E. David Crawford, MD of University of Colorado, Denver in Aurora, Colorado discusses “The Role of Therapeutic Layering in Optimizing Treatment for Patients with Castration Resistant Prostate Cancer.”

Keywords: castration resistant prostate cancer, therapeutic layering, therapeutic agents, RADAR I, RADAR II

Therapeutic Layering for Treating Castration Resistant Prostate Cancer Transcript


E. DAVID CRAWFORD:  We put together a group about four years ago of radiologists, pathologists, urologists, medical oncologists to address the issue of imaging in prostate cancer.  And we saw three areas where there was an unmet need. The unmet need we saw were those newly diagnosed patients, Gleason 6’s, one core getting the bone scan/CT scan.  And that was pretty prevalent.  And there was all of this discussion about medical/legal issues, and you’ve got to scan because once in a while you’ll find something.  And then so what were the guidelines?  And really for all of these things that bucket biochemical failure and the transition from castrate-resistant, non-metastatic to metastatic was not clear either.  What sort of, when do you scan and what’s the value?  And it was to try to cut down on scanning but make the predictive value more is what we really wanted to do.  And so, for the, we did it for the newly diagnosed.  We did it for biochemical, and then we did it for men who were in this castrate-resistant non-metastatic.

When do you diagnose the metastatic disease?  And the importance of that was that all of these drugs kick in when you have metastatic castrate-resistant disease in general.  They’re not for non-metastatic.  They’ll get there.  We heard that, but they’re not there yet.  And so, that, we did that and that was called RADAR I, and we published that, and actually, and everybody’s got guidelines but you know what?  There weren’t any really good guidelines on when to do this in prostate cancer.  And so that actually caught on, and like the EAU and even to some degree now some other organizations are using these guidelines for when to do, and insurance companies, on when to do scanning.  So, that was the RADAR I thing.  And it’s also being incorporated into medical, electronic medical records to kick out when to do scans to diagnose patients with a change in their status.  But you say so what?  But the idea is that in general what happens is when you do that that treatment, earlier treatment is better.  And we know that with a lot of the drugs, and so that was one of the things that we did.  

And then RADAR II was a group we got together last year, and this was just published, and that’s what I’m going to talk about, and the goal in that study was again incorporated in imaging, but to deal with the issue of how you combine these drugs sequentially, combinations, or a term we came up with called therapeutic layering, and the idea was that, is that you keep a foundation and you build on it.  And there is a rationale for that.

And so that’s what this presentation is about, which has never been given before in an audience, and the way it’s going right now it may never. So, what we have here is sort of our presentation on this therapeutic layering, which is a term we came up with and coined a deal with it.  And RADAR III just, as I just mentioned met two months ago at the Broadmoor in Colorado Springs, with a lot of the same people here; myself, Petrelak, Neil Shore, Vogelzang, Tom King, Gomella, Phil Koo has been a real part of it, Raul Concepcion, Neil Stone, Finkelstein, who is from here, you know him, and a number of other people from around the world.  And so that was the, that was the RADAR III thing that we just met.  And the goal of that one was what we’ve just been talking about, all of this new imaging.  How do we incorporate it?  What’s it going to do?  What studies need to be done?  And it’s pretty exciting.  It still shows you that gallium scan, you know, we’re hearing okay you’ve got to wait until the PSA is like 0.6 or things like that.  You know, those things may be used for more advanced disease to look at responses and stuff like that.  So, it’s really a lot of fun and we’re working on that manuscript right now.  So, I want to go over RADAR II.

So, I have ARS questions, I’m not going to ask because that was what was holding us up.  But just raise your hand.  Do you use RADAR I guidelines in your practices?  Anybody use those?  Okay.  Maybe seven people.

And the next one is radium-223 is only indicated in men that had metastatic castrate-resistant prostate cancer and bone pain.  How many say yes?  Okay, one.  How many say no?  Okay, most people say no.  And how many are unsure?  Okay, that’s Dr. Monga, I’m glad you’re unsure because we need to keep you in kidney stone disease, and all of those workups for that because I hate it.  Anyway, all right.

Right now, I want to provide an overview of our RADAR II data, and the goal is I’m going to talk about it a little bit, I’m going to have an introduction.  We’re going to talk about the current landscape.  We’re going to redefine disease progression.  We’re going to talk about initiating and discontinuing therapeutic agents.  We’re going to talk about clinical data for metastatic castrate-resistant disease, focus on therapeutic layering, and a conclusion.

