AKT Inhibitors – Targeting PI3K/AKT/MTOR Signaling Axis - Cora Sternberg

November 8, 2023

Program: Beyond Androgen Blockade – New Pathways and Novel Treatments in mHSPC and mCRPC

Part of an Independent Medical Education Initiative Supported by LOXO@Lilly 


Cora N. Sternberg, MD, FACP, Clinical Director of the Englander Institute for Precision Medicine, Professor of Medicine, Weill Cornell Medicine, Meyer Cancer Center New York, Presbyterian, NY

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Read the Full Video Transcript

Alicia Morgans: Hi, and welcome to UroToday and our online medical education program, Beyond Androgen Blockade: to New Pathways and Novel Treatments in Metastatic Hormone-sensitive Prostate Cancer and Metastatic Castration-resistant Prostate Cancer. My name is Alicia Morgans and I have the honor to moderate today's discussion following a presentation by Dr. Cora Sternberg. The topic today is AKT inhibitors targeting PI3 kinase/AKT and mTOR Signaling Axis. Thank you so much for being here with me today, Professor Sternberg.

Cora Sternberg: Thank you so much, Alicia. It's absolutely a pleasure to be here and to be part of this educational program. In terms of PTEN, PTEN is a tumor suppressor gene located on chromosome 10 in humans, and PTEN is functionally lost in 40% to 50% of patients with metastatic castration-resistant prostate cancer, and it activates AKT signaling. The PTEN loss is associated with poor clinical outcomes and PTEN loss can be assessed by both immunohistochemistry or by next generation sequencing. These methods have shown good concordance in many clinical studies. Ipatasertib is a drug that I'd like to speak about. Tumors with functional PTEN loss status have hyperactivated AKT signaling and hyperactivated PI3K signaling. And when you have PI3K/AKT and the AR pathways are dysregulated in metastatic castration-resistant prostate cancer. So Ipatasertib is an oral selective, small molecule inhibitor of all 3 isoforms of AKT.

Ipatasertib inhibits AKT serine-threonine kinase activity and can improve the anti-tumor activity of AR blockade in prostate cancer models. So when you think about the rationale for dual pathway inhibition, inhibiting both the mTOR, PTEN/AKT pathway and the hormonal pathway of AR inhibition, the reason is, that there's a crosstalk between PI3K and AKT and the AR pathway leads to reciprocal activation when one of the pathways is inhibited, providing an alternative mechanism for tumor growth and survival. So what we really would like to try to do is to do dual targeting of both pathways because the thought is, that this might be able to increase the antitumor activity. So Ipatasertib is a potent, as I mentioned, novel selective ATP competitive inhibitor of all 3 isoforms of AKT. So when given together with a drug such as abiraterone, you will inhibit this crosstalk that one activates the other and doesn't let the other one work.

And that was the thought behind this study that was done. It was a very large phase 3 study done in over 26 countries and regions. It was a study called IPATential150 for patients who were previously untreated with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer. And we stratified the patients according to tumor PTEN loss by immunohistochemistry. And this PTEN loss was defined as a minimum of 50% of the specimens tumor area with no detectable PTEN. And the staining was done by Ventana and the antibody clone 2P218. We also stratified patients by whether or not they'd received prior docetaxel in the hormone sensitive prostate cancer setting. We stratified them by progression if they had PSA only and by presence of visceral metastases, liver or lung metastasis, and again, also by region.

And again, over 1,101 patients were randomized, one-to-one, to either receive Ipatasertib 400 milligrams a day plus abiraterone 1,000 milligrams a day with either prednisone or Prednisolone, 5 milligrams twice a day, as compared to placebo and abiraterone 1,000 milligrams daily plus prednisone or Prednisolone 5 milligrams twice a day. And radiologically assessed disease progression was the primary endpoint. So these are the results of radiologic progression-free survival in the patients who had PTEN loss by immunohistochemistry. And you can see here at a median follow-up of 19 months, that the median radiologic progression-free survival was 16.5 months for those who did not receive Ipatasertib and received abiraterone and prednisone alone with placebo, as compared to a median radiologic progression-free survival of 18.5 months for those who received Ipatasertib and abiraterone and prednisone. The hazard ratio here is 0.77 and this was statistically significant at an alpha level of 0.04.

Now, if we look at the radiologic progression-free survival in the entire population, not taking into account the PTEN loss patients, as I mentioned, should be 40% to 50% of the population and that we look at the median radiologic progression-free survival. It was 16.6 months for those without Ipatasertib, as compared to 19.2 months with Ipatasertib, here the hazard ratio was 0.84, but this did not meet statistical significance at the alpha 0.01 level, for the entire population.

