Christopher Sweeney: Fantastic. So thanks Leslie for the opportunity for Jeff and I to share some of our thoughts that we had at the APCCC meeting Lugano at the end of April, early May. It was a wonderful session where many prostate cancer research clinical care deliverers meet together between urology, epidemiology, radiation oncology, basic science and medical oncology and others.
And everyone gets to share their data and have a conversation, and Jeff and I had a conversation about where are we at in the management of men with high-risk localized or locally advanced prostate cancer who are potentially cured with a local therapy, be a prostatectomy or radiation and what we can add onto that. And what I'd like to do now is actually just revisit some of the observations from the recent data sets, one from STAMPEDE, a second from the ENZARAD study. And Paul Nguyen presented that study on behalf of the ENZARAD team.
It was an ANZUP led study cooperative group with support and teamwork from Cancer Trials Ireland and the Dana-Farber Cancer Institute and Australia, New Zealand. So these are two cooperative group studies and have some interesting findings for us to discuss, and be great to get Jeff's feedback on this like he gave and shared about the current and future care of these men based on what we know now.
So the first slide I have here is the current state. Many places but not all places in the world now perform PSMA PET-CT imaging. And what we do know based on this work that was led by the Peter MacCallum team with Michael Hoffman and Declan Murphy leading the charge and published showing that men with high risk localized disease with nothing seen on a CAT scan or a bone scan, some of these men have disease that can be seen by PSMA PET imaging, but nothing on the bone windows or nothing that would meet RECIST criteria for measurable disease.
So we now actually can identify some of the men with micrometastatic disease, but we enrolled patients on the trials who are M0 conventional imaging. And what we know is that the higher the rate of your risk factors, the more likely you are to see disease beyond the pelvic lymph nodes by PSMA PET positivity, but still conventional scan negativity. So is it possible we can actually refine the use of intensified systemic therapy for just men who are PSMA PET positive conventional scan negative?
We don't know the answer to that question, but also there's the challenge that men who have PSMA PET positive are called metastatic disease and don't get the definitive local therapy. And I think I'll say right now that if your PSMA PET positive beyond the pelvic lymph nodes, but conventional scan negative, we should intensify the therapy with local therapy and systemic therapy and not treat them as metastatic disease. And we'll see what Jeff thinks about that at the end, but I'll just say that's where we're at with PSMA PET positivity at this stage.
There's also this endpoint of metastasis-free survival, which in a very high risk patient population, we can show if that we can decrease the rate of metastasis-free survival as was seen in the STAMPEDE study in a very high risk group of CN1 or two or risk factors of Gleason group four to five, PSA greater than 40, T3-4 disease, three years of ADT with or without abiraterone, we can see that the five-year survival was approximately seven ... So MFS was about 75%, but it was improved with the addition of abiraterone and that did track to a later long-term overall survival benefit.
So the surrogacy, when you have a big treatment effect on MFS in a high-risk patient population, did translate to an overall survival benefit as the ICE-kept database and data working group actually published in JCO in 2017. Phew, that's reassuring that this was the first proof of concept. But again, many of these patients were probably PSMA PET positive and there is data emerging that one of the machine learning with the arterial process can actually refine this even more.
Fast-forward to the presentation Paul Nguyen gave at ESMO last year where we actually saw no statistically significant benefit at the MFS endpoint, but notably we're now having eight year survival of 75%, whereas that was observed in the STAMPEDE at the five-year mark. So we've actually improved the outcome of the ADT radiation alone group, or what I should say is the patients who were recruit were different to the STAMPEDE, they were slightly not as high risk, but we also see that there was actually a PSA progression-free survival. So for some reason, this did not translate into a metastasis-free survival benefit.
Then we look at the overall survival and we now see that the eight-year survival is at the 83% mark, but the eight-year prostate cancer-specific survival is at the 97% mark. So many of these men are having a relapse. They're getting their salvage therapy, whether it be ADT or ADT with an RP at some stage for non-metastatic hormone-sensitive, metastatic hormone-sensitive, or non-metastatic CRPC. So here we are with long-term disease control, but some men are starting to die of something other than prostate cancer, even with high-risk localized disease.
So what I would say is that men in this current era, even on the ADT radiation, are still at high risk of relapse, but they're not at high risk of dying of prostate cancer like they used to be. Now, digging deep into, was there some subgroups who had the same degree of survival benefit, MFS and OS benefit with the intensification with the RP, with enzalutamide like was seen with abiraterone with the STAMPEDE?
