Patient Profile and the Effect of Novel Hormonal Therapies

Patient Profile and the Effect of Novel Hormonal Therapies

I want to highlight some of the results of the pivotal trials and see how we can manage with these new hormonal therapies, what we have these days in our patients, and what kind of advice can come up with so called subcohort analysis.

And these are my disclosures. I tell you that I was in an advisory board and expert meetings with Astellas, Johnson & Johnson, Bayer, and Provenge but the advantage of being in those expert meetings you are become knowledgeable on the different issues there. I have research projects also with the products in my lab which is also interesting to see how we can find tumor based on mainly the marks what we investigate, even the Provenge is what we are doing. I think it’s worthwhile to be involved in those new treatment modalities.

Because the treatment decision is not only based on the effect of the drug but it’s also based on the patients’ characteristics. Actually also the tumor characteristics. The influence what the tumor has on the patient for instance performance status, etc., of course the efficacy and the toxicity of the drug. And actually if you look to the pivotal trials, you also have to be aware of the fact that what was the time this trial was ongoing. What other drugs were available at the time and what patients were included in those trials so the time and availability of drugs I think is important to recognize that for the way the new drugs are implemented in the practice.

And we’ve heard that the castration resistant prostate cancer is the key. The androgen signaling pathway is the key because all these patients have a low testosterone although you’ve heard that agonist, antagonist has a different level of low testosterone. And I’m really eager to know what kind of a castration resistant prostate cancer is degarelix castration, is that different? Does the patient respond different to the other hormonal therapies that this data will hopefully come out in the near future. But definitely we will block the androgen receptor with great efficacy. Is it known that hormonal therapy actually the LHRH analog mostly used is doing the job and decrease the tumor growth, gives apoptosis with the castrate level.

But the reason why we changed the name in castration resistant because these patients are not hormonal resistant. We gave these patients hormonal therapy for more than 40 years and actually it appears that it was not very effective with regard to the androgen receptor. Actually these patients were not independent of androgens after treatment with lowering the testosterone either by chemical or surgical ways.

And it’s not only the androgen receptor blockage and the overexpression which occurs, it’s a lot of varieties of the androgen receptor as depicted here which became clear and is and can be a target for new therapeutic approaches especially for instance the androgen receptor splice variants, but also the other mechanisms which works on the androgen receptor should be taken into account and should be attacked with different treatment approaches.

The treatment options are diverse, and unfortunately we have post and pre chemo definitions because chemotherapy was approved in castration resistant prostate cancer. We’ve heard Sip-T and I will address hormonal therapy somewhat in more detail especially abiraterone combination prednisone, and enzalutamide.

But just a couple of slides on chemotherapy. There will be a lecture tomorrow on chemotherapy, but these are recent data. This is January 2014 where an update of a prognostic model was published in the JCO and that tells you a little bit what kind of a patient should still receive chemotherapy as a competitive treatment option with for instance abiraterone and enzalutamide in castrate resistant prostate cancer.

You can see here that there is way of depicting the prognostic models based on different aspects. For instance, opioid use, LVH level, you see also the ECOG score, albumin level. I think albumin level is very important in these castration resistant prostate cancer patients. Hemoglobin, alkaline phosphatase, and of course PSA. And you can see here that the hazards ratio in all these prognostic factors are important for the effect of chemotherapy in these patients, which make you decide if a patient should be given chemotherapy in an earlier phase or other treatment options should be given.

This is also interesting, years, years after the pivotal study with docetaxel. It appeared that Gleason scoring of the primary tumor is an important prognostic factor of the response in chemotherapy. Remember these patients were treated by mainly the medical oncologists, and the medical oncologists have difficulty in getting access to the Gleason score. You can also see in the other studies that rather limited number of patients had the Gleason score. But if you see the effect of docetaxel just based on the Gleason score, that the differences between docetaxel and the mitoxantrone is especially there in the high Gleason score. Not in the low Gleason scores. It tells you something on the effect of chemotherapy and the decision base on the patient profile like the tumor characteristic Gleason score which makes you decide yes or no to give chemotherapy in these patients.

I was involved in the studies post-chemo, abiraterone, the 301 but also the 302 more interesting for urologists. One of the reasons is because we gave as urologists docetaxel ourselves which is quite different from the U.S. but there was also in the writing committee of this New England Journal of Medicine paper, which is interesting because then you can see all the data and implement and discuss the data which should be presented in the New England Journal of Medicine paper. Actually they are pretty straightforward finally, but to have access to the data and to give the interpretation, it is very interesting to be involved in.

