ASCO 2012, Chicago, USA
 
Advances in pre-operative care in high-risk mCRCP

Professor Eleni Efstathiou – MD Anderson Cancer Center, USA interviewed by Dr Chris Parker – Royal Marsden Cancer Centre, UK


Hello, I’m Chris Parker from the Royal Marsden Hospital and I’m here in Chicago at the 2012 annual meeting. I’m joined by Professor Eleni Efstathiou from MD Anderson. Eleni, you’re presenting some very interesting data at the meeting, can you tell us a bit about it?

Yes, it’s actually my pleasure. I’m not the only one presenting interesting data, of course, but with regard to the pre-operative setting we seem to have a number of very interesting presentations this year. What is changing is the field of prostate cancer therapeutics, as you’ve shown yourself, and importantly we seem to be moving fast towards the earlier disease setting, the high-risk prostate cancer localised disease. We seem to all be very involved in trying to identify probably a fraction of those patients who may be able to be cured by applying, and I’m using this very carefully because we’re not sure of the data, how it’s going to evolve over the years to come, but we have some very interesting snapshots from what is happening in the tumour microenvironment as you treat it with the novel reagents that are now already in clinic in the far advanced disease setting.

You must have started this work some years ago, you were really ahead of the game.

Thank you for saying that but I’m not really sure; it was part of the interest of our institute. MD Anderson has been involved in the pre-operative high-risk platform for years, about fifteen of those. We started early on with the high-risk chemotherapy treatment cohort and we presented that data back in ’99, I wasn’t part of the group back then; I got involved when we had the thalidomide pre-treatment data. But it has always been our focus not to call it neoadjuvant because the primary endpoint of those trials has never been to look at the pathologic complete remission and that’s why we actually elect to treat for a short course, to not get what we call the ghost effect in the tumour but actually have some residual tumour from which we can tell what has occurred in the microenvironment. That makes it different from other neoadjuvant trials that are currently on-going with longer treatment periods.

So back in those days with those other agents, did you ever get some near pathological CRs?

No.

Right, OK.

That is the difference. We were actually pleasantly very happy and surprised to see that we were getting near pathologic complete remissions only after three months of treatment with LHRH plus abiraterone acetate which we have never seen with LHRH alone in our experience.

So tell us then, Eleni, about the current study, what did you do?

The current study is straightforward in the sense that we did a randomisation of 2 to 1 of patients who have high-risk disease, localised. A lot of them T3 clinical stage; a lot of them with what turned out to be, looking carefully at the MRIs, possible lymph node positive disease and then some of them confirmed during prostatectomy, after prostatectomy. Essentially we randomised the patients 2 to 1 to receive LHRH plus abiraterone plus prednisone versus LHRH alone for three months. Following which months patients went on to have a radical prostatectomy, in our experience robotic. All but one patient today have had only robotic prostatectomy and this is the first cohort in our institute that’s completely in the robotic setting. Following that, we looked at the differences in the pT2, the treated pT2 stage, and we’ve almost reached the endpoint of that, reaching statistical significance.

So how many patients in the study?

The total number of patients was 66, but to date 50 patients have undergone prostatectomy and we are presenting data on 40 of those patients during this meeting. So this is a preliminary report of this cohort.

And what were the pathological findings?

With regard to pathology we had what is close to a statistical significance with regard to ypT2 treated pT2 stage. We have near-complete pathologic remission in 24% of the patients who were treated with the combined treatment as compared to none in the LHRH alone; again, this cannot be statistically significant given the number of patients. We have a significant difference in the number of patients with lymph node infiltrated disease and also there is a trend in the margin positive versus negative in favour of abiraterone acetate treatment.

So what was your reaction when you saw you had a 24% pathological CR rate?

Almost, near complete.

OK.

It’s actually very interesting, you have to look at the microscope to see the difference. Essentially the pathologists reviewing with us all these specimens were baffled by the fact that they saw very few cells remaining in the prostatectomy specimen and you actually had to do an extra cytokeratin stain to be able to see if it was actually a remaining tumour cell or just a histiocyte. In some cases it was mainly histiocytes that were infiltrating the region. So you had a very clear impact on the tumour microenvironment seeing the differences in the stroma and what happens following depletion of androgen signalling and you saw very few cells, you would call them not looking very lively. So that was very exciting to see.

