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Case 1 From the Practice of Dr. Neal Shore

N. Shore (USA)

SlotX-3 Shore, N. - Case 1

Neal Shore presents a patient case of a 62-year-old male who presented with an elevated PSA of 11.5, discussing the management and treatment of the patient.

Transcription

It is a privilege to be here at ESMO ECCO and we look forward to an interactive discussion. 

Patient case presentation

I was asked to present this case; this is from my practice.  I have had the interesting distinction and pleasure of administering the first dose of radium-223 in the world post FDA approval, but this is a different type of case and we will see if you agree with all of the management. 

Full transcription

Full transcription

It is a privilege to be here at ESMO ECCO and we look forward to an interactive discussion. 

Patient case presentation

I was asked to present this case; this is from my practice.  I have had the interesting distinction and pleasure of administering the first dose of radium-223 in the world post FDA approval, but this is a different type of case and we will see if you agree with all of the management.

This was a 62 year old male who presented with an elevated PSA of 11.5.  It may not have been during the time that the US task force had now abandoned the recommendation for screening, but lo and behold he had a PSA. 

He subsequently went on because of this, despite a normal digital rectal exam, had a biopsy and a Gleeson 4+3 with six out of 12 cores involved and chose at that point, in early 2013, to undergo a radical prostectomy.

There were positive surgical margins and ultimately the patient went on to get adjuvant radiation therapy and had a nadir PSA of 0.8 prior to beginning radiation treatment. 

Approximately six months later the patient has a PSA of 2.1, clearly suggesting micro-metastatic disease, or perhaps even persistent local failure.

Literally three months later the patient has now had a doubling time to 4.1, his testosterone level is measured; it is eugonadal.  A radiographic evaluation is performed and the patient how has no evidence of disease on full body CT.  Interestingly the guidelines would suggest in the setting of newly diagnosed not to get these radiographic testing, but clearly in somebody who is now with this type of doubling time and failed localised therapy, scans were obtained. 

Technetium bone scan was also negative, but the patient, because of age and the apparent biology of the disease was started on androgen deprivation therapy in the form of the GNRH antagonist, degarelix.  PSA declines, nadir to 0.5, testosterone levels obtained and it is below the recommended level of 50 and, in fact, it is 8µg/dL.

Patient case presentation

Subsequently after a nadir, the patient by early winter the following year now has a PSA of 2.5 and a sodium fluoride PET scan is obtained – sodium fluoride PET is not in the guideline standard of care within the US, but it does have a reimbursement methodology currently and is obtained and these two lesions are confirmed by a confirmatory MRI of the spine.  The patient at this point is asymptomatic.

Voting (1X)

The first question would be, this is a patient who now is now arguably M1, CRPC and completely asymptomatic.

Audience question

Would you treat with abiraterone acetate, enzalutamide, docetaxel or observe?

[Vote]

Okay.  Interesting.  All three answers are in the labelled indication for this patient population.  One could certainly even make an argument for four, depending upon patient preference. Perhaps now is a good time to ask you, Marie, Chris and Francis to weigh in on your thoughts on these responses?

Maria De Santis:  To start with I am a little bit surprised about the “observe” of 31%.  In my practice most probably I would not observe the patient any longer at this point, but start with active treatment.  Perhaps it is not so important which treatment because we know all the treatments we have in hand provide a survival benefit and also a quality of life benefit etcetera.

I would rather not wait any longer, but I wonder how Chris and Francis are seeing this?

Chris Parker:  I agree.  I would definitely not observe; we have many therapies that will improve this man’s survival and unless we get on and start using them he is going to die before he gets them all.  It is an important principle that this man wants to have all the life prolonging therapies that are available and so don’t delay now. 

In the UK most of my patients would much prefer to have Abi or Enza rather than docetaxel; invariably they choose the less toxic treatment before the more toxic.  I also think in the UK probably the most common choice is none of the above; I think dexamethasone 0.5mg daily would be the preferred therapy in the UK.  It is 1,000 times cheaper than abiraterone or enzalutamide and has a response rate of about 50% and a median time to progression of 12 months.

Maria De Santis: Any comment from your side, radiologist?

