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Metastatic CRPC: Multiple Choices...a Double-Edged Sword? + Panel Discussion (all Faculty)

M. De Santis (United Kingdom)

SlotX-2 De Santis, M.

Maria De Santis talks about clinical trials in mCRPC and considers the results. The presentation looks at the use of biomarkers in daily practice. A panel discussion follows.

Transcription

Multiple choices – a double-edged sword? 

Have we made progress in extending survival of patients with metastatic CRPC?

I think and I hope you agree, we have made progress in the treatment of metastatic castration resistant prostate cancer.  We have extended the survival of patients.  Remember ten years ago in the TAX-327 trial patients lived around 19 months.

Full transcription

Full transcription

Multiple choices – a double-edged sword? 

Have we made progress in extending survival of patients with metastatic CRPC?

I think and I hope you agree, we have made progress in the treatment of metastatic castration resistant prostate cancer.  We have extended the survival of patients.  Remember ten years ago in the TAX-327 trial patients lived around 19 months.

In the more recent COU-AA-302 trial with abiraterone, the median survival of the patients was nearly three years.  Admittedly another patient population and we can’t compare those trials directly, but I think we all agree we have made progress.

Key phase III clinical trials in mCRPC since 2004

This is a slide summarising the trials that were conducted, randomised Phase III trials since 2004 and those agents with the red frame are the combination trials with docetaxel.

Key phase III clinical trials in mCRPC since 2004

And here you see that many of those trials, the randomised Phase III trials failed but those in the green boxes were the trials that made it to approval for the treatment of metastatic CRPC.

Similar magnitude of survival benefit by available treatments

And these agents, docetaxel, sipuleucel-T, abiraterone, enzalutamide, radium-223 and cabazitaxel showed a similar magnitude of survival benefit.  The hazard ratios were very similar and the survival benefit was between three and 4.4 months.

Guideline summary:  No clear sequencing recommendations provided

Now all those agents we have in hand now are recommended by the guideline groups in Europe and also across the ocean in America, in the US and North America.

But as you can see here they are all recommended.  However, we have a lack of guidance how to use them and the guidelines actually are not of so much help with this respect.

ESMO Magnitude of Clinical Benefit Scale (MCBS)

The ESMO made a new initiative and it developed a tool to show the magnitude of clinical benefit in a scale, the MCBS and I think this is an interesting tool allowing the evaluation of drugs with combining factors of overall survival and factors of improved quality of life and reduced toxicity.

Key Aspects of the ESMO Score

Here is a visualisation of that interesting scale and with non-curative therapies it is a scale from one to five, five being the best benefit and one being the lowest grade and I would like to encourage you if you are interested in this scale and that field to join the ESMO symposium on Monday which is on especially that topic.

ESMO Magnitude of Clinical Benefit Scale for prostate cancer

Now this scale was also tried out and published in the Annals of Oncology for prostate cancer and this is the table from the Annals of Oncology showing that the agents with the best benefit according to this scale are radium-223, abiraterone and enzalutamide which you can see on the right-hand side here.

Unmet medical needs in mCRPC

Still I think we all agree there are unmet medical needs for mCRPC; the need for a predictive biomarker to take treatment decisions, for example.

We still do not know exactly how to best sequence therapies, we need to better understand resistance and we need indications how to switch treatments.

Slide

Let’s go again to the voting devices and I have two questions for you.  The questions are related to the biomarkers.

E-voting question

Do you routinely test for these markers and you can start now with your voting; PSA only, ALP only, LDH only, PSA and alkaline phosphatase, PSA, alkaline phosphatase and LDH or none of them?  Please vote.  [Pause for voting]

Let’s see how many of you are staying with one marker.  Okay, PSA only, 23.1% - very interesting and all the three, nearly 50%. We will come back to your answers after my talk and I will ask the panel what they think of it and we will ask them to comment.

E-voting question

The second question is do you base your treatment decisions on PSA alone?  Here just yes or no – please vote now.  [Pause for voting]

Oh wow, this is interesting – 92% for no.  We will discuss this later on and see which other markers you use for treatment decisions.

Biomarkers for daily practice?

→ general use and nomograms

I would like to go on and show you the biomarkers that made it to a nomogram.  The Halabi nomogram is shown here published in the Journal of Clinical Oncology and you see, and what I wanted to point out actually is there, that down here you have PSA and you see that PSA has actually little impact on the nomogram points up here, much less than for example ECOG performance status or other markers.