We then looked at radiologic progression-free survival in PTEN loss patients by looking at next generation sequencing. This was done with the foundation one assay, and this was not exactly preplanned, but what happened was, we found very interesting results. The median radiologic progression-free survival was 14.2 months for those who did not receive Ipatasertib, compared to 19.1 months for the patients who did receive abiraterone and Ipatasertib. And you can see that these curves are really separating quite nicely, and this is for the PTEN loss population, when we looked only by next generation sequencing as opposed to immunohistochemistry, which should be similar, but was not exactly similar. If you look also at the radiologic progression-free survival for patients who have PIK3CA/AKT1 and PTEN loss, altered tumors by next generation sequencing. Again, the hazard ratio is 0.63, even more impressive than what I just showed you for the PTEN loss population. And again, not preplanned, but again, the curves are separating very, very nicely for these particular patients, who have quite a difference if they did receive Ipatasertib.

So this is the safety profile of Ipatasertib and abiraterone versus placebo and abiraterone, looking at the overall population as compared to those patients who had PTEN loss by immunohistochemistry. And although we know that those with PTEN loss may have a more aggressive disease, there really was no difference in the side effects between those two populations. The abiraterone exposure was comparable between the two arms, but the Ipatasertib exposure was numerically lower than the placebo exposure. The safety profile, again, was similar in both of these two patient populations. If we look also at the frequency of key adverse events that we know do occur with Ipatasertib, one is diarrhea and you can see with the placebo and abiraterone, that occurred in 23%, as compared to 80% of patients who received Ipatasertib.

Hyperglycemia is a known side effect, and you can see it occurred in 48% of patients, as opposed to 18% who did not receive Ipatasertib. There was one patient, I can't recall exactly what country this patient was in, who had severe hyperglycemia, and it wasn't noticed until the patient, I think left the hospital and this one patient did die. Afterwards, there was an amendment made and the glycemia level, the glucose level was monitored very, very carefully in all patients who received Ipatasertib and nothing occurred again after that one patient. In terms of rash, again, more rash did occur with Ipatasertib than with placebo, and the transaminases were increased as well, in 24% as opposed to 12%. But again, this did not meet any of the criteria for Hy's law that would indicate severe liver injury. Among the key adverse events and the grade 3/4 adverse events and the serious adverse events, leading to discontinuation of placebo or Ipatasertib, they were more frequent in the patients who received a Ipatasertib versus placebo.

So the drug is effective, but it is obviously more toxic than placebo alone. So just to conclude, Ipatasertib plus abiraterone significantly improved the radiologic progression-free survival, compared with placebo plus abiraterone, in patients with metastatic CRPC with PTEN loss tumors. There was no significant difference between the groups and the intention to treat population. Adverse events were consistent with the known safety profiles of each of these agents, abiraterone and Ipatasertib. But the data suggests that combining AKT and androgen-receptor signaling pathway inhibition with Ipatasertib and abiraterone, is a potential treatment for men with PTEN loss with metastatic CRPC. And this is a population that we know has a very poor prognosis. Thank you very much for your attention.

Alicia Morgans: Thank you so much for that Dr. Sternberg. That was incredibly, very detailed and really, really helpful. And I think it's so interesting how we could see the differences really by that PTEN biomarker, even when we assess the biomarker in different ways, as you showed us with the IHC being maybe less selective than the next generation sequencing. Can you speak to us a little bit more about that and how the importance of the way that we test for biomarkers may be something that we really need to be cognizant of in prostate cancer and in general, as we move forward?

Cora Sternberg: So the phase 3 trial was based upon a trial called, A. MARTIN , that was a phase 2 trial. It was a randomized phase 2 trial, it was a smaller trial in which immunohistochemistry was used. And based on that trial, we had the idea that we could see a difference in radiologic progression-free survival, and that was the reason that the immunohistochemistry was used. But although they should be somewhat comparable and they are comparable in many ways, it seemed that when we looked at patients with next generation sequencing, we can get more data and can be more specific and more clear about which are the patients that really do have PTEN loss or AKT abnormalities. So I think that, as that becomes cheaper and cheaper and as we go along, that's maybe replacing immunohistochemistry in the future.

