Contemporary Sequencing in the Treatment of Prostate Cancer - Neal Shore, Alicia Morgans and Charles Ryan

May 31, 2019

Alicia Morgans, Charles Ryan, and Neal Shore discuss the clinical evidence and considerations in treating prostate cancer progression as patients fail first-line treatment in the nmCRPC and advance to metastatic castration-resistant prostate cancer (mCRPC).  They highlight the need to change the mechanism of action and the opportunities that each Sipuleucel-T, (Provenge®) an autologous cellular immunological agent and radium-223 dichloride (Xofigo®) a radioactive therapeutic agent offer in patients progressing to mCRPC.  These agents have each demonstrated improved overall survival while being tolerable and safe.  


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.

Charles J. Ryan, MD, the President and Chief Executive Officer of The Prostate Cancer Foundation (PCF), the world’s leading philanthropic organization dedicated to funding life-saving prostate cancer research. Charles J. Ryan is an internationally recognized genitourinary (GU) oncologist with expertise in the biology and treatment of advanced prostate cancer. Dr. Ryan joined the PCF from the University of Minnesota, Minneapolis, where he served as Director of the Hematology, Oncology, and Transplantation Division in the Department of Medicine. He also served as Associate Director for Clinical Research in the Masonic Cancer Center and held the B.J. Kennedy Chair in Clinical Medical Oncology.

Neal Shore, MD, FACS is the Medical Director of the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina. He serves on several industry advisory boards as well as academic and advocacy networks: including the Society Urologic Oncology Clinical Trials Consortium, Bladder Cancer Advocacy Network, and the Large Urology Group Practice Association. 

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Alicia Morgans: Hi, my name is Alicia Morgans, and I am excited to have here with me today, Dr. Chuck Ryan and Dr. Neal Shore. We're going to be talking about really some advances and changes in the landscape, particularly after we've had really some advances in the non-metastatic CRPC setting, metastatic hormone-sensitive setting. Can you tell us a little bit about what's been going on in the non-metastatic CRPC setting?

Neal Shore: Thanks. Yeah, we had a really great presentation, I thought, by Karim Fizazi at ASCO GU, and I was honored to be part of that trial known as the ARAMIS. And it's really a third and very important trial globally conducted for men with non-metastatic castration-resistant prostate cancer. And essentially, a very similar study scheme to what we saw with earlier trials known as PROSPER and SPARTAN, and very similarly, a primary endpoint of MFS or metastatic-free survival composite endpoint of radiographic progression and death, which met its primary endpoint, essentially delaying MFS by about two years. And this is an oral medication taken twice daily.

I was involved earlier with some Phase II data with this darolutamide therapy. And what was really notable for me was the tolerability and the safety profile of the therapy. And I think it, Karim did a very nice job in presenting it, and we've now published it in the New England Journal of Medicine article that came out essentially almost the same day.

And the safety tolerability is something that I think will resonate a lot to clinicians, urologists, and medical oncologists. We didn't see any significant differences in hypertension. There were no different signals in rash. Patients with seizures were allowed to be part of the trial. And even the fatigue and cognitive impairment that we saw was really essentially balanced between both arms. Falls, fractures also, for the most part, really balanced. So I think, if and when the drug does get approval, it'll really resonate for clinicians and patients regarding tolerability and safety profile. Of course, we don't have direct comparative trials yet, but I think it's actually going to be a real benefit to the patient population.

Alicia Morgans: I agree. I think it's always nice to have options. And now that we may, should the FDA approve and provide regulatory approval for darolutamide, we would have three choices in the non-metastatic CRPC setting, it's always great to have that, to really match the right treatment for any given patient. At the same time, though, it presents good challenges for us, as we think through, what do we do downstream? What do we do next for our patients? If we're using really heavy AR directed therapies in the frontline, what are we going to do when we get to the metastatic CRPC setting? So how do you think about that, and sequencing perhaps the treatments that we already have at our disposal and these tried and true options next?

Charles Ryan: Yeah. I want to make a quick point about the ARAMIS trial and that space, which is that we may end up at a point in this disease where we have three agents that all look really good in one clinical space, and we may not ever get the comparator data that would arise. And we may, as clinicians be forced to develop our own way of using these therapies for patients in an individualized manner that's not really data-driven. And I think that's one of the things you see. You see that outside of oncology in antihypertensives and psychiatric medications where you just can't compare everything to always have the best therapy. So I was struck by that point, as you were making that description, Neal.