So in the metastatic castration resistant setting, PSA seems not to be so important to predict survival.

Primary resistance to AR-targeted agents

Resistance, one of the other unmet needs; predicting resistance seems to be important.  You see here out of the COU-AA-301 trial and the AFFIRM trial that one third to one fourth of patients is primary resistant to these all hormonal drugs.

AR-V7 as a predictor of treatment outcome to enzalutamide and abiraterone

AR-V7 is a truncated form of the androgen receptor that lacks the ligand-binding domain for enzalutamide and abiraterone has been discussed a lot for the last year.

AR-V7 is associated with outcome (PSA50, PFS, OS) of Abiraterone and Enzalutamide

AR-V7 is associated with outcome, with outcome PSA, PFS and overall survival outcome.  This has been published in the New England Journal of Medicine by Antonarakis and this association is true for enzalutamide as you can see here as well as for abiraterone.

AR-V7 is associated with outcome (PSA50, PFS, OS) of Abiraterone and Enzalutamide

So maybe the presence of AR-V7 on circulating tumour cells might become a new predictive biomarker. If so it would be the first predictive biomarker for prostate cancer.

When to switch therapies?

The last question is when to switch therapies?  Which factors should we consider to guide our treatment decisions to switch and we will come back to this question in the case presentations and also in the presentation of Francis Sundram.

The optimal sequence or combination of approved agents is currently unknown

And last we have very little data on the optimal sequencing of drugs unfortunately.  Two of the few ongoing trials are listed here, the PRESIDE trial and the PRIMCAB trial.

The PRESIDE trial looking at patients progressing on enzalutamide and then randomising to enzalutamide plus docetaxel or docetaxel alone and in the PRIMCAB trial looking at patients being resistant to abi or enz and then randomising to cabazitaxel versus abi or enza, depending on the primary treatment.

I would like to give your answers to the questions, to the biomarker questions back to the panel now and I would like to ask Neal to begin with, how do you take the answers?  Many actually do more markers than just one but there are some answers with only using PSA as a biomarker for the prostate cancer treatment decisions.  Would you like to comment here?

Neal Shore:  Thank you, Maria.  I think when you look at the second question, which addressed just using PSA and I think it was 97% of the audience said they would not base their decisions only on PSA and that just tells me that we have a medical oncology group.  If there were a lot more urologists in here they would have probably said that we had probably had the answer wrong, so it’s good to see that that’s not really an educational teaching point here.

But it is for urologists who are very PSA-centric as many of our patients are, so like all of you I look sort of a triad of a stool where I look at all the different markers, serologies, PSA, alkaline phosphatase, LDH, haemoglobin, those classic Halabi prognostic factors as well as clinical progression, symptomatic progression and then radiographic imaging.  New lesions are a particularly worrisome finding.

So yes, I would also say positively responding to the first marker questions that I absolutely look at PSA, alk phose, LDH as well as haemoglobin as both prognostic and predictive in making an informed decision with patients.

I think as we move forward with all these therapies that you did such a great job of showing Maria, and the guidelines, what the guidelines don’t tell us is they don’t tell us how to best sequence or combine and they don’t tell us when to stop therapy and that’s still one of the biggest challenges with the current guidelines.

Maria De Santis:  Just one question to daily clinical practice.  In your practice, do you measure all the markers every three months or what do you do?

Neal Shore:  So you know, I tend to be pretty rigorous in repeating the various markers but of course I try to minimise venipuncture and blood-letting if I can.  If someone is particularly stable and I’m not worried about progression of disease, then sometimes it’s still we have the ability to look across the table and size up the patient to evaluate if they are progressing or not.  I know that’s sort of not the algorithmic way but it still gives us sort of the art of medicine.

But yes, I as a general rule, my patients with CRPC, it’s fairly routine that I’m checking lab work on almost a three-month basis.

Maria De Santis:  Okay, so Chris Parker, what about your practice?  Do you measure all the markers every three months?

Christopher Parker:  So I absolutely agree with Neal that all the markers should be measured, by which I mean the PSA, alk phos, LDH, haemoglobin and albumin because they all give us a clue as to whether patients are responding or progressing and often of course it’s not entirely clear whether they are responding or progressing, especially when they have bone only disease and the imaging is not particularly helpful.

And as for how often I measure them, it depends how often the patients come in to clinic, so if they are coming for chemotherapy every three weeks or abiraterone every four weeks, I’ll measure all the markers every time.