IPATential150: Phase III Study of Ipatasertib plus Abiraterone vs Placebo plus Abiraterone in Metastatic Castration-Resistant Prostate Cancer - Cora Sternberg

October 28, 2020

PTEN-loss is relatively common in advanced prostate cancer and is associated with worse prognosis as well as reduced benefit from androgen-axis targeting agents. Ipatasertib is a novel oral anti-cancer agent, under investigation in prostate and breast cancers. Orally administered, it is designed to target three isoforms of AKT (protein kinase B), in order to block the PI3 Kinase/AKT signaling pathway. This pathway is known to contribute to prostate cancer carcinogenesis and also potentially in the resistance to anti-androgen therapies.

In this conversation with Alicia Morgans, MD, MPH, co-author of the Phase III study IPATential150, ipatasertib plus abiraterone vs placebo plus abi in metastatic castration-resistant prostate cancer (mCRPC), Cora Sternberg, MD details this study which was an oral presentation at the Second Presidential Symposium at this year’s European Society of Medical Oncology (ESMO) 2020 Virtual Annual Meeting, presented by Dr. Johann De Bono. This phase III, double-blind, placebo-controlled, randomized controlled trial assessed ipatasertib in combination with abiraterone acetate and steroid (prednisone/prednisolone) as compared to placebo plus abiraterone acetate and prednisone.

Official Study Name: Ipatasertib Plus Abiraterone Plus Prednisone/Prednisolone, Relative to Placebo Plus Abiraterone Plus Prednisone/Prednisolone in Adult Male Patients With Metastatic Castrate-Resistant Prostate Cancer (IPATential150) NCT03072238

Biographies:

Cora Sternberg MD, FACP Professor Medicine and Clinical Director of the Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York.

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.


Read the Full Video Transcript

Alicia Morgans:  Hi, my name is Alicia Morgans. I am a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University. And I'm so excited to have here with me today, a friend and colleague, Dr. Cora Sternberg, who is the Medical Director of the Englander Institute for Precision Medicine at Weill Cornell Medicine and a GU Medical Oncologist, as well as being a Professor of Medicine. Thank you so much for being here with me today, Dr. Sternberg.

Cora Sternberg:  Thank you. Thank you very much, I'm very pleased to be here.

Alicia Morgans:  Wonderful. Well, Dr. Sternberg, we invited you here to speak about the Phase 3 IPATential150 study that was presented at ESMO.  You are one of the authors of that study, one of the lead investigators. I'm wondering if you could tell us a little bit about this Phase 3 trial, why it was important, and how you put it together?

Cora Sternberg:  Okay, so the trial is in patients with metastatic castration-resistant prostate cancer, and we know that some 40 to 50% of these patients have a loss of the Akt phosphatase PTEN, and what happens is they have a hyperaccumulation of a PI3K/Akt signaling. And this loss is very important because when you have a loss of this pathway, this pathway is very important in the cell cycle.  It's related to cellular quiescence, proliferation, longevity, and PI3K activation, activating Akt localized in the plasma membrane, will cause increased tumor growth. So, when you have PTEN loss, it is the loss of function of the PTEN suppressor gene, and it is actually one of the most common events in many types of cancer, but it does happen in 40 to 50% of prostate cancers, and with that loss, there is an increase in signaling.

And we also know that apart from being associated with a poor prognosis, there is this kind of crosstalk between the androgen receptor and the PI3K/Akt signaling. So, blocking the AR can activate the PI3K/Akt signaling and vice versa, and Johann de Bono had conducted a phase two study of dual blockade of AR and PI3/Akt inhibition, using abiraterone and prednisone plus ipatasertib, and ipatasertib we know is a blocker of all three moieties of Akt. So, in that trial, we show that there was a prolonged radiologic progression-free survival in this small Phase 2 trial, so this trial was designed to further look at that work. So, as I mentioned, ipatasertib binds to the ATP binding pocket of all three isoforms of Akt, inhibits Akt serine/threonine kinase, and then ultimately blocks AR.

And we mentioned that there's a crosstalk between the PI3K and Akt, and the AR pathway, so when you block one the other one can increase. So, what we wanted to do in this study was a dual blockade. This was an international study, a large study.  There were 200 sites in 26 countries, and it was, the patients that were put on this study had to have two rising PSA levels more than a week apart, having at least one nanogram per ML, or radiographic progression, or both, and they were previously untreated patients with abiraterone or any other androgen synthesis blockade. And, as you know, the abiraterone blocks CYP17, androgen biosynthesis, and they could have had prior chemotherapy with docetaxel, that was allowed. They had to have a baseline hemoglobin A1C of less than or equal to 7.5% because this drug can cause hyperglycemia. And then we destratified the patients by tumor PTEN loss by immunohistochemistry, and we chose 50% of the cells having PTEN loss by immunohistochemistry, and prior docetaxel in the hormone-sensitive prostate cancer setting.  If they had progression by PSA alone, and if they had the presence of liver or lung visceral metastasis, and then it was also stratified by region.

And there were 1,101 patients enrolled in this study, randomized one-to-one between ipatasertib.  We gave them 400 milligrams a day plus abiraterone, which is 1,000 milligrams a day and prednisone, or placebo and abiraterone 1,000 milligrams and prednisone. And the co-primary endpoints were radiologic progression-free survival in the intention to treat population and in the PTEN loss population, as I mentioned, by immunohistochemistry. The PTEN assay was the Ventana assay, and we chose this PTEN loss by 50% of viable malignant cells. And when we were looking deeper into the data, we saw that if we had chosen 60% or 70%, perhaps 60% might have been a better cutoff, because the higher up we went, the better responses we actually saw.  But this was the way the study was designed.  It was chosen for more than 50%.