But you bring up an important point about what do we do after the progression on an AR targeted therapy? Now there's a couple of key points to think about. One is that in the apalutamide study, the SPARTAN study, there is an entity known as second progression that was evaluated. And for what it's worth, the patients who received apalutamide who developed disease progression and went on to another therapy were actually more likely to have a more prolonged time to second progression than patients who were treated initially with placebo. And that makes us think a little bit about the disease biology, and it's a little bit counterintuitive or counter to what I might have hypothesized previously. Because what a lot of our data has shown is that once you've been exposed to a novel potent AR targeted drug or abiraterone, and you develop disease progression, that the disease is much more likely to be highly aggressive and lead to more rapid progression and even death from the disease.

So the second progression data almost suggests that, if you will, pre-therapy, if you will, with apalutamide, makes the next therapy more effective. Now, it'll be interesting to see what happens with that concept of second progression. If people begin to describe that and study that and measure that. The challenge is that the second progression is expensive to measure, there's not a set of criteria upon which we can decide what is truly second progression. So that may end up as being one observation, an important observation from one clinical trial, that doesn't enter into the standard lexicon of our disease.

But anyway, let me get to the point of, what we do in the CRPC setting. So I guess I would start out by saying, it's possible that we will get to a point that what's old is new again, in a way, which is to say that we may end up seeing a patient with CRPC who progressed from non-metastatic CRPC to metastatic CRPC, who may have a low volume of disease with a low PSA with indolent disease progression. And that may not be in light of the second progression, that may not be a biologically distinct patient from the one we saw 10 years ago when we started treating everybody with abiraterone and enzalutamide. Right? And so that's a very interesting phenomenon.

So then we go back to our classic CRPC treatment paradigm, which is, do we use sipuleucel? When do we use radium-223? Do we use a second AR targeted therapy? I think that's probably the critical question. And of course, when do we use docetaxel? So all those old questions kind of become new again.

Alicia Morgans: So what do you think now about, do we stay on the same mechanism if we're going to do an AR targeted therapy, and we've just progressed on one in the non-metastatic CRPC setting, for example, or metastatic hormone-sensitive, do we stay on an AR directed therapy path? Do we move to another option? And that might also depend on what your patients look like as they're progressing, how aggressive is the disease? What are their symptoms?

Neal Shore: Sure, great points. So I just want to comment on this notion of this PFS2 that you're alluding to, which was an exploratory endpoint, very clever in the design. And so I appreciate that in the SPARTAN trial but again, an exploratory endpoint, and sort of counterintuitive to what we've experienced in the M1 CRPC population, where we talk about the switch, going from one novel hormonal anti-androgen therapy to another, going abi to enza, enza to abi. And virtually all of that data, and some really nice work by Kim Chi and others, has shown that that's really a really rather limited value, that the benefit is really short-lived. So this was a bit counterintuitive in the SPARTAN study.

My concern is, although it's interesting to think about, and the data is fascinating to review, but my concern based upon your question, Alicia, is, we have therapies that are remarkably well-tolerated and don't preclude other therapies. And that specifically would be sipuleucel-T and radium-223 for the right patient. And so sipuleucel-T, which has been around and approved since 2010 and available in the United States, and I had the opportunity to review immunotherapy use in prostate cancer at EAU recently in a program, it's still the only approved therapy in prostate cancer that's an immunobiologic, so to speak. So for me, I still think it has a great role, especially in patients early on in the disease process, M1 CRPC patients, and that definition could be moving a little more proximally, depending upon the imaging that you choose to use. What I've always found appealing is the short duration of therapy, you give it in over essentially a month's time, the tolerability, the unique mechanism of action, and the fact that it doesn't preclude using an NHA or a subsequent chemotherapy or radium.

And as it relates to radium, almost very similar, and they have similar issues, there's not a lot of PSA decline. Radium is remarkably well-tolerated. It's given over a six month period. There are some ongoing data looking at how to best use it concomitantly or in sequence. And maybe we'll talk about that.

Charles Ryan: Should also point out that sipuleucel-T has been demonstrated to be essentially safe and no less effective when given with abiraterone plus prednisone. That was a study that looked at whether or not the prednisone was going to mitigate or reduce the immune stimulation. And that data has been published now for a few years.