So, my introduction.

The RADAR I group was a faculty that included prostate cancer experts from the field of urology, oncology, and nuclear medicine.  And the goal of the faculty was to make recommendations on appropriate timing and frequency of imaging among different patient types with prostate cancer to help identify metastatic disease early.  And the assumption was, and we have the data to substantiate that, that early identification of metastatic disease has a salutary benefit.  

We, again being cost conscience, wanted to caution against overutilization of imaging.  As you well know, in a lot of clinical trials for drugs that we have right now the imaging was sort of standard, every three months or whatever.  We felt that there’s a different approach to that.  We would initiate imaging when considering starting the therapy, before changing therapy to establish a new baseline, and after completing treatment to monitor progression.  

The importance of PSA trends and clinical context; we need it to discuss PSA is not going away, that it does add something, and also, we wanted to look at performing subsequent imaging when clinically or consistent and convincing biochemical progression is identified.  And so, that was sort of one of the things that we wanted to do.  

RADAR I put patients into three buckets; newly diagnosed disease, biochemical failure, and M0.  Newly diagnosed disease patients were being scanned with low PSAs, Gleason scores of 6 and so forth, and the yield on that was very small.  We felt after reviewing the literature and studying it, and our analysis that what should trigger imaging in newly diagnosed disease, whether they’re going to get surgery, radiation, observation, whatever, is a Gleason score of greater than 7, a PSA level of greater than 10, or palpable disease.  So, any two of those three would be a reason to image somebody.  

Biochemically recurrent patients; okay, those are men who have rising PSAs usually, and are started on androgen deprivation therapy.  What we do know is that we have no trials there to identify a benefit to doing that, yet that is the most common way people get to be castrate resistant today.  So, depending on who your reader believed 40,000 to 60,000 men a year will fall into that biochemical recurrent category, and then undergo ADT.  And that was an unmet need too to look at that.  We thought that this should be done, the first scan should be done when the PSA level is between 5 and 10.  We did not find really a lot of evidence to suggest to do it below that.  And then imaging should be done as second scan if it was a PSA above 20, and every doubling thereafter.  Okay?

This is a different group than this group, the castrate-resistant group.  This group you can have a positive bone scan when your PSA is less than 10.  And in fact, we felt that the first scan should be done when the PSA is less than 2, or greater than 2.  Imaging frequency would depend on these sort of PSA bound, when a PSA got to 5 and then every doubling thereafter is a reason to do another scan.

But what we can say despite improvements in survival metastatic castrate-resistant prostate cancer continues to pose clinical challenges.  Survival has improved due to our new therapies, all of the new drugs we have out there.  We have for instance, and a number of these things are showing early is better than later, and improvement in overall survival rate with sipuleucel-T.  Paul Schellhammer reported this.  We reported this.  In quartiles when you’re PSA was less than 22 you enjoyed a 13-month survival benefit.  When it was 75 to 100 what was seen is you’ve got a survival benefit, but it wasn’t 13 months, it was 3 to 5 months.  This is not lead time bias because this was a randomized trial.  The same thing has been seen with abiraterone, enzalutamide, moving it up earlier, studies being looked at, randomized trials showing early is better than later.   

So, now castrate-resistant prostate cancer continues to be a challenge due to the heterogeneity of the disease.  And one pathway to treat this and put in another drug with similar inhibitions in the pathway together does not always make sense.  So, the approach is different pathways and different ways to attack it, and maybe we’ll have a better approach.  The optimal use of the current therapies to achieve maximum clinical benefit is not well established.  Clinical research is ongoing.  But what we’re doing is sequencing A, B, C, and D rather than more combinations initially or adding things on, which we call therapeutic layering early.  

So, the goal of our group for RADAR II was to provide a consensus on sequencing, combinations, and this new term we came up, and I’ll define that, called therapeutic layering.  

Combination therapy is not uncommon in oncology, and it’s not uncommon in prostate cancer.  We will do things like ADT.  We might add an anti-androgen.  That’s combination therapy.  We called it that way a long time ago.  We may add chemotherapy.  We may add other things.  

We define therapeutic layering as different from combination therapy.  Therapeutic layering represents a clinical point where one or more agents are added onto an existing therapy.  So, here we have this agent.  We might start right here with another one.  We might start right here with another one.  So, we’re layering these things on as we go through this.  