And so what next? What do you think are the implications for clinical practice and for future trials?

It’s very early to call this anything close to practice change. We know the hurdles of actually doing pre-operative treatment and when it becomes multi-institutional it’s even harder because you have different methods of processing tissue and how we’re going to make anything out of all these differences, make it mean something for patient care. But during the years, a few years to come, I do believe that we have the unique opportunity to drive what we now, in the past couple of months, are calling precision therapy, instead of individualised therapy, towards finding that subset of patients who may be cured with this approach i.e. combining your radical prostatectomy with a type of androgen signalling inhibition equivalent to LHRH plus abiraterone acetate or other androgen signalling inhibitors.

The patients at the moment who are not cured by surgery alone, where are they failing? Are they failing with recurrent disease in the prostate bed or are they failing with metastases? Is the primary prostate the right target, if you see what I mean?

That is a very good question and it all has to do with the timing of when the intervention happens and you’re very correct in assuming that, to an extent, you might have advanced disease by that point and a level of micro-metastases. That would essentially ask for a longer treatment with androgen signalling inhibition likely similar to what we’re doing with the combination of radiation therapy and the three year androgen ablation strategy that we’re using right now. But you have and you’ve seen in your practice that there is a subset of patients who do and did get in trouble with their local disease. So that’s a smaller fraction of the patients but that is a big problem in the clinic in about, I would say, 10% of that cohort.

It brings me on, I wanted to ask you about the work that you’ve done looking at bone marrow samples in patients with advanced disease treated with abiraterone. So tell us about what you’ve done there.

Thank you very much for giving me the opportunity to talk about that. That was the initial phase of treating patients who had received different types of therapy, most of them cytotoxic therapies, and most of them were of a performance status of 2. A very high volume of disease and in 50% of those patients we were able to identify bone marrow infiltration with prostate cancer cells. So we wanted to actually be able to identify some predictors of outcome or resistance, primary resistance, to this new treatment, abiraterone acetate, as we were then getting the signal from the phase II that we were having wonderful responses. That led us to identify a subset of about 25% in that cohort of far advanced disease that seemed to be primarily resistant. What we saw by measuring the testosterone in the marrow, and the periphery of course, and looking at the characteristics of the tumour cells within that were infiltrating the bone marrow was that if you do have lack of one or two, whether it be over-expression of the nuclear androgen receptor, your end terminal presence of androgen receptor, or lack of the expression of the enzyme CYP17 or the testosterone in the bone marrow not in high enough levels, that patient would not respond to abiraterone acetate or you could call him primarily refractory to the reagent, very similar to what we call primarily refractory to cisplatinum in ovarian cancer treatment, that was the paradigm that I was trying to get to.

That’s interesting. Did you do serial bone marrows, including patients who were actually on treatment?

Absolutely. We went on beyond the baseline, the pre-treatment, and we’re treating prostate cancer more like a hematologic malignancy, like you would do with myeloma, like you would do with leukaemia. On week 8 we would repeat the biopsy. What has not been reported essentially in that paper and we’re seeing it with other trials of similar design, is that the patients who actually get a benefit have the regression, as you would expect, of the bone marrow infiltration in their bone marrow. Essentially it’s the identical pattern that you see with hematologic malignancies. That’s something we’re building on right now to report. Then we would go on to perform the final bone marrow biopsy when the patient got off treatment, upon progression usually.

So when patients are treated with abiraterone and we do the bone scans, we often see a bone scan flare at around about eight weeks. Is there any sort of pathological correlate that you saw in your samples?

Not essentially. You would have to study the osteoblasts and we are trying to create a bigger bank of bone marrow biopsies to be able to study that effect. We’re actually doing a prospective validation of our signature in a cohort of 180 patients right now and that will give us the opportunity to look at that effect more carefully because it does have to do with the bone turn over.

Have you got any preliminary data on the osteoblasts?

Not yet. Not something that I could share.

I’m interested in that question because of the thought of combining abiraterone with radium-223 so I’m really anxious to know what happens to the osteoblasts.

So you will be the first to know.

OK.

The moment I have it, I’ll send it. Yes, that’s a wonderful question.

Thank you very much. Thank you for giving us your time.

Thank you. Thank you for having me.