Neal Shore: Yeah, thanks. I mean, we were part of that. There are two separate studies. They were small Phase II studies looking at sequencing and concomitant use of either abiraterone acetate, or enzalutamide with sipuleucel-T. Both studies essentially showed, they were small Phase II studies, that the CD54 upregulation was not impacted negatively, in fact, it was quite positive. So I think that's something to consider. Of course, there are issues of accessibility and cost. But in a perfect world, and I think you alluded to this earlier, this is a terminal disease, we all know this, and so at the end of the day, we want to make sure that patients are afforded all the approved therapies that could potentially have life impact survival benefit. And you've made this point, the three Ps, prolong survival, prevent complications, and...

Charles Ryan: Preserve.

Neal Shore: Preserve, there you go.

Charles Ryan: Yeah. Preserve function.

Neal Shore: Yeah, exactly.

Charles Ryan: Yeah. I want to make a quick point, going back to this issue of what do we do with a patient who's progressed on novel AR targeted therapy, now he's got CRPC, and he's abiraterone or apalutamide or darolutamide resistant? We need to make sure that the clinicians out there know that this would be an opportunity to sequence the patient's tumor if you can because we have a number of important trials going on with PARP inhibitors, which are right in that space. And the idea there is, by sequencing patients, you're going to identify maybe 15% of your patients who may be amenable to therapy with a PARP inhibitor. This story is still being told, but these are patients who have a therapy that they can benefit from.

Also, while we're talking about sequencing, we need to recall that up to 3% of our patients may have MSI high disease and be able to be treated with anti checkpoint inhibitor therapy. So we don't want to forget about that sequencing piece.

But even beyond sequencing, I really think this is an opportunity where we need to look at our patient not as what's on the scan and what's their PSA. We need to delve a little bit deeper into prognostic variables. And this is where I do this. I look at alkaline phosphatase, LDH, hemoglobin, PSA, PSA doubling time, all of these parameters. And this is where I begin to think about whether I want to treat the patient with docetaxel, or whether we want to treat the patient with radium, or whether I want to treat the patient with sipuleucel. Because those are three very different treatments in terms of what the outcomes that are expected from them are. And the patient populations who go down those pathways should be different.

And one of the points that keeps coming back about the sipuleucel-T data is, as I've been saying for many, many years, is that the patients who had the indolent disease with a good prognosis had more indolent disease and a better prognosis when they got sipuleucel on the IMPACT trial. That's a key point. So if we were to take the patients who had rapidly progressing disease, maybe pre-symptomatic, or maybe they probably were best served by docetaxel, those, in my view, are not the patients who are going to benefit from sipuleucel, and that's where I don't use it. But there are plenty of patients out there with the low volume disease, the normal alkaline phosphatase, the slowly rising PSA, and they may have no other comorbidities that threaten their lives, and they're going to live three, four, or five years. And those are patients where, if you look at the IMPACT data, the improvement in survival was about 35% at three years between the placebo arm and the sipuleucel arm. So that's a key thing to remember.

Neal Shore: You're 100% correct on that. And you're alluding to that Schellhammer paper in Urology, and the quartile data. And then a retrospective analysis of the 9902B of the IMPACT trial, as you said. The patients who had PSAs in the first quartile as opposed to even in the last quartile, all benefited, all benefited actually. So higher volume, lower volume. But you're absolutely right-

Charles Ryan: The delta over placebo was better in all quartiles.

Neal Shore: In all quartiles. But really the best in early, relatively asymptomatic, lower tumor volume. So I completely agree. And I think your other point regarding MSI high is very important, and there's even some data to suggest that patients who have progressed on a novel hormonal agent, abi/enza, have even a higher, maybe it's a little over 5%, maybe MSI high. So that plus the possibility of DDR mechanism gene deficiencies for PARP inhibition as well are something that's really exciting, I think, going on in the future. But not approved yet. And still today in 2019, it's only sipuleucel-T that is an immunotherapeutic is approved, with, if you add a for MSI high, the pembrolizumab information. So I think it's really important that clinicians test these patients, do genomic sequencing. I think that's absolutely key, the whole notion of personalized therapy.

One of the things I just wanted to bring up is, we're about to publish, and Oliver Sartor is the first author on this, is a large registry since the approval of sipuleucel-T, known as the PROCEED registry. And the bottom line is a remarkably, impactful benefit on the African-American population versus non-African-American. So this was in a patient cohort of over 1900 in this registry. So in this notion that we talk about personalized healthcare, whether it's your genomic sequencing versus racial differences, profiles, comorbidities, it makes us all better at choosing the right therapy for our patients.