The questions that we considered when we put together this group was disease progression and how do you define it, when do you scan, and so forth.  And then initiate and then discontinuing therapies, and I’ll go through each one of these here in a minute.  How should they be initiated?  What should be initiated, when to stop, when to continue, when to go and rescan and so forth.

But before we begin we have to know what the tools are, what the players are, what’s the current metastatic castration resistant prostate cancer treatment landscape?

And this is a dynamic landscape that’s changing, although the primary agents we have are listed on this, and include immunotherapy with sipuleucel-T, we have chemotherapy with docetaxel and cabazitaxel, we have abiraterone acetate, we have enzalutamide, and we have radium-223.  

So, we have five different categories with different patterns and different results, but what we do know is when they were studied in metastatic castrate-resistant disease that all of them resulted in an overall survival benefit, and most of them in a progression-free survival benefit.  But then they have different mechanisms of actions.  Our friend PSA isn’t so helpful in monitoring actions and responses with sipuleucel-T and with radium-223.  

We have various cycles that are used; sipuleucel-T is three, docetaxel ten cycles every three weeks or so, abiraterone as it is here, and radium again is a six-cycle drug.  

So, the current guidelines aren’t very helpful.  We have, I lose my pen here Paul.  We have the NCCN, we have the AUA, we have ASCO, Canadian Urological, and ESMO.  And what happens with all of these if you look here in the bottom what we see is they line all of these things up, but they don’t give you an answer on how to sequence them.  Okay?  So, we’ll go to the next slide.  

And the concept here is in fact this thing about layering, and where we sort of, is it because I pushed this maybe?  Let’s try it.  Okay.  Okay.  Keep talking?  All right.  So, the concept going back to, there it went, there it is, going back to the, I don’t know what Lee did but okay.  So, the concept is that we have some, you know, this transition from asymptomatic to symptomatic mRPC.  So, we’re in the mRPC category here.  And so, we always use best supportive care.  We always continue ADT, whether right or not, and then how do we put this stuff in?  Where do they fit?  And we’ll talk a little bit about immunotherapy fitting earlier.  We call these things androgen pathway inhibitors.  So, that includes enzalutamide and abiraterone.  And then we have targeted alpha therapy.  We’re being very specific about what radium is.  It’s not beta therapy, chemotherapy, and so forth.  

So, let’s redefine disease progression.  Let’s do it.

How is disease progression define?  What is the best way to determine progression while a patient is being treated with these therapeutic agents and so forth?

So, the RADAR II group defines progression as convincing evidence and a consistent rising PSA.  PSA has to play a role, and it probably plays more of a role here than it does in the biochemical failure stage.  Evidence for a radiographic progression is strong, and clinical symptoms.  So, these are some of the three things in the mix.

So, how do we put these together?  And there was a lot of discussion.  How do you, not using the word sequence, but how do you layer these things?  Well, certainly immunotherapy there’s plenty of evidence that that works better earlier, and not just in prostate cancer, but in general, that immunotherapy works better.  So, that puts sipuleucel-T here, and we feel that it should be up there, and this is what’s in a lot of guidelines; it should be considered for all newly diagnosed asymptomatic and minimally symptomatic disease.   

Then comes the androgen pathway inhibitors.  They can be initiated right away, which we think is something to consider, or you can wait for a change in the PSA or some other sign of clinical progression.

We also feel that the targeted alpha therapy, which means radium-223 can be introduced on the first sign of progression on androgen pathway inhibitors for patients with bone metastases and symptoms.  And we emphasize that radium-223 has an indication for symptomatic prostate cancer, not for bone pain.  And it’s in that umbrella.  Symptomatic prostate cancer means a lot of things.  You have muscle pain, you have lethargy, other things like that that happen.  You have problems sleeping because moving around, and not necessarily bone pain, but things like that.  So, there are a whole bunch of things that fall into that.  

And then chemotherapy is moving away from early to later, and we know that we’re going to see some patients that have had chemotherapy earlier because of the CHAARTED data, but we’ll talk about that in a minute.  Chemotherapy can be administered after abiraterone or enzalutamide, and radium-223.  But what you can’t do very well is administer chemotherapy concomitantly with radium-223, and we’ll hear more about that.

So, the recommendations on initiating and discontinuing therapeutic agents.

How early should treatment be initiated in men with metastatic castrate resistant disease?  And in the metastatic setting?  

