ASCO GU: Current thinking in mCRPC

Dr Howard Scher - Memorial Sloan Kettering Cancer Center, New York, USA

There is debate about whether we should be calling mCRPC hormone resistant or castration resistant, what is your view?

Part of the reason for coining the term castration resistance was based on an understanding of why the tumours are actually progressing on standard hormonal therapy. So typically a patient receives a GnRH agonist antagonist, will lower their androgen levels to what is considered a castrate range and then typically you’ll see the PSA rise as the first sign that the tumour is becoming resistant. There were a series of analyses at the molecular level as to what changes are going on within the tumour and two in particular stood out. The first, which was a bit counterintuitive, was that the synthetic machinery to make testosterone actually became up-regulated. So the tumours actually learned how to make their own androgens as a mechanism of escape.

The hormones are more important even though the patient has become refractory?

They’re resistant in the setting of castrate levels of testosterone in the blood but that doesn’t always reflect what’s going on in the tumour. And it has actually been shown that the levels of androgens in the tumour can be higher than what you measure in the blood, simply because they’re making their own androgens. The second alteration that occurs very frequently is that the binding site of testosterone is the androgen receptor. So another mechanism of escape is that the tumour learns to make more of the receptor so it becomes hypersensitive to whatever androgens may be present. Two drugs that target these specific alterations, one is abiraterone, which blocks the biosynthesis of androgens, and the second, enzalutamide, was actually developed based on a screen of compounds that would specifically block models, prostate cancer models, that have too much of the androgen receptor.

Specifically you have been looking into the use of corticosteroids, tell us more about this?

So there has been a fair amount of evidence from different venues which suggests that in certain contexts corticosteroids can actually stimulate prostate cancer growth. One of the ways that the enzalutamide and abiraterone were developed was by understanding some of those mechanisms. So the history of corticosteroids goes back to the 1970s; they’re known to be beneficial in terms of having anti-tumour effects, they’re known to lower androgen levels, testosterone levels, which drive the tumours further in patients who have already undergone surgical castration. They’re used to palliate symptoms and they’ve also been used to prevent some of the symptoms that can occur with drugs such as chemotherapy. So in certain contexts they are definitely beneficial in terms of anti-cancer effects and improvement in quality of life. In the enzalutamide trial the patients, there were a group of patients who were on steroids as their cancers were progressing and before they entered their trial. There was another group of patients who had seen the glucocorticoids only during their chemotherapy and then it was stopped. We did not randomise and this is what is called a post-hoc analysis: it was not planned, it was just on the finding that there may be some relationship between tumour growth and corticosteroids. We asked the question, ‘What is the outcome of patients who have corticosteroids either while entering the study or got it while they were on the study versus those who had not?’

What is the data coming out of this?

What it showed was the group that were not receiving glucocorticoids were doing better. So then you say, OK, is there a difference in those patient populations that are obvious? So it turns out the group of patients who were taking glucocorticoids were sicker, they had more advanced cancers and they needed the glucocorticoids for symptom control. So what you can do is look at a number of different factors to see if you account for how bad the disease is; if you account for how sick it is and how sick the patients are, does the glucocorticoid treatment still influence survival? And in the analysis we did it did.

Give an overview of the data so far?

The two main observations were first, the patients who had glucocorticoids either at entry or on study did worse after accounting for known prognostic factors and measures that they were sicker. In addition, independent of the steroid use, the benefit of enzalutamide was evident in both patients who had glucocorticoids and those who had not received glucocorticoids. There are clear contexts where glucocorticoids have clear benefit in terms of anti-cancer effects, improvements in quality of life, but the difference in the patients who were going onto this trial, they were on glucocorticoids and their cancers were progressing. So it’s not the same as somebody who has never seen glucocorticoids at all.

Are there any implications for patients taking steroids with abiraterone?

The glucocorticoids and abiraterone are used to reduce some of the hormonal side effects that occur with the drug. But if you look very carefully at the results of their trial the patients who just got the glucocorticoids responded. One of my longest responders on the trial where patients were randomised to abiraterone plus placebo, abiraterone plus prednisone versus placebo plus prednisone, turned out to be a patient just getting prednisone. So it clearly has anti-cancer effects, however the combination of abiraterone plus prednisone is superior to prednisone alone, independent of what your hormone levels are.

Could you summarise the clinical messages on the use of corticosteroids in mCRPC?

The clinical message is the context of use of corticosteroids will differ in patient management. In some cases they are used for anti-cancer effects, they are used to improve symptoms and they are used to reduce the toxicities of therapies that have been shown to prolong life. That is different than somebody who has been taking them and now goes on to a clinical trial while their cancer is progressing. Our suggestion is that there are some cases where the glucocorticoids can actually be contributing to the progression of the cancer and this is what has to be proven prospectively because at this point it is still a hypothesis.

What is your advice on the use of corticosteroids with abiraterone and enzalutamide?

Right now, with abiraterone they are needed in order to reduce some of the endocrine side effects. There are some patients who have been treated without prednisone and over time they do need some additional hormones such as prednisone etc. In the context of enzalutamide, while the data are not definitive, if you can have a patient off glucocorticoids or corticosteroids I would say that is preferred but there is not hard evidence to say that it’s mandatory that you stop it.

Tell us about the overall improvement in the therapy of mCRPC with these new agents?

Again, the first use of these agents or the first indication for both of these agents was in patients who had failed both hormones as well as chemotherapy. At the time that these trials were conducted there was no standard of care for a person who had already progressed on chemotherapy, which at the time was the only proven life-prolonging treatment. Now these agents have been shown to work in a patient population who progressed on both hormones and chemotherapy and part of the reason for doing that is these patients had a major unmet need, no standard and the fact that their prognosis was worse enables you to show the benefit of the drug more quickly. Abiraterone has since been shown in the pre-chemotherapy setting, where hormones have traditionally been used in the past, to delay progression of disease and also to prolong life and now has a broad indication. So, again from a patient point of view, if you have a choice of a cytotoxic drug or a hormonal agent that’s essentially a pill, again, practice would go for the less toxic and also effective treatment. There are still patients who need chemotherapy; what our job is is to better understand who will respond to drug A versus drug B versus drug C, when to use chemotherapy and some of the other approved drugs and, again, to better tailor our approach to the individual patient.

What is your take home message for clinicians from ASCO GU?

We’re focussing very hard on understanding the biology of each person’s cancer. We have drugs that target those unique biologies and this has already been proven with the development of abiraterone as well as enzalutamide.