ESMO 2020 Expert Clinical Conversation on Prostate Cancer - Oliver Sartor
September 28, 2020
A. Oliver Sartor, MD, Professor of Medicine and Medical Director, Tulane Cancer Center; C. E. and Bernadine Laborde Professor of Cancer Research, New Orleans, Louisiana
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.
IPATential150: Phase III Study of Ipatasertib plus Abiraterone vs Placebo plus Abiraterone in Metastatic Castration-Resistant Prostate Cancer
Final Overall Survival Analysis of PROfound: Olaparib vs Physician’s Choice of Enzalutamide or Abiraterone in Patients with mCRPC and Homologous Recombination Repair Gene Alteration
Invited Discussant: (LBA4) IPATential150 and (610O) PROfound
Abiraterone Acetate plus Prednisolone for Hormone-Naïve Prostate Cancer: Long-Term Results from Metastatic (M1) Patients in the STAMPEDE Randomized Trial
Invited Discussant: Abiraterone Acetate plus Prednisolone for Hormone-Naïve Prostate Cancer: Long-Term Results from Metastatic (M1) Patients in the STAMPEDE Randomised Trial
Quality of Life in the Treatment of mHSPC: The STAMPEDE Trial - Hannah Rush
Alicia Morgans: Hi, my name is Alicia Morgans and I am a GU Medical Oncologist and an Associate Professor at Northwestern University. I'm so excited to have here with me today, a friend and a colleague, Dr. Oliver Sartor, who is the Laborde Professor of Cancer Research, as well as being a professor of medicine at Tulane University and the Medical Director of the Tulane Cancer Center. Thank you so much for being here with me today, Dr. Sartor.
Oliver Sartor: Well, thank you, Alicia. Glad to be here.
Alicia Morgans: Great. Thank you. And so today is going to be quick and brief. We want to have a high yield, super strong, sort of focus on some of the main prostate cancer presentations at this year's ESMO. And we will do a more protracted and a really in-depth dive into ESMO prostate cancer, but we want to have just a couple of really deep dives into a few of the presidential presentations, as well as one of the STAMPEDE updates. So can you tell us a little bit about the ipatasertib/abiraterone study that was presented? Johann De Bono participated in this and presented this at ESMO 2020.
Oliver Sartor: I was really looking forward to this presentation and this was going to be abiraterone in the context of, I'll call it the "Cougar three-oh-two", the metastatic CRPC with asymptomatic, minimally symptomatic. None of that pre-chemo space, if you will. And it was going to be a pretty simple trial design. It was the abiraterone/prednisone, plus or minus, say ipatasertib. And the ipatasertib is an AKT inhibitor, and very specifically designated to look at the PTEN altered subset. Now it's important how they looked at it because they looked at PTEN alteration by immunohistochemistry and also by next-generation sequencing. So the two different elements, but the primary was around the immunohistochemistry. So the primary end-point was rPFS and, kind of the short punchline is; in the "intent-to-treat" population, there was not a statistically significant benefit. It did not meet the pre-specified endpoint for the rPFS. And in the PTEN deleted group, it did.
But the hazard ratio was 0.77 for rPFS. And it turns out that the differential was only two months. So it went from like 16.5, to 18.5. So it was not a strikingly positive study in my mind. The overall survival data was not presented; it was said it was too premature. And then there was another element, and that is, about 20% of the patients actually had to discontinue the ipatasertib because of side effects. Some hyperglycemia, some GI effects, transaminitis, and more. And I was a little bit concerned about the toxicity.
So what we've got is a top-line positive on the PTEN altered subset by IHC, but significant toxicity. Now it turns out that if you look at the NGS designated PTEN subset, and it was a smaller group of patients. This smaller group of patients turned out to look better in terms of the rPFS, but that was not the primary endpoint of the trial. It was a smaller subset.
So I think we have a lot more to learn. We want to see more mature data. We want to see overall survival. I want to hear more about the NGS, but this trial was presented really the first gate AKT inhibitor to show a positive effect. And it is positive. It's just not very strikingly positive. Only two months on the rPFS.
Alicia Morgans: This is important because I think in prostate cancer, we actually have a number of things now that we're really excited about, including things like PARP inhibitors, which were recently approved. PARP inhibitor combinations, which looked like they may expand the population for which we can use those drugs. And certainly things like lutetium and other radio-pharmaceuticals that are coming down the line. Androgen receptor degraders, all of these things are really coming into play and we're very excited about them.
So do you think that this particular trial, this data is going to change your practice pattern? Or where do you think this is ultimately going to end up?
Oliver Sartor: Okay. So I'm a 'wait and see' guy right now. I'm not one to commit. I will simply say, there's a little bit of disappointment with the toxicity and the magnitude of the rPFS. I think it might be able to be better. You might be able to choose the patients better. Maybe it's NGS, maybe it's just alteration and the IHC scoring system. I'm not quite sure, but I'm not ready to change practice certainly at this time. But I do want to see more.
Alicia Morgans: I agree with you. And I think that at least it's encouraging that in select populations, we may be able to have a benefit here. And there certainly are ongoing trials looking at ipatasertib in this population of patients. And those patients with AKT mutations may ultimately benefit there? They're included in things like the TAPUR trial and the MATCH trial. And so we will get more data in this area and we definitely look forward to hearing more.
So one of the other presentations that were one of the highlights of ESMO this year, one of the other highlights of ESMO was the olaparib overall survival data from the PROfound study. So what do you think about that?