We looked at the subgroups here and what we can see is that interestingly enough, men with clinical N1 who got radiated as well, and that was mandated for clinical N1, or those who were chosen for pelvic radiation had marked MFS of 0.43 and 0.47, and as you can see, the patients who were planned for pelvic radiation had a subgroup, a minor component were actually clinical N1. So there were patients who were clinical N0 who got pelvic radiation and had this MFS benefit. Also, younger men tended to end towards having a survival benefit, which would make sense in terms of at longer period of risk of dying of prostate cancer and not of a comorbidity.
So how do STAMPEDE and ENZARAD stand up? Well, for the clinical N1, there was the same treatment effect with hazard ratios of MFS 0.49 and 0.43. So apple with apple, same treatment outcome and treatment effect, reassuring, but the overall survival ... So the overall effect for all patients, 0.53 versus 0.88. So yes, there were more clinical N1 in STAMPEDE and then there was ENZARAD only 11%, 39 versus 11, higher median PSA based on the inclusion criteria, including a risk factor of a PSA greater than 40, a greater rate of clinical T3, T4, and we think that's mostly MRI.
Interestingly enough, 82% got radiation, 18% didn't because this study was conducted at a time where ADT alone was considered a standard of care for high risk localized disease, whereas everyone got radiation in ENZARAD. And then there was basically the similar split of Gleason eight to 10. But again, highlighting the data sets complement each other rather than compete with each other based on the different patient populations and looking at that treatment effect.
Then let's drill into this patients who got pelvic radiation hazard ratios of 0.4, 0.48 for clinical N0, Gleason six to eight, or clinical N1 or Gleason nine to 10. Greater numbers, more surety around this, but even this group, we don't know who these patients are. And Jeff proposed that maybe these were patients on ENZARAD who had PSMA PET positive lymph nodes. It's possible, but we just don't know. Only about 20% of patients got PSMA PET on the ENZARAD study, given that the study was conducted mostly before PSMA PET was widely available. But there was clearly no evidence of benefit in those who did not get pelvic radiation.
And that leads to looking at the MFS, 80% MFS rate at five years translating to an overall survival of 79% in the group that got ADT radiation and bicalutamide nonsteroidal antiandrogen. Whereas if you've got the enzalutamide, 89% MFS, which translated into an 88% overall survival. So there may be something going on with the pelvic radiation.
And is it the patients who are selected for the pelvic radiation with super high risk and benefited from it? Or is there some biological interaction between pelvic radiation and ADT plus potent AR inhibition whereby we amplify the anti-cancer systemic immune response, possibly the abscopal effect? These are hypotheses that we need to explore and work out how we can finesse our treatments.
But fortunately, we've got a number of data sets where we'll be able to combine the data and look at subgroups and get the right amount of power and the confidence of which subgroup is benefiting. Similarly, as we've done with other data sets like the STOPCAP analysis for identifying who benefited from docetaxel added to ADT across all the studies. But we'll have a tsunami of data to ask some very interesting questions, and to that, I'd love to hear Jeff's take on some of this.
Jeff Michalski: Thank you, Chris. And that was an excellent summary of both trials. Here we have a tale of two trials that we're trying to ask the same question, does enhanced hormone therapy, the addition of an ARPI in the form of either abiraterone or enzalutamide improve the outcomes of patients with high-risk prostate cancer and we got two very different answers to that question on each trial.
The STAMPEDE trial showed that addition of abiraterone improved the patient's outcomes including their overall survival, whereas the ENZARAD trial showed that there was no difference in metastasis-free survival or overall survival. So what can explain this? Well, first of all, as was pointed out, the patient populations are very different. And in that decade from STAMPEDE to ENZARAD being run, there may be some stage migration taking place. But we see on the ENZARAD trial, there were only about half of the patients had T3, T4 disease compared to 90, 92% on the STAMPEDE trial.
The median PSA on STAMPEDE was 35 versus 14. There were also differences in the approach to how the radiation was delivered. 40% of the patients on the ENZARAD trial received pelvic radiation electively, whereas that's not really stated clearly in the STAMPEDE trial, so we just don't know about that. And the radiation doses were different. On the STAMPEDE trial, it was 74 gray versus 78 gray in conventional fractionation schedule.
And as you are aware, Leslie, being a radiation oncologist, this is the steep part of the dose response curve were four gray, while it may not seem like a big difference, just two fractions, the difference actually might matter. So different patient populations, different radiation approaches, and what I found really intriguing is that the patients who had lymph node-positive disease are the ones that benefited to the addition of an ARPI in both trials. And as was pointed out, there might be an interaction, maybe we need that extra hormone boost when we're delivering a radiation to a pelvis that has a high infestation of malignancy, high infestation of tumor cells in the lymph nodes, whereas when the risk of lymph node metastasis is low, radiation plus standard ADT is sufficient.