Charles Ryan: You know, what's interesting is this point about African-Americans, is that this has emerged in sipuleucel-T 10 years ago. I remember this very early data. So it's interesting to see that data continuing to evolve. We've now got the data on African-Americans having a favorable response to AR targeted therapies. And you wonder if there's something about that, the confluence of those two mechanisms, that's suggestive. I don't know. Interesting observations.

Alicia Morgans: I agree. I think, as we're thinking about choosing these different clinical factors or thinking about sequencing, we also could think about asking our patients. So these therapies are all delivered very differently. They all have different side effect profiles. When I use things like sipuleucel-T, it's typically in an asymptomatic patient, and as I have that conversation there is some upfront payoff, where the barrier to getting this, you have to go through apheresis and come back and get your reinfusion. But it's given over a relatively short period of time. There are very few side effects to that treatment. And patients can get that out of the way, and then as they need to, move on to the next therapy. And for most patients, it has minimal impact on their quality of life and is something that many seem to appreciate.

When we compare that with a patient who may be best for chemotherapy, it may be a more aggressive disease process. That patient may be more symptomatic. And so I feel clinically that's the best option. But a patient also has to buy into a different set of side effects as they're getting that therapy. And so that's something that I think about as well. Radium, if you have a patient who has a lot of bone pain, maybe the patient that would go to radium first, radium may be more effective in an earlier setting than it is after you've given multiple other therapies. So engaging the patient on the financial implications, on the time and commitment that it takes to get a therapy, and then the side effect burden, can be another way that we think through, how do we match that treatment with the right patient?

Charles Ryan: As long as we're having conversations about sipuleucel, it's really interesting to think about sipuleucel in light of what we know about checkpoint inhibitors across oncology, right? In bladder cancer, where we've had a number of conversations about them, the idea was that the pembrolizumab's and nivolumab's were going to really revolutionize bladder cancer, and it's been a big deal, and it's an important development for bladder cancer, but still, there's a relatively small proportion of patients who benefit from checkpoint blockade in other malignancies. And yet it's changed the standard of care in a lot of us.

And with sipuleucel, it's a different paradigm. We don't have that immunotherapy paradigm of the checkpoint blockade where 22% of patients respond for a long time, and 78% of patients have no benefit. We don't know that kind of data for sipuleucel. So it's almost a population-based immunotherapy. And that's why my recommendations about its use in the indolent disease population were made, which is to say that that is, I think, the group of patients who benefited from it.

Neal Shore: Yeah. Well, I'll tell you, you're right. If you're not meeting positivity for one of the PD assays or not having IHC positivity, as opposed to a T-cell activated therapy in sipuleucel-T, you're absolutely right. And as Alicia points out, I mean, the therapy is given over a month, and short of just undergoing apheresis, it's remarkably well-tolerated, not impactful to patient quality of life, and very, very short duration, and you give it, and it's onboard.

A point you made though, I think, about, it's very important that patients, they get their taxane-based therapy. There's no doubt the impact and benefit of taxane-based therapies. But when you have an opportunity to give a therapy such as radium-223 or sipuleucel-T, which are so well-tolerated that gets and speaks to preserving quality of life, avoiding any further worsening of cancer-related fatigue, both of those therapies really have minimal to almost no impact on fatigue, which taxane therapies do, AR directed therapies do. Maybe there's a signal now that the darolutamide has less of that impact, but it still has some. And so I think that's my experience now over all these years is that the fatigue factor and quality of life is really important. We're seeing more data come forth on that as well.

Charles Ryan: I think, treating CRPC, treating prostate cancer is a bit like running a marathon, right? It's a long journey. You're going to have hills. You're going to have times when it's going to be difficult. You're going to have uphill runs and you're going to have downhill runs. And you're going to have times when you're sort of coasting, and times when you're really sprinting, but you never stop running. And the point I make with that is that you have your difficult times with your patient where you say, "Look, you need chemotherapy." And you've got to hold your patient's hand through that time because they're going to feel it, right? They're going to feel the effect of the treatment, but hopefully, see the benefits of the treatment. So that's like your uphill part in your marathon.

And then your downhill part in your marathon, you're still running, and you still want to move forward and do positive things for the patient, but do you want to have it be where it's just a lighter load. And that's like Xofigo® can do that, of course, we're giving Xofigo® to the patients with pains, that's a little different.

