it to fulvestrant.'

Adam M. Brufsky, MD: But if we’re going to use fulvestrant, I think most people would say we should use 500. No one has said to use 250.

Christy A. Russell, MD: I agree.

Adam M. Brufsky, MD: That’s what I’ve gotten out of all of these trials, is the dose.

Hope S. Rugo, MD: The other thing is that if you sometimes have these patients in the adjuvant setting, they really have high-risk disease and they will not take oral therapy. You know they have too much problems with the AIs, they won’t take tamoxifen for whatever reason. And I have to say that the biggest impact of the FIRST trial for me is that I used fulvestrant in those patients.

Adam M. Brufsky, MD: I think that’s great. Now we have to say it’s off-label.

Hope S. Rugo, MD: It is so off-label.

Joyce A. O’Shaughnessy, MD: But you’ve had people accept it, Hope.

Hope S. Rugo, MD: Absolutely.

Joyce A. O’Shaughnessy, MD: Because I’ve never done that.

Hope S. Rugo, MD: I could get a shot.

Adam M. Brufsky, MD: I could get a shot in a bottle, oh yeah. They’re doing it with Lupron. Think about it; you do Lupron with this.

Joyce A. O’Shaughnessy, MD: Oh yeah, definitely.

Hope S. Rugo, MD: I don’t know how long to give it, but I give it.

Joyce A. O’Shaughnessy, MD: That’s great. That’s good to know.

Sara A. Hurvitz, MD: But the lack of arthralgias, it’s so much better tolerated.

Adam M. Brufsky, MD: It is.

Sara A. Hurvitz, MD: If they can handle the injection in the clinic.

Hope S. Rugo, MD: Even the tamoxifen, actually.

Adam M. Brufsky, MD: That is really stretching the data.

Hope S. Rugo, MD: Well, it’s a first-line untreated population, same as FIRST. And you figure if the drug is going to be better in this trial, it’s probably as good, so that’s where I come to it.

Adam M. Brufsky, MD: No, I agree with you.

Hope S. Rugo, MD: And it’s so much better to get something than nothing.

Joyce A. O’Shaughnessy, MD: Oh, absolutely.

Transcript Edited for Clarity