So I think that is part of it. Another thing, as was pointed out, 20% of the patients, give or take 20%, on the ENZARAD trial did have PSMA PET imaging. Now in fact, PET imaging wasn't a requirement for enrollment. The enrollment was based on conventional imaging, but as we know, patients oftentimes will come with PET imaging from the community, in our own practices, and as Chris was saying, practices were changing in Australia and New Zealand around that time.
And so if you have a patient who you know have distant metastasis on their PET scan, you probably wouldn't enroll them on a trial like this. Yet if they had positive nodes, you may very well enroll them, even though the conventional imaging may or may not be positive, but as a radiation oncologist delivering treatment to those patients, I'm going to be more inclined to add pelvic radiation to those patients who I know have PET positive disease, even though the conventional imaging is negative.
And so I think patient selection, the decision on the part of the radiation oncologist I think was they were picking the real losers, the real adverse patients, and who knows what was going on in their minds could have been the PEN information, it could have been the volume of disease on biopsies, it could have been other unknown factors, but they clearly were picking patients who needed that extra treatment with both pelvic radiation and the ARPI.
So one of the things that I shared with the group in my presentation is that there are now biomarker studies that are taking place. Chris showed some of them on the prior slide, but we also have some data from the STAMPEDE trial where they used the multimodal artificial intelligence test to determine if there was a group of patients who might benefit from enhanced ADT with an ARPI. And indeed, if you look at the patients with the MMAI score in the lower three tertiles, they did better and they did not benefit from the addition of the ARPI, whereas the patients in the top quartile, the worst quartile, those patients indeed benefited from the addition of an ARPI, in this case, abiraterone on the STAMPEDE trial.
And so I think the NRG PREDICT-RT trial was collecting genomic classification for patients enrolled on that study and it may help us identify patients who will benefit from enhanced hormone therapy. One of the provocative questions after our presentation was, well, right now for patients who have high risk disease, we give two years of ADT, why don't we just intensify the treatment for six months or 12 months, and that might allow us to reduce the duration of unpleasant side effects these patients have to experience.
And that might be an important question to be asked going forward. And that's one of the aims of the NRG-08 trial and 09 trial, INNOVATE and the PREDICT-RT to see if we can de-escalate the patients with the favorable biomarkers, whereas the ones with the unfavorable biomarkers we're going to intensify treatment. So I think in the next three to five years when these trials mature and we have the biomarker data to support our decisions, we will be able to better tailor treatment to the patient's true risk and predicted likelihood of benefit from these treatments.
Leslie Ballas: Thank you so much. Both of you presented all that information so well. And I think that what Dr. Michalski, you brought up at the end about the de-intensification, when you look at that ENZARAD data, although certainly a more favorable population it looks like than STAMPEDE, the prostate cancer specific survival of 97% out at eight years is really quite exciting.
And so what we can do to improve quality of life for these men by potentially decreasing the amount of time they're on ADT, I would say another question that could exist is given the LUNAR and RAVENS data, is there a way of getting radioligand therapy in for these patients and having eugonadal prostate cancer specific survival benefit? What do you think is going to be the role of radioligand therapy in these higher risk patients?
Christopher Sweeney: I'll take that. I'm a little bit nervous about that because of one, very few are dying of their prostate cancer and they've got a long, long life expectancy and we have longer term concerns about potential bone marrow suppression and dysfunction and renal dysfunction, especially if they don't have a target to hit. So if the PSMA PET isn't there, where's it lodging? It's going to lodge in the bone marrow and the kidney.
So I would say they're research questions and I wouldn't do it off protocol by any stretch of the imagination, but it's a question to ask. I'd actually potentially propose that if from what we see from EMBARK, ADT looks similar to enzalutamide in the non-metastatic PSA rapidly progressing poor risk non-metastatic disease. So I'd actually say you could possibly consider using an RP monotherapy in a testosterone sparing approach, Leslie. And I strongly think we should start to explore that. Can we have a castration-free recipe for these patients in the lower risk and only intensify in those with the higher risk?
But I'd actually ask Leslie and Jeff, patient comes into your clinic and they are conventional scan CN0 PSMA PET positive Gleason-9 and you can access an RP. How would you treat them in 2026? Gleason-9 PSMA PET positive in the pelvic lymph nodes but CN0. So now the patient has two grains of prostate cancer beating out some images of PSMA positivity in their para-aortic lymph nodes and they are clinical N1 with PSMA PET positivity in their pelvic nodes. How would you treat that patient?
