The experimental medicine buparlisib helps treat metastatic hormone-receptor-positive, HER2-negative breast cancer that has been treated with an aromatase inhibitor, but grew after being treated with Afinitor (chemical name: everolimus) and Aromasin (chemical name: exemestane). In this podcast from the 2016 San Antonio Breast Cancer Symposium, Ruth O'Regan, M.D., professor of hematology and oncology at the University of Wisconsin and one of the researchers who did the phase III BELLE-3 trial, discusses the results of the study and explains why the mechanics of how buparlisib work are promising, even if buparlisib probably isn't the right medicine to treat breast cancer.
Listen to the podcast to hear Dr. O'Regan talk about:
- how buparlisib works
- why inhibiting the PI3 kinase pathway may help treat metastatic, hormone-receptor-positive disease that has stopped responding to hormonal therapy
- buparlisib's unacceptable side effects
- how she plans to talk to her patients about buparlisib
Running time: 5:04
Show Full Transcript
Jamie DePolo: This podcast is made possible by the generous support of Lilly Oncology.
Welcome to the Breastcancer.org podcast. I’m Jamie DePolo, senior editor at Breastcancer.org. We’re down here at the 2016 San Antonio Breast Cancer Symposium. My guest is Dr. Ruth O’Regan. She’s professor of hematology and oncology at the University of Wisconsin, and she’s presented results from the phase III BELLE-3 trial, which looked at buparlisib and Faslodex [chemical name: fulvestrant] in postmenopausal women who’d been diagnosed with hormone-receptor-positive, HER2-negative, metastatic disease who’d been treated with an aromatase inhibitor previously and had the cancer grow on or after treatment with Afinitor [chemical name: everolimus].
Can you tell me what buparlisib is and how it works?
Dr. Ruth O’Regan: So, buparlisib is a pan-PI3-kinase inhibitor. So, it basically blocks the PI3-kinase pathway. And we now have data from a couple of randomized trials looking at this particular agent and its ability to inhibit PI3-kinase pathway in estrogen-receptor-positive, metastatic breast cancer.
Jamie DePolo: And so why is that pathway important? What does it do in the body?
Dr. Ruth O’Regan: So, the PI3-kinase pathway is very important. It’s really in all cells in the body. Its importance in estrogen-receptor-positive breast cancer is that, as you develop resistance to endocrine therapy, this pathway becomes activated. And we’ve known this for a long time, and just to back up a little bit: So PI3-kinase also feeds into mTOR, and we know that the mTOR inhibitor everolimus appears to be able to re-sensitize estrogen-receptor-positive, metastatic cells to endocrine therapy. So, we think that this pathway starts driving these cells when they’re endocrine resistant, and that, if you block it, therefore, you can kind of make the endocrine therapy work again.
Jamie DePolo: So the idea behind this study, my understanding is that you’d want to use something like buparlisib instead of chemo with the idea that the buparlisib would be less toxic and potentially more effective?
Dr. Ruth O’Regan: Yeah, absolutely, because, you know, we always want to know what’s driving the cell, and if we know it’s the PI3-kinase pathway, then blocking it with buparlisib makes sense more than giving chemotherapy that’s not really a targeted treatment. And the problem with chemotherapy, of course, is that it has a lot of off-target toxic effects. So, the hope would be that this drug would be very effective at targeting cancer cells, particularly when they have mutations in this pathway and not targeting normal cells, basically. That was the hope, essentially. The problem is that the BELLE-3 study, which randomized patients who’d had both endocrine therapy and an mTOR inhibitor to be part of Simplus Fulvestrant versus Fulvestrant alone, did show some degree of efficacy in that the disease control was improved. The progression-free survival was improved by a couple of months. But the problem is it was quite toxic, because the most serious side effect is it gets into the brain, causes anxiety and depression. And there were some suicide attempts in the buparlisib arm of the study. Along with that, it does cause elevation of liver function enzymes, which is another concern with this drug. So, even though it shows us that there is a signal there and that by inhibiting this pathway, it does appear to be beneficial for patients to some degree, the toxicity’s a problem with this drug.
Jamie DePolo: So even if patients were screened for any psychiatric problems or potential depression, anything like that, the drug sounds like it’s still not ideal. Inhibiting that pathway seems like a good thing, but perhaps this just isn’t the right drug to do that.
Dr. Ruth O’Regan: Yeah, absolutely correct. So, actually, anybody on any buparlisib study is screened before they go on for depression, anxiety, both from their medical records, but also there’s a questionnaire given to them. So these were patients who didn't have underlying issues, and yet you still had this, you know, fairly significant incidence of anxiety and depression. So, yeah, absolutely. So I think this drug has efficacy, but the toxicity is probably going to preclude its further development. We don’t know that yet, but there are other PI3-kinase inhibitors in development.
Jamie DePolo: So, how are you going to talk to your patients about this if they’ve got metastatic disease, it’s hormone-receptor-positive, it’s grown after it’s been treated with Afinitor. Are there other options besides chemotherapy, or — what are you going to say to your patients, basically?
Dr. Ruth O’Regan: Yeah, so, at this point, in general for patients coming off everolimus, we generally would recommend chemotherapy because we know that the cancers are not going to respond to endocrine therapy again in most cases. So I think I would tell them that this pathway is important. This trial proves that, but there are other agents that may be less toxic coming down the pipeline. So, there is an alpha-specific PI3-kinase inhibitor that’s actually in a clinical trial right now, and that may end up being, hopefully, more effective, but hopefully with a better toxicity profile as well.