And the patients on the study, there is still some 35% of patients in both arms that are in survival follow-up.  In the placebo and abiraterone arm, there are 554 patients altogether, and ipatasertib and abiraterone, there are 547 patients altogether, and 33 and 36% are still on treatment, and we are looking at them for survival too. So, very few were lost to follow up, but there have been 25% deaths in the placebo arm and 22% in the ITT and the ipatasertib arm. The patients who got prior taxanes was about 18% in all of the arms, and some 50% of patients in all of the arms were put on the study with PSA regression only.  Some 12% with visceral metastasis and more than 80% in both arms had bone metastasis.

Alicia Morgans:  Well, clearly this was a population with aggressive disease, and I think it's interesting that you said there was really this correlation, it seemed, between response and the degree of expression or the degree of inactivation or PTEN loss, actually, in that response. That is really, really interesting. As you think about the data, it really was the patients in the PTEN loss arm who seemed to have some radiographic progression-free survival benefit with the combination of the ipatasertib and abiraterone, right?

Cora Sternberg:  Yes, they were the only patients.  The patients with the 50% loss by Ventana, as we described it, were the ones who had a significant difference in radiographic progression-free survival. And that was not true in the ITT population.  There was no statistical difference there, in the PTEN loss population, the median radiographic progression-free survival for the ipatasertib arm was 18.5 months as compared to 16.5 months, and this was a hazard ratio of 0.77, it was really highly, highly significant. And if you looked at the whole population, this was not significant. The other thing is, that if we look at the overall response rate and duration of response in both the PTEN loss and the ITT population, patients on ipatasertib had a better, confirmed overall response and duration of response. And also, the response rate was higher in the overall population.  In the PTEN loss, the response rate was 84%, but in the ITT population, it was 81%. So, there was an improved response rate, but that was not the main endpoint of the study at all.

Alicia Morgans:  No, of course, and I think it was interesting. And to meet part of that co-primary endpoint with the radiographic progression-free survival prolongation in the PTEN loss population is certainly, I think, thought-provoking. But, when I look a little bit deeper into the duration that RPFS was prolonged, and then the side effect profile, it makes me think a little bit about how likely it is that this combination might ultimately move forward. And certainly, as you said, there's actually a substantial portion of the patients still in the trial, still being followed for survival data, which ultimately I think would be what would push us in one direction or another, in terms of integrating this kind of approach into our daily practice. But, can you tell us a little bit about the AE profile, how patients tolerated it both from the study and from your personal perspective, and how likely it is at this point, do you see this moving into a combination in the future that might be integrated into clinical care?

Cora Sternberg:  I agree with what you have said 100%, Alicia, as usual. I think that we really do need overall survival data to make this a really viable combination, and I think that is important, and so many patients are still in follow-up. I think you are just right on with it because I can't say it was without toxicities, at all. We put quite a number of patients on the protocol, and if we looked at the toxicities that were more present in the combo with the ipatasertib, this was hyperglycemia which was why we had to have patients that had to have a fasting glucose of less than 150.  And we looked at the A1C level before putting them on, and we were very closely following that. There was more diarrhea, there was some more increased alanine aminotransferase, some more rash, and some more dehydration.

But other than that, I think the biggest problems were with rash and hyperglycemia and some diarrhea, in terms of side effects. So, I think we know that abiraterone is quite effective on its own. So, to push this combination forward, I think what is really interesting is, it is really one of the first molecularly targeted combinations based upon PTEN loss, and I think that makes it extremely interesting. We use the immunohistochemistry cutoff, 500 of the patients were eligible for next-generation sequencing, but that is not how the study was designed, but in those patients who have had next-generation sequencing, there was an even wider distribution in radiologic progression-free survival in those patients, but that again was not the primary endpoint.

So, I think the improvement of radiologic progression-free survival in the PTEN loss, as we defined it, was statistically significant. We need to wait for overall survival, clearly, to make this a viable combination that will go forward, but the fact that we can have a combination based upon PTEN loss, there is the biologic rationale to this that makes this an extremely attractive combination and supports combining AR and Akt blockade with ipatasertib plus abiraterone as a treatment option in the future. And I think that we may have other ways of measuring Akt and PTEN loss that may even make it an even more viable combination one day.

Alicia Morgans:  I completely agree, and I really want to commend you and the other investigators for doing, as you said, this molecularly targeted combination, and really taking it to a Phase 3 setting, and helping us to understand on this broader level that we can enroll these kinds of trials, that we can complete them, and we can draw conclusions. We can move our field from a clinically identified groupings of, "You have the visceral disease, you have high volume disease, you have high-risk disease," into this molecularly targeted approach, and we are moving in the right direction. So, I truly commend you. As we wrap up, can you mention just, what would your summary point be to the audience who is listening on the IPATential150 trial?

Cora Sternberg:  Well, the IPATential150 trial as presented by Johann de Bono at ESMO, will be published in the future, and the first author will be Chris Sweeney. The safety profile was consistent with prior clinical trials.  But I think it really supports the combined AR and Akt blockade with ipatasertib plus abiraterone as a treatment option.  And molecularly targeted therapy option is what is new and what is really the most interesting part, I think, of this study. That we can select those patients with PTEN loss, which we know have a very poor outcome and very aggressive tumors, and target particularly those patients with this Akt inhibitor.

Alicia Morgans:  Fantastic. Well, we look forward to hearing updates, we look forward to seeing the publication of the study. And, again, congratulations to you and the team, and thank you so much for your time.

Cora Sternberg:  Thank you very much, Alicia.

 

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