Alicia Morgans: Hi, my name is Alicia Morgans, and I’m a GU medical oncologist at Dana-Farber Cancer Institute in Boston. I am so thrilled to have here with me today, a good friend and colleague Dr. Cora Sternberg, who is a professor of medicine, and the clinical director of the Englander Institute for Precision Medicine, at Wall Cornell Medical College, in Cornell University, in New York. Thank you so much for being here with me today, Dr. Sternberg.
Cora Sternberg: Alicia, it’s always a pleasure to be with you, and you know that. I’m happy to be here.
Alicia Morgans: Oh, well, thank you. It is truly, always a pleasure for me to speak with you too. You’re always innovating, and always giving us more precision information on our patients. I really commend you, and your team, for working on the IPATential150 trial. And I think today, we’d really like to review the work that you and the team have presented at ESMO 2021, really digging into the safety analysis for that trial.
Before we dig into exactly what you presented at ESMO, could you remind everyone of the specifics of the IPATential150 trial design, and what the initial findings were? And then of course, we can go into safety.
Cora Sternberg: The IPATential150 trial is a trial of ipatasertib, which is an Akt inhibitor, plus abiraterone and prednisone, in patients with metastatic CRPC, as compared to abiraterone and prednisone alone. This was published in the Lancet, just recently in June, the entire trial. And what the trial, it was a Phase III global multi-central Phase III trial, randomized placebo controlled, with more than 1000 patients, again, getting ipatasertib and abiraterone and prednisone, or prednisone, or an active comparator was abiraterone and prednisone and prednisone.
These were men with asymptomatic, or just mildly asymptomatic, metastatic CRPC, so they were on androgen deprivation therapy, and failing it. And what we found in this trial was, a 23% reduced risk of radiologic disease progression, or death, in the men with PTEN loss tumors, by immunohistochemistry, who received ipatasertib, which is an Akt inhibitor, and works on the Akt PTEN pathway.
And similarly, we found that, looking at next generation sequencing for PTEN loss tumors, the risk of radiologic disease progression, or death, was also reduced significantly, in those patients. A statistically significant risk reduction was not seen in the whole intent to treat patient population, and we’d don’t have overall survival data, as yet. So in the poster that was presented with ESMO, we looked at the adverse events with the ipatasertib and abiraterone, both in Asians and in Western populations, to look at the adverse events in the manageability, essentially. And what we saw was with the ipatasertib and abiraterone, there was increased rates of drug discontinuation and dose modifications. Some 20% of patients did have to have dose modifications. And that usually occurred, I think, it was at a median of about 1.7, six months. So pretty early on, they had to have those dose modifications done.
The major side effects were diarrhea, hyperglycemia, rash, and transaminase elevations. And most of these did resolve pretty quickly with dose modifications, by lowering the dosage.
We also looked at about 20% of the patients were Asians, and sometimes it’s thought that Asians don’t tolerate medicines as well as Western population. But we saw really, no difference among the adverse events in the Asian population, and in the Western population.
So I would say, that this drug is fairly well tolerated. It has those side effects. It was also tested in a breast cancer population, where they gave medicines, such as loperamide and antihistamines. I think, that perhaps, if we do another study with this drug in prostate cancer, we would do that, and put those measures into effect, to give the prophylaxis with loperamide and antihistamines, to decrease some of the side effects.
Alicia Morgans: I think, that’s a great idea. And just to touch for a moment, back on your subgroup analysis by Asian and non-Asian population, I thought that was a really interesting analysis. And I think, just for all of the listeners to be reminded, that there’s different metabolism of some drugs, between some of our Asian populations, and then, in more Western, or non-Asian populations, I should say. And so there are differences in dosing for things like docetaxel sometimes, and some other agents. And so, I think it’s fantastic that this was something that you guys could look at in a subgroup analysis, and really understand, in this particular combination, there is no difference. I think that’s really useful, particularly, if this combination moves forward. And if you find that there is a survival benefit, or other benefits, particularly in that subgroup population, with the biomarker selected group, I think that that’s a really important analysis for you to have worked in, on the front end.
Cora Sternberg: It was really interesting, in that, in looking at the biomarkers, looking at PTEN loss, was done by immunohistochemistry. And then, we went back and looked at a subpopulation of those patients, by next generation sequencing, we found even better results in that patient population. So maybe that would be a better way to go in the future, but it was done with immunohistochemistry. It was a practical study. It was multicenter, it was a global study. It was over 1000 patients. So, it was easier I guess, to do it with immunohistochemistry. And that’s the way the earlier study had been done. It was called, A. MARTIN Study, by de Bono and all.
Alicia Morgans: True. True. And I think, it was a large study, and so you needed to do it in the practical way that you did, and you still learned, and I think that’s important, as well. And then moving forward, we will see what we see.
So tell us a little bit more about your idea for supportive management. Because as you said, this is a drug that we have seen used in breast cancer populations, and with appropriate supportive management, it seems to be a tolerable agent. Do you feel like this is something that could be done safely, and in a way that is acceptable to patients, if we give the proper supportive medications?
Cora Sternberg: I think so. I mean, if one of the main side effects is diarrhea, and we know that in advance, we give loperamide. When I was first working with irinotecan, it was called CPT-11 back then, people were dying, until we started to understand they were dying from diarrhea, and we started to give loperamide in those patients. And now, people get irinotecan all of the time, and they’re not dying from that drug. But one has to learn what to do.
If they have a problem with rash, and we give antihistamines, and know that rash is a problem, and give prophylactic antihistamines, I think that it could possibly make a big difference. The transaminase elevations, I’m not really sure. I think maybe we could tell, we could look at if the patients are taking statins, we could tell them not to drink alcohol. We could see what we could see. But there was not a difference in the Asian population, even in the transaminase elevations. Which is kind of interesting, because sometimes we think that perhaps the Asian populations metabolized differently, than the Caucasians, or the Western Europeans.
Alicia Morgans: Great. Well, thank you so much for this. I feel like we always learn a lot when talking to you, especially when we dig into IPATential150. So concluding thoughts, what would your message be?
Cora Sternberg: I think this is a very interesting drug, with an Akt inhibitor targeting PTEN, is a very viable way of improving, at least, radiological progression free survival, in men with metastatic CRPC. I’m also looking forward to the overall survival results, to see whether or not we’ll bring this forward into another study, or whether or not it would even be approved, based on this study, if there is an overall survival benefit that’s meaningful.
Alicia Morgans: Well, I look forward to that too. And again, congratulations to you and your team. Thank you to the patients. And thank you for taking the time to really go through this with us today. We appreciate it.
Cora Sternberg: My pleasure.