PracticeUpdate Oncology February 2019

CONFERENCE COVERAGE 30

Lasofoxifene vs Fulvestrant for HR-Positive Breast Cancer Interviewwith Lee S. Schwartzberg MD, FACP by Farzanna S. Haffizulla MD, FACP, FAMWA

primary breast cancers. So these are something, per- haps a small clone or one that develops over time, that emerge after therapy and in gender resistance. Dr. Haffizulla: Can you share with us a little bit about the mechanism of lasofoxifene and how it’s been used in the past? Dr. Schwartzberg : This is a drug that’s a SERM. Laso- foxifene is a SERM. A selective estrogen receptor modulator, so it’s in the same general class as tamox- ifen. It’s been used in osteoporosis, and it’s been tested in many thousands of patients. What led to its use in breast cancer is, when it was tested in osteoporosis, the number of breast cancers that developed was dramatically less, and so it showed that it had SERM-like properties, and it’s really a very potent SERM. What’s interesting about it, and the reason we’re doing this trial is that, as opposed to other drugs, it actually has activity across these mutations in ESR1, so it works to block the estrogen receptor, even if you have an ESR1 mutation, at least pre-clinically. So the study that we’re doing is a ran- domized phase II trial where we’re looking at this versus fulvestrant. Fulvestrant is a selective estrogen receptor down-regulator, so a drug that’s already approved as an anti-estrogen endocrine therapy, and we’re testing this drug to see how well it does. Dr. Haffizulla: What is a target accrual? Dr. Schwartzberg: It’s a small trial, so it’s under 100 patients, but it’s really to show proof of principle… the goal is to actually show a 50% improvement in progression-free survival, even in a small trial. Dr. Haffizulla: Any prior data on this drug, on lasofoxifene? Dr. Schwartzberg: Yeah. Again, mostly phase I, but a lot of data, and the safety is very well known in the osteoporosis setting. Dr. Haffizulla: So, that sets a nice stage for this par- ticular trial? Dr. Schwartzberg: Right. Dr. Haffizulla: Excellent. How about your expecta- tions to use lasofoxifene in the clinical setting? Dr. Schwartzberg: Well, we’ll be participating in the clinical trial, and we’re hoping that this study will accrue pretty quickly because we’re in need of better SERMs. We had tamoxifen for 40 years, but two-thirds of patients don’t benefit from tamoxifen. And there’s a lot of opportunity to develop better SERMs, including those that work in the ESR muta- tion, since they’re more common than we would have known a few years ago. Go to www.practiceupdate.com/c/77342 to watch this interview with Dr. Schwartzberg.

Dr. Haffizulla: I want to talk a little bit about lasofox- ifene versus fulvestrant today. We know that you’re part of an ongoing trial of these two drugs for hor- mone receptor-positive breast cancer in patients with an ESR1 mutation. Can you tell us a little bit about how common ESR1 mutations are in breast cancer patients? Dr. Schwartzberg: Sure. This is an emerging field in breast cancer. We’re seeing now that under the selective pressure of taking aromatase inhibitors in the adjuvant setting, which most women do, that one of the way that breast cancer cells develop resist- ance to their endocrine therapy is to have a mutation in the ESR1, which is the estrogen receptor gene. And these mutations are typically in the ligand-bind- ing site. And so when they occur, they turn on the estrogen receptor, basically and so you don’t, they become estrogen-independent and estrogen block- ing independent. So, in this case in particular, AIs don’t work anymore. ESR1 mutations are roughly being found in about a third of patients after expo- sure, typically in the adjuvant setting, to AIs and we don’t see them, interestingly, except very rarely in

© SABCS/Scott Morgan 2018 " We had tamoxifen for 40 years, but two-thirds of patients don’t benefit from tamoxifen. And there’s a lot of opportunity to develop better SERMs, including those that work in the ESRmutation… "

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