Francis Sundram:  Just a comment on the imaging side of things.  Perfectly sensible approach, using multi-modality imaging.  If the CT and the bone scan is negative certainly the way to go for bone metastases would be PET sodium fluoride bone scan, which has proven increased sensitivity and also specificity for detection of bone metastases.  Obviously, depending on availability, expertise and the reimbursable aspect of it, a choline PET CT is also something to be considered in the case of a rising PSA, where conventional imaging is negative or equivocal. 

Maria De Santis:  One question from my side: the patient had two new bone lesions, you did not consider radium-223?

Neal Shore:  It is a very interesting question.  We could have considered radium-223, except he was asymptomatic and based upon the label – we will probably get to this as well, he was not any type of analgesic for these bone lesions and that is why it was not considered.

Marie De Santis:  Thank you.

Neal Shore:  Just to respond to you, I would agree that there has been this overwhelming historic nihilism about avoiding treatment in the asymptomatic patient for so long, both within the urology and the medical oncology community, but there is so much more data now, at least with these choices, that we have life prolonging agents, especially in somebody who is asymptomatic.  Chris Parker’s point is a really good one in that my way of thinking is to make sure if I am going to treat a patient that I have that shared discussion so that they have an opportunity to receive all of the CRPC therapies before they potentially could succumb to the disease.  I have that rather frank discussion with my patients and I am glad that Francis agreed with the imaging so that I wasn’t over-using it at the current time.

Abiraterone in chemo naïve mCRPC

The patient actually went on to get abiraterone and this is the Kaplan-Meier curve of the COU-AA-302 trial that really demonstrated the first oral agent that would have a life-prolonging effect in patients prior to receiving chemotherapy and the final, overall survival benefit of 4.2 months.

Patient case presentation

The patient goes on to receive abiraterone acetate plus prednisone and sees a decline in his PSA to 1.7.  Testosterone levels, as you would expect typically, by lowering the androgen biosynthesis impact of adrenal androgens and potentially metastatic sources of androgen you end up checking the T level and it is virtually undetectable. 

Over the course of time and a rather rapid time, his PSA starts to increase and goes from 1.7 to 4.5 over approximately a five month basis.  He has a repeat sodium fluoride PET and there is no significant change in the lesions.  He is, at that point, asymptomatic.

Patient case presentation

A few months later his PSA goes up rather briskly to 7.9 and CT scan imaging is repeated and there are now three new retroperitoneal lymph nodes, each with greater than 1cm in size.  A repeat sodium fluoride PET reveals new T spine as well as rib lesions.  Going now from axial to appendicular lesions. 

In discussion with the patient, and I remember this and this is an interesting phenomenon that I see in many of my patients, that he declined to acknowledge any type of change in symptomatology.  He was fine taking his abiraterone acetate and prednisone, wasn’t having any real significant complaints, but in discussing it with his wife she noticed that he was now taking large doses of ibuprofen as well as Acetaminophen. This was something that was new and was also impacting his daily performance of his activities, although he, himself, was not complaining of pain.

Voting (1X)

Here is the next question.

Audience question

As Maria was asking earlier, would you use radium-223 for a patient who is not on opioid analgesics?

[Vote]

This is a very bright audience; this is great.  You will be familiar with this slide then.

Radium-223 demonstrated a consistent overall survival benefit regardless of patient subgroup

If you look at this forest plot, the subplot analysis post-hoc in the ALSYMPCA study one can see, using alkaline phosphatase as a baseline marker for patients who had improvement in starting on therapy and all that reflective of median overall survival, in that study bisphosphates were also stratified as a pre-hoc analysis and whether or not patients received docetaxel or not.  One also sees a benefit to receiving radium-223.

What is interesting is at the very bottom one can also see the opioid use, whether it was present or not and roughly 55% of the patients were on narcotic analgesics.  Another 45% of the patients in the ALSYMPCA trial were taking things such as ibuprofen, Acetaminophen, COX-2 inhibitors. 

These patients benefitted as well from a survival standpoint.  The 63% who voted “Yes” obviously understood that data.

Survival and opioid use at baseline in ALSYMPCA

Here is the Kaplan-Meier curve again showing survival benefit vis-à-vis opioid use or a lack of opioid use at baseline, demonstrating the impact of the prolongation survival by using a full course of radium-223, which is six cycles.