Alicia Morgans: So helpful and really so clearly different with that NGS versus the IHC, so really important as we're moving forward. But as I think about this, and we're not necessarily getting regulatory approval based on this study, but of course, we're still interested in this pathway and on future developments. There are some unique side effects that we're not necessarily used to dealing with in our clinics in terms of prostate cancer populations, including things like diarrhea, maybe hyperglycemia, even rash we see sometimes, but some of these are a little bit distinct. What is your approach in clinic and how do you help investigators and clinicians think about integrating these agents at some point perhaps and how we really support patients through those effects?

Cora Sternberg: I think whenever we start with new drugs, we have to learn how to manage them, and we have to learn how to manage diarrhea and hyperglycemia and rash, and we do that with many, many of our drugs. The one patient that was in a South American country I believe, that did have the hyperglycemia, we had many steering committee meetings about this and discussed this at length and amended the protocol to make sure that the glucose levels were measured regularly and that this never happened again and it never did happen again. So that was the only one patient that had a problem and I think left the clinic and they weren't able to reach the patient. I'm not sure exactly what happened, but something happened in that one patient only and we were really on top of it after that.

I don't think that the diarrhea was such a difficult problem to manage with normal things like Immodium that we used, that was not such a serious problem. The liver function abnormalities were something that I think bothered the doctors more than the patients, which often happens in many of the studies that we do. And I don't think that Ipatasertib was really very toxic. I think it's a really good agent that will be used and we'll be hearing more about it in the future, maybe with other tumors. I'm not sure if they'll continue with prostate cancer or not, but I think it makes a lot of sense to cut off that pathway, the AKT mTOR pathway, which leads to aggressive tumors, in many other solid tumors as well, not just prostate cancer.

Alicia Morgans: So helpful. And so thank you for thinking that through, especially because Ipatasertib is not the only agent that's really targeting this pathway, that we may ultimately see in prostate cancer. It's really interesting I think, as we look forward, that there's a phase 3 that's currently out there, the CAPItello-281 study, that is looking at patients with de novo metastatic hormone sensitive prostate cancer, selecting patients who have PTEN deficiency and treating them with Capivasertib plus abiraterone versus abiraterone alone, in that first line setting. So lots for us to continue to think about with this pathway. So as you kind of mull all this over and think through what you talked about with us, can you just give us a summary? What should we think about when we're considering this particular pathway? And in general, how we move forward with targeted therapies in prostate cancer?

Cora Sternberg: I think it's a very important pathway. I'm happy to hear that there's another study going on. If it's an international study, I don't know if we'll be able to do next generation sequencing because immunohistochemistry is much cheaper and often when there's studies that are done in 200 countries, as this one was done, that's one of the reasons why immunohistochemistry is used. And so we need to be sure that we are selecting the right patients and the right criteria, and we use immunohistochemistry in having more than 50% PTEN loss. I don't know if that was enough or not enough or if that was the problem with that particular study. And with the study you're mentioning, if it's a large international study, I would imagine that it's difficult to do next generation sequencing on all the patients. I think that in the future we will be doing it more and more and more, but I think the price needs to go down, because I know in Europe it's not generally available to get next generation sequencing for many, many different studies.

Alicia Morgans: You're absolutely right. And that study is using PTEN deficiency by IHC as their primary mode of picking patients. So I think it will be really interesting to see in their perhaps, exploratory analysis or maybe secondary analysis for those patients who had access to next-gen sequencing. What did the curves look like there? To your point, I think as we're thinking about personalized medicine, it's about the target, it's about the mutation, but it's also about the way that we test. And this is going to be increasingly important as we continue to advance in prostate cancer with these molecularly targeted therapies, hopefully giving new opportunities for our patients along the way.

Cora Sternberg: I agree with everything you said, and I think that even if they're doing the study with IHC, they probably should be collecting the tissue and then eventually looking at next generation sequencing, as well, and to see if there's any differences, but they can do that afterwards also. I think that that would make a lot of sense. It's been done with a lot of different other studies, where they've gone back and looked at homologous recombination and deficiency, although it wasn't maybe thought of to look at upfront, but they went and looked back and they understood how important it was. So with other biomarkers, I think it's important to do that and to be looking to the future.

Alicia Morgans: Absolutely, and I look forward to that study coming out, and we can have another discussion about all of the ins and outs of the study, again on UroToday, when that happens. So thank you so much for your time and your wonderful expertise, Dr. Sternberg. We always appreciate speaking with you.

Cora Sternberg: Thank you so much. It's always a pleasure to talk to you too, Alicia.