In this exclusive MedPage Today video, Debu Tripathy, MD, chairman of the Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, discusses key developments presented at this year’s San Antonio Breast Cancer Symposium, many of which may set the stage for new directions in care of patients with metastatic breast cancer, including several areas of the treatment landscape on the cusp of change.
Following is a transcript of his remarks:
Oral selective estrogen receptor downregulators, or SERDs as they’re known, have now come into the market and are coming out of trials, I should say, and are being tested in phase II and now in phase III trials. The first one to report mature data from the phase III trial was elacestrant [Orserdu], which was reported at ASCO earlier this year. And a follow-up was done looking at the outcomes of patients in terms of progression-free survival, depending on when they progressed on their prior therapy.
If they have progressed on CDK inhibitor-based therapy within 6 months or less, it turns out that their outcomes were worse. And we’d already had a hint of that, but now we got some quantitative information as to by what degree it was less than if patients had recurred over a year or more than a year.
And certainly we’re seeing what we expected in terms of worse outcome or short returns, but we now can look at these curves and after about a year, and going from a year to longer really doesn’t make much of a difference. But there is a big difference in the shorter times of progression at 6 months versus longer. And this is going to be important in terms of modeling how we might look at other therapies or how we might compare the different trials.
Importantly, patients do progress on these diseases, on these therapies, and we need to understand what array of treatments might be helpful beyond progression as new agents come into clinical use.
So, following up on the new agents, an important trial was reported looking at another inhibitor of the so-called AMPK pathway. This is a pathway that is one of the more well-understood and probably more heavily utilized — I call it a superhighway — signal transductions that can emanate from many different growth factor receptors.
PI3 kinase typically is activated by these signals, but can be activated by other signals as well. It sits right at the cell membrane, and then it activates AKT, which then activates the several downstream mediators, including mTOR, and ultimately propagates the signal of growth, survival, and some other phenotypes as well. So, blocking some of these components has of course been looked at ever since mTOR inhibition was reported 10 years ago now, and led to the approval of everolimus [Afinitor].
PI3 kinase itself has been targeted by general inhibitors and has a lot of toxicities, particularly CNS [central nervous system] toxicities. And these have mostly been abandoned in favor of the most selective inhibitors.
The catalytic subunit of PI3 kinase comes in several different isoforms. The alpha isoform is the most commonly mutated one in breast cancer. So that has been a focus of targeting this pathway. The alpha catalytic unit activates or governs the activity of the alpha isoform. So alpha selective inhibitors, such as alpelisib [Piqray], were tested and led to the approval of alpelisib over 2 years, almost 3 years ago. And this does block the pathway; it does induce a benefit over fulvestrant [Faslodex] alone. It has a significant toxicity, including nausea and diarrhea. But it is now commonly used in the second-line setting.
The targeting of AKT, which is just downstream of PI3 kinase, is also another potential target, and doesn’t necessarily require activation of AKT. Now these inhibitors are more potent in the presence of an AKT mutation, but those are quite rare. So, capivasertib, an AKT inhibitor that was tested in all-comers, not necessarily on the basis of AKT amplification mutation, and was looked at in patients specifically who were on CDK inhibitor therapy.
And the control arm is fulvestrant alone versus fulvestrant plus capivasertib in the CAPItello trial. And this trial reported its mature findings, and did in fact show an improvement to progression-free survival, which was the primary endpoint, and a hazard ratio of about 0.65. So clearly a benefit. It did show some of the expected toxicities of blocking a pathway, particularly nausea and, not so much nausea, but diarrhea. But to a lesser extent that has been seen with alpelisib.
So this looks good for this class of drugs. Benefits are about similar to alpelisib, but less toxicities. And we suspect it may replace alpelisib. It’s a little early to tell and we need to understand a little bit more about what are the predictive factors. It does seem that PI3 kinase mutations might favor it a little bit, but not as much as the case with alpelisib.
So beyond that we’re still looking for more therapies. There’s going to be an opportunity for newer SERDs, and then a newer class of estrogen receptor targeting drugs and known as PROTACs [PROteolysis TArgeting Chimeras]. These are small molecules that link the estrogen receptor to mediators of proteasome degradation. And so it leads to rapid degradation of the estrogen receptor — sort of like fulvestrant, but to a much more rapid and greater degree.
And these results now we’re starting to see from earlier-phase trials — phase I and phase II. The phase II trial was reported clearly showing activity and effectiveness. And we would now look forward to randomized phase III trials and see where that drug might be positioned.
So we would like to really introduce more and more therapeutics that have acceptable toxicities into this population of patients. Ultimately, unfortunately, patients do become more and more refractory to endocrine therapies and we need to look at chemotherapies and antibody drug conjugates and things of that nature. And so that was also covered at this meeting, but I will stop here and certainly refer you to looking up updates from those trials as well.
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