Patient case presentation

At this point the patient was, in my clinic, added; we did initiate a course of radium-223 based upon discussion that I had had, not only with him but with his wife, and six cycles were completed.  As we have seen and it has been my experience, I would be interested to hear the rest of the panel, it is very well tolerated and the patient was kept on his abiraterone acetate despite the rising PSA. 

Radium-223 significantly improved overall survival regardless of prior docetaxel use

As I mentioned and you saw a minute ago, in the subplot analysis, the forest plot, everything to the left demonstrating statistically significant benefit of the use of radium in the trial, whether or not they had received chemotherapy or not and so now myself and others, Hoskin has published in Lancet Oncology that when we break down that group the totality of the overall survival for ALSYMPCA was a 3.6 month survival benefit versus the placebo infusion that they received.

Both arms received best full supportive care, but if you look at this slide, you see the patients who did not receive chemotherapy versus those who did receive chemotherapy and the median overall survival benefit in those prior to receiving chemotherapy is a 4.6 month survival benefit versus a 3.1 month in those after chemotherapy, which seems to be intuitive, but of course one needs to understand that and see that in the context of looking at the analysis.

In my own personal experience, when radium-223 was first approved in May of 2013, the overwhelming number of my patients that I treated were all post-chemotherapy and this patient now, in 2014, like most of my patients today, are invariably in the pre-chemo population.

Disease Progression Despite Hormonal Therapy           

This graph really illustrates very nicely and we are all familiar with this rollercoaster progression of our patients who we treat with localised therapy.  20 to 30% may fail surgery or radiation. The truncation of the timeline until we start them on androgen deprivation therapy and then invariably they will progress over a one to three year period, depending upon the biology of their disease and develop CRPC after they have nadir.

Once we start them on therapy, and one can look at this data from the COU-AA-302 and it is rather superimposable if you were to put in the PREVAIL trial as well is that often times the earliest sign of change is PSA elevation, yet the patient is not complaining of any symptomatic progression.  What usually comes next is radiographic progression, so there is this drift, as Howard Scher and others have described, this drift of the PSA, particularly in those who have had a very strong response to the novel orals, whether it is Abi or Enza, but then there is this moment when we are saying to ourselves and our patient “The PSA is going up.  They are not complaining of any symptomatology.  When is the best time to order that radiographic test and am I asking all of the right questions at the right time regarding their symptomatology and perhaps even their care givers need to be brought into the discussion?”

Patient case presentation 

After completing a course of therapy, repeat scans were obtained and I believe here was again a CT scan and a technetium scan and there were no new lesions.   The PSA had increased to 11.2 and the patient was now completely asymptomatic.

Four months later there was a complaint now of renewed back pain.  Scans again did not show any demonstrable change, except CT scan reveals new, small pulmonary nodules, clearly distinct from previous scans.

Voting (1X)

Audience question

Instead of a PSA rise we have a patient with new lesions who does not have a significant change in symptomatology.

How would you treat the patient now?  With either palliative car, enzalutamide, docetaxel or a clinical trial?

[Vote]

That is really interesting.  I will stop for a second; any thoughts on that management by the audience, Maria, Chris, Francis?

Maria De Santis: Chris, would you like to start?

Chris Parker:  I agree with the audience.  I think docetaxel would be the preferred option at this point.  Palliative care would be completely wrong because we still have three agents that will improve this man’s survival.  Of course one can’t argue against clinical trials at any time.

If I could make a comment on your management, Neal, earlier on?

Neal Shore:  Yes; do I need to wear a shield right now?

Maria De Santis: This is what I expected; very good.  I will lean back.

Chris Parker:  When the patient was progressing biochemically on abiraterone and prednisolone I agree it was entirely appropriate to add in radium.  I would have switched the prednisolone to dexamethasone so that steroid switch from Abi-pred to Abi-dex we observe a PSA response in around about 20/25% of cases.  That is helpful, particularly with patients on radium, because I guess this guy’s PSA carried on going up throughout his radium treatment.  It is just easier to keep people on treatment when their PSA is going down and so for that reason I would have done the steroid switch.

Neal Shore:  That is a great point.  I have adopted your championing of dexamethasone, but usually I do it in my post-chemotherapy patients.  You have done some great work with it.  Interestingly I haven’t pushed that in the pre-chemotherapy population.  I have sometimes with this population in the past, I had switched to enzalutamide such as the 16%, but a lot of the single institution data that we have out there, whether it is retrospective of prospective, shows that you may see benefit, you may get PSA declination as you are describing, but often times it is very short-lived.      