This is the pivotal trial, the 302 study is a 1:1 randomization with the primary endpoint both a coprimary endpoint progression-free survival and overall survival. Somewhat different, from the post-chemo study where overall survival was the primary endpoint.

This is a preplanned analysis, one of the reasons why overall survival within this study was not significant although the curves look exactly the same as the other prechemo trials.

But what kind of a patient was included in these studies? You can see here some of the characteristics depicted here. And I think this is also of interest to see what kind of a patient was treated with prechemo abiraterone. You can see these are patients which are relatively high, high burden of disease where 50% have bone mets also another 50% mainly lymph node mets, but you can also see here that 50% of these patients has a high Gleason score, about 50% of the patients the Gleason score was available. Balance of course, but these are the characteristics of patients with a median of about 40 PSA. Median time from initial diagnosis to the first treatment dose was 5.5 years. There may be some differences in different countries there but this is the patient profile which entered the study.

You can see that there is a progression-free survival benefit, also overall survival benefit but rather consistently with the hazard ratio with all the prognostic factors like the level of PSA, level of alkaline phosphatase, the performance status, the bone mets. Actually all these patients both progression-free survival and overall survival had a benefit which is good, effective drug. On the other hand it’s bad because it’s difficult to find tune the drug because it works in all subcohorts of these patients.

This is the secondary endpoint, were quite consistently the effect on ECOG score was positive but also the other secondary endpoint, opiate use etc., had a positive effect. And also PSA progression was a secondary endpoint.

The side effect profile; it’s a safe drug. We’ve heard that combination with prednisone makes that the differences between the abiraterone prednisone first is the placebo prednisone was not there, part from the liver function disorders. And most of the liver function disorders was there in the first three months of treatment. So also for hypertension, cardiac disorders, hypokalemia, with the combination of prednisone, you don’t see the differences anymore so therefore it’s considered a safe drug.

The duration and the reason for discontinuation were in favor of the active abiraterone arm, and it also tells you that median cycles of treatment ranged 15 months. If you have a discussion and we have in Europe much more discussion on the cost of treatment, this is 15 times 3,000 Euros, so it’s 45,000 Euros and maybe $55,000 for treatment of a patient in a prechemo setting. And especially in the U.K. NICE is really looking into this which may be difficult to have access to the drug because of the cost. I think that’s a big difference with the U.S.

What was given after progression on abiraterone or on placebo? Of course especially docetaxel was given also cabazitaxel. Some patients received Sip-T and it also tells you a little bit on how these patients were sequenced.

Because I showed you the hazard ratio, and what happens also here with abiraterone, the same thing is with enzalutamide. We looked into a detailed analysis on elderly patients versus younger patients. We published that in European Urology quite recently.

And it’s shown here quite a substantial number of these patients were elderly patients with patients that have more comorbidity. In these patients the question was, is it safe to give abiraterone especially also prednisone.

What you can see here, busy slide, that there are no differences between the younger patients and the elder patients. The elder patients over 75 were an old subcohort. You can see here the benefit of the drug. And it’s not expected that especially in the elderly patients the benefits should not be there.

So that was the conclusion, a very busy slide here but you can see here all these side effects where monitored quite in detail in this study, and actually there is no, if you go into detail there, there is no difference between younger patients than elderly patients.

This is the conclusion that the elderly patients have clinical benefits similar than the younger patients.

When we shift to the post-docetaxel space there are different drugs now approved. The reason why I put this slide on because I’m aware of the PREVAIL data that were presented quite recently and the article is under submission now. But we don’t have the data here but we have the AFFIRM data, we have the 301 data, we also have the availability of cabazitaxel in patients who are progressive after docetaxel. And Radium-223 can be given post-docetaxel and pre-docetaxel.

Some details on the enzalutamide study, the AFFIRM study also a large study with a 2:1 randomization, primary endpoint, overall survival. The effect was already discussed by David. The study design endpoint, overall survival.

And this is the patient profile which is actually quite similar from the other studies what was done. The average age about 70, not very many patients had an ECOG score 28.8%, and also that the bone disease was there in these patients more than 90%. And soft tissue mainly lymph nodes was there in patients of 70%. So this is the patient profile which entered the study.