All right, so we know, let’s go back to what we know from CHAARTED, STAMPEDE, and GETUG trial and so forth.  And what this is going to do, if it’s widely implemented, is it’s going to affect how we look at things down the pike when somebody has already had, they’ve had Taxotere, which we’ll talk about cross-resistance, they’ve had androgen pathway inhibitors and so forth earlier on.  But we do know, just going back and looking at CHAARTED and things like that, I think there’s pretty clear evidence, we all know that high-volume disease, chemotherapy should be administered early in newly diagnosed metastatic prostate cancer.  The study was not somebody that was diagnosed a year ago, is on ADT, and doing okay, and adding Taxotere.  That was not the study.  The study was adding docetaxel upfront newly diagnosed disease within three months.  Okay?  So, when people start saying well I think we should do this at two years that’s not what the study was.  

The study also showed low-volume disease did not benefit.  And so, people say well you’ve just got to give it some time.  This study did not show that low-volume disease benefit.  And there may be a biological reason for that.  And what we do know is in our opinion, that starting patients with newly diagnosed metastatic castrate-resistant disease, unless they have soft tissue, liver, things like that, is that chemotherapy is not the first thing that we recommend.  

So, clinical data, let’s go through it.  

We go through immunotherapy, everyone is familiar with the sipuleucel-T trials.  This trial was positive, favoring sipuleucel-T.  We feel that going along with the results of the trial that this sort of asymptomatic, minimally symptomatic patients, low disease burden, and sort of indolent disease characteristics.  As I already mentioned, we showed that a lower baseline PSA of less than 22 actually conferred a 13-month survival benefit.  In the post-chemotherapy setting sipuleucel-T can also be used.  There’s evidence that the immunological aspects of it last for a long time, in some studies up to nine years.

And the other thing is there was always this worry about putting somebody that’s on sipuleucel-T on say abiraterone where you’re using a steroid.  Would that interfere?  And we’ve known for a long time that that’s sort of a homeopathic dose of steroids.  It’s not a huge dose of steroids, and that it’s not going to interfere within it.  So, it’s been looked at with enzalutamide, abiraterone, and radium.  

Second-generation androgen pathway inhibitors a big step forward, and current guidelines recommend early initiation of these things, abiraterone and enzalutamide for patients with or without minimal symptoms in the prechemotherapy settings.  So, those were the studies that were done.  The COUGAR-302, PREVAIL trial, things like that that showed that giving the drugs earlier mattered.  

The RADAR II recommends second-generation androgen biosynthesis inhibitors following immunotherapy at some point.  And I don’t think you have to wait a long time.  Get your immunotherapy in and add it is my opinion.  That is therapeutic layering, start with one of these.  

We also know that in de novo trials that not everyone responds to these androgen pathway inhibitors.  Here is an example of enzalutamide from Cancer in 2013 showing some people have a wonderful response, some people have an intermediate response, and some people fail to respond at all.  

Targeted alpha therapy, I’ve mentioned that, and this is one of the only studies that showed a survival benefit that following second-generation androgen pathway inhibitors in patients showing some signs or symptoms, symptomatic prostate cancer with bone mets that radium-223 should be added.

There are also these doublet trials ongoing with radium-223, which is targeted alpha therapy, and using it with some other combinations, including the targeted alpha therapy and so forth.  And as mentioned, there may be some rationale for this targeted alpha therapy and affecting stem cells.

Just the last couple of things; when should therapy be changed?  And should treatment continue beyond progression?  Do you abandon your treatment?  Changes is therapy should occur after careful consideration of the mechanism of action and the type of progression.  So, sipuleucel-T, radium doesn’t really affect PSA as we well know, things like that.  

Changes based on PSA alone are not generally recommended, particularly in the setting of favorable PSA kinetics.  So, a PSA going up very, not very abruptly versus like that is completely different.  And the St. Gallen prostate cancer conference that Neil Shore and a bunch of people were involved, again cautioned against stopping treatments with a proven survival benefit on the basis of a PSA alone.  That was our RADAR I thing about other imaging and so forth.  

And symptomatic and radiographic progression is more of a reliable tool.  PSA progression alone should prompt reimaging but really should not result in change unless you see some changes.

When should treatment be started and when should treatment be discontinued?

Consider augmentation rather than switching.  That’s the layering, so somebody is not responding to our androgen pathway inhibitors or their PSA is failing doesn’t necessarily mean you should stop them.  Maybe because what we do know is that this group of treatments may be suppressing some clonal diversity, and by releasing that you may have an upswing in growth in that clone.  If that makes sense.  So, sequencing may allow clone suppressed by the current treatment to re-emerge.  So, that’s why we said maybe continue it and do the therapeutic layering.  Similar therapeutic layering, adding a new agent to ADT is what we sort of do already.  