The question is does this patient, what type of mutational pathway has happened to him now that is AR has become activated?  Is it a splice variant or is it something else?  Of course docetaxel is abundantly reasonable at this point in time.  Maria?

Maria De Santis: I just wanted to step in here because one year ago at the ESMO meeting we had a similar discussion about the change of prednisone and dexamethasone and I remember that Eric Small jumped up and said “There is no data for that and this should not be adopted for clinical practice”.  You do it in your clinical practice and you would not be cautious to use it without having level 1 evidence, right?

Chris Parker:  I guess one is never going to get level 1 evidence; there is never going to be a randomised trial comparing that approach versus not.

Maria De Santis:  You are confident that this is safe and you do it on a regular basis?

Chris Parker:  We do it all the time.

Maria De Santis: Okay.  My second question may ask another question to Chris here.  What about combining drugs with radium-223?  Do you also adopt this for your daily practice, just continuing with one of the hormonal agents and then adding radium or the other way around?

Chris Parker: Throughout the development of radium-223 it has always been used in combination with best standard hormonal treatment.  As the best standard treatment has evolved so as the appropriate combination. In my particular practice I don’t have the ability to use radium in combination with abiraterone or enzalutamide; if I did I would.  Therefore, I tend to use radium in combination with dexamethasone.

Maria De Santis:  Okay, thank you.

Neal Shore:  That is a great comment, Maria, that it is true that there isn’t any level 1 evidence that Chris purports and he is a big champion of the doses of dexamethasone.  I have seen and you might have seen it, some really nice PSA declines.

Interestingly when I use abiraterone in this patient population I will often times go from the 5 BID to the 5 QD now in most of my patients, just for simplicity and compliance purposes.  The important question you brought up was the concomitant use.

We have here at ESMO today, there is a poster presentation. I believe Oliver Sartor is the first author, I am one of the authors on it; Chris, I think you are on it as well, or if you are not you should be and you have probably done such great work with it. 

Basically we looked at the expanded access programme and this is the first little less than 200 patients in the United States and there was already in the expanded access programme a tremendous amount of concomitant use of both abiraterone and enzalutamide.  It is an important point, as Chris brings out in the ALSYMPCA trial, best standard of care was allowed, i.e. ketoconazole and a sort of more muddy androgen biosynthesis inhibitor. Earlier generation lutamides, such as bicalutamide, nilutamide and flutamide were all allowed as well as steroids, oestrogen and radiation therapy.  That was built into the trial and it was balanced amongst the arms.

In my own clinic we have just completed an investigator initiated study of 40 patients who received concomitant abiraterone acetate, full dose prednisone 5 BID and a full course of radium-223 and have to have received all six cycles to be considered valuable.  We plan to present that efficacy and safety data, hopefully at GU ASCO this year.  That is how I am doing it now in my clinic.

Fortunately we have not had problems in reimbursement currently.

Maria De Santis:  Just one more sentence, the only combination that is excluded is a combination with docetaxel, right?

Neal Shore:  It is a great point.  There is a nice paper by Mike ?Mars recently – they presented at ASCO using some dose modifications of docetaxel 60mg and even some slight modification of radium scheduling and showed very nice tolerability.  Maria is exactly right, there is only one drug that is concomitant exclusion and that would be a taxane based therapy.    

Maria De Santis:  At least for the time being, until we have more data.

Neal Shore: Yes. Great point.

Patient case presentation

The patient continued to have his mild back pain as you see in the results here.  He was offered docetaxel but instead he elected to enrol in the PRIMCAB trial, Maria showed you that earlier, which is an interesting trial looking at presumed mutational progression, potentially AR-V7.  These are patients who get randomised who have progressed on either Abi or Enza to cabazitaxel or in the other arm to either Abi or Enza, whichever one they did not progress on.  That is where he is today.

Case Summary

Here is a case summary of how this patient was managed.  There are some great take-home points about the concomitant use of therapy.  Some of the scans that we chose to do at that time, I am really interested to hear Francis’ presentation because that is an area that is obviously undergoing as much mutational analysis as all the different markers are in the field of prostate cancer.  Thank you.