Oliver Sartor: Well, I think it was really quite strikingly positive with a called "Cohort A". So just to back up, just for a moment, these are patients, all of whom had failed like in abi-enza. But then they were randomized in the control group to get the alternative abi-enza, and some of the patients (by the way) had already been treated with both. So I think there is some legitimate criticism about the control group here. You might've [inaudible] supposed that taxane would have been most appropriate, but that was not the control group. And by the way, there was a stratification for taxane, no taxane in terms of pre-specification. Well, that being said, the "Cohort A" is a BRCA1, BRCA2, and ATM. And it turns out that there are a lot of BRCA2s, and that's really what's driving it. And the BRCA1s help, but the BRCA2s really drive the study.
The ATM, in terms of the overall survival, really did not seem to show much, if any, of a benefit. As a little bit of a complication there because there are pre and post taxane. And that is a little bit odd, but I'll simply say that "Cohort A" was pre-specified, by BRCA1/BRCA2/ATM. And in terms of overall survival, there was a lot of crossover. There was a 66% crossover at this analysis. What even the pre-specified analysis was positive, taking fully into account the crossover.
Now those patients could be a crossover or not, was still an overall survival benefit. But they took into account the crossover. It was really quite striking. The hazard ratio got down to 0.42. That's strong and the curves are widely split apart.
So the bottom line is I think for the BRCA mutation as a PARP inhibitor, it's probably ought to be a standard of care. You can argue, perhaps that maybe it ought to be tested against platinum. Maybe you want to be testing it as taxane, but I know that PARP inhibitors work, and they do prolong survival and those with BRCA mutations. That's a strong conclusion.
Alicia Morgans: Well, certainly, and we do know that the FDA has approved olaparib, based on the PROfound data, to treat patients who have these DNA repair defect mutations, particularly BRCA2. We know that those patients seem like they're going to benefit, but there's a splay of mutations. When you were thinking about choosing olaparib or some other treatment in your practice, and this is not ESMO based, this is putting you out on a limb as I just did on the last question. What do you think about in terms of things like ATM mutations or other mutations that may not have shown such a strong benefit?
Oliver Sartor: Yeah, so basically I'm thinking gene by gene today, Alicia, I'm not grouping. So there is some preliminary positive data for things like RAD54L. Now that's a rare mutation, but actually, it looks kind of interesting in some of the subset analysis. RAD51B also looks pretty good. PALB2, looks pretty good. A tiny amount of data with [inaudible], and one patient with GRIP1.
So as we move into these rare subsets, we really have a deficiency of data, but there are, I think, some emerging trends that looked positive to me. We really need more research. In terms of ATM, there actually is some positive data with the ATR innovation. That's a separate trial and I'm actually trying to gear up and get that trial going here at Tulane with the ATR inhibitor for ATM mutants. But I think we're just going to have to go gene by gene. You can't generalize across these DNA repair defects. As it turns out, there are some of these defects that are sensitive to PARP and some that do not appear to be sensitive to PARP. For instance CDK12. CDK12 is not really a part of the homologous recombination pathway, but I do not see the activity in CDK12.
Alicia Morgans: I completely agree with you. And I think what's so interesting is that we're really in an area of discovery. We have an approval, but we will continue to understand and discover with our patients.
I certainly had actually a PALB2 and a CHEK2 patient actually respond really well to treatment with olaparib, which gives me an N of one for each of those. And doesn't actually prove anything, but it does. The label at least does allow us to have that flexibility and to continue to learn. And of course, ongoing trials will continue to inform our practice here, which is really important as we try to make these decisions with our patients.
So finally, we did have updated data from STAMPEDE, of course, in the metastatic hormone-sensitive population. This was the STAMPEDE arm that included abiraterone. What are your thoughts on that?
Oliver Sartor: Wow! Was it positive! Hazard ratio and long-term follow-up of 0.6. Toxicity really was better than expected. I thought it was a home run. That was a big-time presentation. Long-term follow-up, high-risk disease, low-risk disease using CHAARTED, which you're very familiar with, didn't matter. It was positive. It was positive. And I really thought the data was strong. So I've been using abiraterone in that setting. And now I have even more confidence when I choose that particular drug.
Alicia Morgans: I completely agree with you. We will, of course, tell professor James that you said it was a home run. He will love that comment. And you know, one of the things that one of the discussants brought up, Maria De Santis, that I thought was really interesting and important, is the quality of life data that was presented (at least partially by Hannah Rush) at GU ASCO earlier this year. The papers still in process, but you know, that data suggested that there may be a quality of life benefit to treatment with abiraterone if you average across the span of treatment, that is a little bit greater than that quality of life benefit that we see with docetaxel and chemo-hormonal therapy, particularly because we do have that deficit of quality of life around the three month period when we're in the midst of chemotherapy.
How does that play into your treatment decision-making process?
Oliver Sartor: Well, it does. And you know, I get a little bit shy about talking to you about quality of life. So yeah, particularly on CHAARTED and other such studies, which you happen to be the author of, but as it turns out, yes, that data isn't [inaudible] the may. You don't have the deficit that occurs with Docetaxel. With docetaxel, you have deficit, but then you recover, but on the other hand here, there really was no deficit. I think it's strong data. I think people did it well, they did better than with ADT alone. This is used in the STAMPEDE quality life. And I'll just simply say that I thought it was impressive.
Alicia Morgans: I would agree with you, and thank you for mentioning that. But I would also say that the STAMPEDE group, though I am not living in the UK, has actually invited me. And I'm an author on that paper with Dr. Rush, and with Dr. James. So excited and really happy because I think that we all need to come together on these things and try to understand things without bias in any direction. And the data speaks what the data speaks, and we will definitely listen to it. So as we continue to evolve in prostate cancer care, based on what we've learned in ESMO 2020 and beyond, I sincerely want to say, thank you so much to Dr. Sartor who has given us this quick minute on some in-depth really important presentations at ESMO 2020. We will do a further analysis in the near future. Thank you so much, Dr. Sartor.
Oliver Sartor: Thank you. Enjoyed it as usual.