Jeff Michalski: So many radiation oncologists consider the para-aortic lymph nodes to be the next echelon above the pelvic lymph nodes. We know that you can have skip metastasis that can be draining directly to the para-aortic nodes. And so I've been more aggressive about treating patients with para-aortic nodal disease, treating even as high as the inferior border of the kidneys or even up to the renal hilum in special circumstances.
That's not standard of care, but I think many of us when faced with a patient with limited, I guess, oligometastatic nodal disease, we might consider extending our radiation portals that high. I have the luxury of having proton therapy and when you treat the para-aortic nodes with proton therapy, there are really very few side effects. So I'm not suggesting this is a reason to run out and buy a proton machine, but it is a disease site that is treatable and tolerated well with IMRT or proton therapy, as I said.
Christopher Sweeney: Leslie, how would you treat that patient?
Leslie Ballas: We would either treat that patient given sort of the M1 disease, you can either...
Christopher Sweeney: Micro M1, not clinical, not [inaudible 00:23:00].
Leslie Ballas: PSMA detected M1 disease. Many people would treat it just as Jeff explained. I think some people would consider radiation to the prostate pelvic lymph nodes and then depending on the separation between the common iliac border and the area where the para-aortics are, would you give MDT to that area with an SBRT treatment after you complete the fractionated radiation?
Christopher Sweeney: And so I'll just double down on what you both shared, I think, is that you do not treat them as incurable metastatic disease. You treat it as potentially curable and the patients who need the most intensification, both local and systemic is what I'm hearing.
Jeff Michalski: Yes, I agree with that statement.
Leslie Ballas: As do I.
Christopher Sweeney: And frankly, I think the node positive and even these ones that sneak up into the para-aortic, are probably the patients who contributed to most of the deaths from locally advanced prostate cancer. And if we can do this, increase their MFS to 89% and they're OS to 88%, I think this is where we'll be able to have the greatest contribution to decreasing the death from prostate cancer in this high risk patient population. So I wholeheartedly agree they're the patients we need to intensify and not treat as palliative metastatic.
Leslie Ballas: One thing I would love for our listeners to get your perspective on Professor Sweeney is, do you think there is any difference between these ARPIs? Certainly there are some side effect profile differences, but STAMPEDE used abiraterone acetate and prednisone, ENZARAD used enzalutamide. Is there any difference there?
Christopher Sweeney: I don't think biologically when you get to the nucleus as to whether the androgen is getting to and stimulating the androgen-driven cancer processes, whether you take away the ligand, whether you take away or block the androgen receptor directly with the amides. There is the very fact that amides work after abiraterone and abiraterone doesn't work after an amide, I suspect maybe there's a bit of more potency with the amide than the abiraterone.
Having said that, with the STOPCAP data showing that men over the age of 75 don't have a survival benefit, overall survival, they have a prostate cancer-specific survival, but not an overall survival because blocking the adrenal glands and the prednisone seems to be causing an increase in non-prostate cancer deaths such that overall survival is not seen in metastatic hormone-sensitive prostate cancer.
And we don't see that with the amide so my preference would be to avoid abiraterone and prednisone. Two years of prednisone is a problem, poor cardiovascular and bone health, the older people need their adrenal. So I think when we've got a non-adrenal hitting way of blocking the AR more intensely, I tend to steer away from abiraterone for that reason and then choose the AR inhibition of choice between the other amides based on the patient profile.
Leslie Ballas: Thank you.
Jeff Michalski: One point I was going to make, and it gets to what Dr. Ballas raised about the use of radiopharmaceuticals or radioligand therapy in these patients, as well as the statement that you made earlier, Chris, that the overall survival and prostate cancer specific survival is actually very good. What that tells me is that high-risk prostate cancer has become a chronic disease of sorts, and if a patient develops a biochemical recurrence or even a metastasis, it isn't the death of them today. There is much that we can do and we need to consider that as we intensify some of the earlier therapies.
We want to make sure we don't hurt the patient's kidneys or bone marrow to the point that we can't add additional therapies later. Of course, it's a balance between risk of progression and the emotional psychological burden that that carries with it, but when you see prostate cancer specific survivals of 97%, that's pretty remarkable in this day and age for patients who before, when given a diagnosis of high risk prostate cancer, couldn't expect to live five years without a recurrence.
Leslie Ballas: I think that's a really important point. Thank you, Dr. Michalski. I just want to say thank you to both of you for sharing your expertise and going over your discussion from APCCC. We are truly honored to have you both join us today.
Jeff Michalski: Thank you for the invitation. It was lovely to see you both.
Christopher Sweeney: Exactly. Thank you.