So, the last thing is should second-generation androgen pathway inhibitors, abiraterone and enzalutamide, be used sequentially?

And the answer is the ideal sequence of abi and enzalutamide has not been established.  Sequential administration may reduce anti-tumor activity.  Therapeutic layering of both together may be okay.  There have been some small studies.  There is some suggestion because they have different mechanisms of action, but we don’t know.  Even with PSA responses magnitude and duration of response may be diminished with second-line androgen pathway inhibitors.  We know about the AR-V7 study, the story rather.  We know that chemotherapy can also, docetaxel may interfere with the androgen receptor and things like that, so then maybe that cross-resistance that occurs.  

And so, that’s this slide, the cross-resistance has been demonstrated between cabazitaxel and androgen pathway inhibitors.  Cross resistance with taxanes and abiraterone and enzalutamide has also been shown as microtubules have important role of shuttling androgen receptors to the nucleus.  Okay, so you knock that out, and as you know, these are microtubular inhibitors.  Taxane efficiency may be reduced in tumors that have developed resistance to these things.  AR-V7, we talked a little bit about that, that that may be a marker and is a marker.  There’s probably lots more, and the importance of this is here, but we’ll probably get more information on that in the future.

Switching from one generation androgen pathway inhibitor to another after progression is not recommended in most situations.  Based on the current state of data, switching therapy from one second generation to another after progression on the first agent is not recommended.  However, a switch may be considered under the following circumstances; prolonged treatment response greater than 12 years, 12 months rather, or if the patient is a poor candidate for or declines on taxane therapy.  

Radium-223 here is an option that can be layered on these second-generation androgen biosynthesis inhibitors, pathway inhibitors.  If chemotherapy is administered between one novel hormone agent and another there may be re-sensitization of the patient’s tumor to the second generation androgen pathway inhibitors.  

So, focus on layering, finishing up here.  

Most effective sequences, combinations, or therapeutic layering in metastatic castrate-resistant prostate cancer.  We think that potential benefit of combining agents for metastatic castrate-resistant prostate cancer were assessed in several small trials with larger trials ongoing.  So, this is happening.  The optimal timing, the sequence, and the combinations are being studied.

So, the most effective way I think to look at this is we have had the androgen pathway inhibitors, they’re easy to layer on with ongoing trials and chemotherapy.  We just, we’re seeing that.  It’s easy to layer on with sipuleucel-T.  We know that radium-23 can concur in administration of radium-223 in second-generation androgen biosynthesis inhibitors, is well tolerated, there are studies ongoing with radium-223, denosumab, abiraterone, enzalutamide, and so forth.  

And also, sip-T successful administration, concomitant administration of abiraterone with that with prednisone is effective, and there was some concern about that, but that doesn’t seem to be real.  The same thing with enzalutamide, which obviously you don’t need prednisone with that, as well as radium-223.  

So, this is exciting times.  Despite great strides in metastatic castrate-resistant prostate cancer management selecting a treatment to optimize outcome remains a challenge.  I showed you these guidelines and they just line these things up.  There’s no direction given.  And you can be a purest and say we don’t have randomized trials to prove all of this stuff, but we do know that some of this makes sense, this therapeutic layering.  

Metastatic castrate-resistant prostate cancer is best managed with different agents, especially those with unique and complementary mechanisms of action to avoid cross resistance, as long as we don’t have increased toxicity.  Optimal treatment selection may depend on molecular characterizations, genotyping, lots of other things that out there.  We’re getting more focused precision medicine.  We know that in some men PARP inhibitors make sense, if you’re BRCA 1 and 2 positive.  

Clinical trials remain an important need, and we need to do those.  They’re not easy to do, and they’re getting harder to do because of all of these drugs out there.  And the competition for patients and you can’t blame a company that has a new drug.  They’re not all willing to say I want to put that with five other drugs and have a mixture.  You know, it’s unfortunate, but that’s the way of life.  And yeah, a lot of these studies are being done outside of the United States.  

The RADAR II group recommendations are based on available trial literature and real-world experience, but optimal patient care continues to be the judgement of each physician.  But at least there’s some excitement here, and that’s what we did with this RADAR II thing.