Recent Updates for the Advanced HR+ Breast Cancer Setting

Video

Charles E. Geyer, MD and Ian E. Krop, MD, PhD touch on recent advances in the metastatic HR+ breast cancer setting and evaluate PROTAC estrogen receptor (ER) degraders compared with other ER modulators.

Dr. Ian Krop: We did see some, a small data set from another type of estrogen receptor degrader. This was this PROTAC type of drug ARB 471, which is a very interesting mechanism of action targeting, is a very sophisticated way to target a protein of interest to the proteasome, which I just think it's incredibly, it’s just a neat idea and the fact that we can, that technology has gotten to the point where we can, where we can design drugs to do things like this, it's just amazing to me. This is a phase two study that they presented in a post CDK population. They saw clinical benefit rates around forty percent. It didn’t seem like it had a reasonable adverse event profile like we saw with Capivasertib with the other, the standard, I don't know if you call them standard SERDs, but the other, the SERDs we've already known about. It does look like there was a little bit more activity in the ERS1 mutants as well. So, I don't, you know, I think this was just encouraging data that there may be more. Another class of estrogens, after degrader in the pipeline. And of course, you know we'll see more data from this drug as with time goes on. But certainly, the more options, the better.

Dr. Charles Geyer: I think the PROTAC technology is going to really become very important in oncology because it's, from what I understand, you can pretty much target any overexpressed protein you want with the technology in theory. Of course, you have to do it and then we have to see it work. But, the UNTARGETABLE tumors may end. And so, I think a lot of it developed. They just decided to go to a space where there was an established protein that was there. So, this is why they're in the breast cancer space. But it is a neat technology.

Dr. Ian Krop: They're doing the same thing with androgen receptors and prostate cancer. So, switching gears, the other target therapy and the other positive disease that we saw data for. This was definitive phase three data, was from this Capitello 291 study, which is looking at this AKT inhibitor, Capivasertib. So again, same pathway is Allosteric and Everolimus, the PIT kinase AKT pathway, this one directly targeting AKT. We did have some AKT inhibitors in clinical development some years ago, had problems with toxicity and not enough efficacy there to move forward. This one looks a little different. This was a study that looked at patients, who most of whom had progressed on CDK. I think about a half had prior chemotherapy. So, similar populations to some of the other drugs we've been talking about. Varenicline faced retrial. Fulvestrant SERD, Fulvestrant Placebo or Fulvestrant Capivasertib and a clearly positive trial hazard ratio.6, about a doubling of progression free survival. I think it was 3.6 versus 7.2 months. So, I think three plus month difference which, in my book, is clinically meaningful. My general sense was that this was a little bit better, looking at the numbers was a little bit better tolerated than what we have been seeing with the PF kinase inhibitors. You don't see as much hyperglycemia with this. You did see diarrhea which is, I think about 9 or 10% Grade 3. Rash didn't seem quite as significant as with the PF kinase inhibitors. What would, I mean, again, I haven't used this in the clinic. I don't know how this compares to Alpelisib in practice. But clearly a positive trial in that second line population, post CDK that we've talked about, is an unmet need.

Dr. Charles Geyer: I agree. And just the number of patients discontinuing a drug to at least a total of thirteen percent, which is kind of in line. I mean, this is a space where you do immediately compare the toxicity tables to the opalescent tables, and that is a challenging agent to use. And it is interesting that the study is sort of, targeting patients who have PI3 kinase a AKT alterations. But most of the alterations, when they did the foundation 1 testing, were PI3 kinase mutations. It was a subset that were AKT mutations. So clearly, with the efficacy of the drug, it does work for patients who have the PI3 kinase mutations as well as the AKT changes. And it may be that the hazard ratio was a bit more pronounced. They looked at AKT altered pathway and its hazard ratio there was.5. If you looked at the group without alterations, it was about.8. So, it wasn't that there was no activity in the non-AKT altered, but it clearly looks like you really do want to think about the drug in that pathway. The other thing I think that was important with this, from what I, is that if their exclusion criteria for diabetes were less stringent. Basically, as long as the hemoglobin A1C was less than 8 and patients weren't requiring insulin, they were allowed on the study. So, I think, you knowing that, and then seeing that relatively low rate of hyperglycemia, I think it does look like this has activity and probably a better safety profile. So, I think this one, when it's approved, I think will be something that we’ll want to need to learn how to handle and give it to our patients with least minimal side effects.

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