But with sipuleucel, it's like one of those things that you do in the times when you're not in the uphill battle. You don't need to bring out the big guns. Now I'm mixing metaphors. But you can take, a third metaphor, which is, take your foot off the accelerator a little bit. So when you're running the marathon, you take your foot off the accelerator and you bring out the big guns.

Neal Shore: Yeah. Love the metaphor mix.

Charles Ryan: Maybe the editor can take that out.

Neal Shore: Yeah. But just one little point of clarification. When I first started using radium 223, Xofigo®, and I'm proud of the fact that we actually gave the first dose in the US post-FDA approval, and we've been giving it for quite a long time now and being part of EAP, we weren't part of the ALSYMPCA, but now having done multiple other studies, when I first started using it, it was really as a sort of end-of-line treatment, back into that yesteryear thought processes of other radiopharmaceuticals. That's completely flipped for me now. Ninety percent of the patients that I give radium-223 is prior to taxane-based therapy.

Charles Ryan: Yeah, that's where it's been used.

Neal Shore: Yeah. And I think that that's really important because I still hear from our colleagues that, "Oh, I'm going to save this to the very end", which I think is a big mistake.

Charles Ryan: Well, let me point out that radium-223 is approved for patients with metastatic bony disease, right? So you have this window or almost a dilemma. If you have a patient with metastatic CRPC with symptoms, you can choose docetaxel, which will bring their PSA down, shrink their disease burden, or radium 223, which may have a palliative effect and a survival benefit, but doesn't have that remission inducing effect. But remember, those two have been combined. And we participated in this trial led by Michael Morris, where we were able to combine radium-223 with docetaxel. We gave it to patients who were quite symptomatic. And there's a Phase III trial looking at this combination now.

So when we think about the really symptomatic patient with a high burden of bony metastatic disease, there are some data now to support the fact that this is safe to do. And I would urge listeners to consult the publication because the docetaxel was not given at the standard dose, it was given at a slightly lower dose. But it gets to the point of, maybe we don't have to face that dilemma of whether we do docetaxel or radium. We have evidence to show that they can be given together.

Alicia Morgans: I would just caution everyone to consider doing that in the context of a clinical trial, given some of the data that we saw in a larger population, had some data where we were there was a higher complication rate potentially with combinations, that we wouldn't necessarily expect would result in that. We should probably make sure that we complete this Phase III clinical trial before we do a lot of that off-label.

Charles Ryan: I've not giving combination off of a clinical trial. But I'm just saying is that, it gets to the point of this idea of, are we going to have to think about chemotherapy or radium?

Alicia Morgans: And maybe we won't. But I think that that still is to be determined at this point.

Neal Shore: But one of the things that you make me think about, you're talking about combination therapy with radium, I think it was, if you talked to Chris Parker and the folks who were involved in the ALSYMPCA trial, which led to its approval, that there was always the opportunity to combine with, at the time, the BSOC or the best standard of care. And at the time, it was first-generation AR inhibitors, the lutamides, possibly estrogen, ketoconazole, steroids. So the concept of radium was, because of its unique mechanism of action, really well-designed to potentially combine. And of course, we now have a couple of trials that are coming forward right now. There's the PEACE III trial, which is using concomitant enzalutamide with radium-223 in the M1 CRPC bone predominant disease population versus enzalutamide alone.

And we're actually starting a study, hopefully, we'll have the first patient in before the end of the year, called [inaudible], like PEACE III, but different. And the difference is, is we'll have a lead-in period of about 12 weeks of enzalutamide, and then be randomized to receive a six-month full course of radium-223. And this was done on the heels of trying to better understand what's going on in the bone micro-environment, the bone compartment, because of the ERA 223 data, which was somewhat counterintuitive when we saw some increase in fracture risk. And of course, there are issues around the importance of, and you and I talked about this, having bone targeted therapy concomitantly, whether it's denosumab or a bisphosphonate. So I'm super excited about that. And I think that'll really help us better understand the optimal use of radium-223.

Alicia Morgans: So I really think that, in the context of all of these advances in the non-metastatic CRPC setting and the metastatic hormone-sensitive setting, we've had a lot of enthusiasm. But what this conversation reveals is that there's still a lot of enthusiasm to understand how to best treat our patients through the whole spectrum, including the mCRPC setting. And there are many questions that we still have to answer. So I really appreciate both of you taking the time to talk through these issues and really unearth both what some of the data is and where we're going with new trials. And I appreciate your time.

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