In patients prior hormonal therapy, prior chemotherapy, the average number 8.5 and 9.0. And there is diversity there because in different countries, there is an average, for instance in Germany the average docetaxel is not more than 6 because the definition of no effect on docetaxel was given earlier in the German patients. So there are regional differences in these studies.

This is the prolonged survival. Substantial with an effective drug like enzalutamide especially PSA response is a rather good monitoring of the response on enzalutamide also in the post-chemo setting. And you can see that time to PSA progression ranged in the placebo arm for 3.0 to 8.3 months which is really substantial.

Time to skeletal related events, also delayed with the enzalutamide which is also important as a clinical benefit. And also characteristics of the patient’s well being and that this should not be disregarded, because that has… this also have a big impact on the patient’s well bring. You can see in all these physical well-being fact and analysis that the effects of enzalutamide were beneficial for these patients.

The side effect profile, and this is I think very important for urologists. Actually you can conclude that this is a product which does not have side effects. If you see the balance between placebo and enzalutamide, there are no real differences. There was a discussion on the seizure because pharmacokinetics studies earlier on in the high dose showed seizures. That is a limitation in the patient profile that sees it as an exclusion criteria. On the other hand in the PREVAIL study, the prechemo study seizures are actually was hardly seen. So I think seizure is not a big issue in enzalutamide anymore.

I’ll show you same data of something what we did in the subanalysis between European and North American men which may be of interest, if there are differences. Actually the conclusion is that it had similar effects. But it’s also interesting to see if we can look to some of their differences between the two regions?

Actually for… it’s pretty much balanced if you see all the differences although in the U.S. cohort there is somewhat more higher ECOG score. In the U.S. cohort, you see PSA is quite similar. In the U.S. cohort there are somewhat more patients with cardiac disorders. Prior chemotherapy is rather the same, so there is no difference there.

The number of prior hormonal therapy also pretty much balanced. Bone lesions also pretty much balanced. On the other hand, if you see the median time from initial diagnosis in months, you may see here that there is some disbalance here between the placebo arm and the enzalutamide arm in the U.S. patient profile. It’s not that it is significant of something to worry about, but it’s something which came out when you look into details to the demographics differences.

The side effects exactly the, same. No differences also not in liver function abnormalities etc.

This is the slide hopefully you can see. It’s a little bit gray, the gray line. You can see the differences in the blue line, the European patients. The effect, the beneficial effect of enzalutamide is exactly the same in the U.S., the gray, as the European patients. On the other hand, I’m always surprised and this is exact the abiraterone, that the survival lies of the European study are somewhat higher than the survival lines of the North Americans study. Although the patients with characteristics look a little bit the same I depicted some of the difference in the earlier slides. But on the other hand, it’s apples and pears. On the other hand I’m really eager to see in the discussion what is the reason why there us a difference. We didn’t do a statistical analysis there because the differences are the same but the curves are also in other drug is different.

The secondary endpoints, once again no differences in the different regions. Also with regard to progression-free survival medians, exactly the same time to skeletal related events exactly the same, but you’ve seen the lines of overall survival.

This is the time to skeletal related events. Europe and North America consistent better although, well, maybe it’s because of the low numbers there.

Subsequent therapy also the same so the availability of the subsequent therapies was exactly the same in Europe as in North America, as you can see here. A substantial number of these patients progressive after enzalutamide received abiraterone.

So the subanalysis in the AFFIRM trial show there was no differences also not in the secondary endpoints. The bone protective substances like Zometa was rarely used in both sides of the Atlantic. And the conclusion there was that apart from the survival curve which is of interest that there actually are no differences between Europe and the U.S.

So in conclusion, the decision of the treatment of castration resistance prostate cancer is dependent on the patient profile. I showed you some of the differences which may help you in deciding what kind of treatment is best for the patients. The detailed interpretation I think of these pivotal trials is really necessary to learn on the next patient profile for a certain drug. Also the data coming out of the expanded access programs, and also the sequencing data have really keyed in the decision what kind of a treatment we should give. And I think one of the most interesting things, I gave yesterday a talk on biomarkers, especially here in castration resistance, prostate cancer, histological biomarkers is of importance to see what is the effect of the drug, and it may help you to decide what change you need for these patients. At this moment, in most of the castration resistant prostate cancer we take routinely biopsies for investigational use and hopefully these markers on the androgen receptor, on splice variants, etc., will help us to make a better decision on what choice of treatment we should give.

Thank you for your attention.

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