The development of PARP inhibitors a new drug to treat prostate cancer

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Published: 10 Nov 2010
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Dr Johann de Bono - The Institute of Cancer Research & Royal Marsden Hospital, Surrey, UK

Dr Johann de Bono speaks to about PARP inhibitors, the benefits that these drugs have shown and what still needs to be done before they can be approved. Dr de Bono suggests how modifying the way patients are selected could speed up drug approval and discusses what challenges must be overcome when developing drugs with novel mechanisms of action.
Dr de Bono talks about advances that have been made in the treatment of prostate cancer and discusses abiraterone acetate, a new drug which targets the CYP17 enzyme, is highly active and has been shown to increase patient survival rates.

ESMO 2010


Dr Johann de Bono - The Institute of Cancer Research & Royal Marsden Hospital, Surrey, UK


The development of PARP inhibitors a new drug to treat prostate cancer



You chaired a lovely session this afternoon about PARP, what was your lasting thought? You had the concluding remarks, you were more putting out questions than wrapping it up, but can you wrap it up for the people who are not at the ESMO meeting?


Well I think PARP inhibitors are now established as drugs that have anti-tumour activity in patients with advanced cancer. But despite the work of many people over many years in developing these drugs, we still have not yet got a PARP inhibitor approved. So the key thing is to be really strategic in our thinking about how to best develop these drugs so we can get them through that regulatory hurdle and really help our patients who are suffering from this disease, these diseases, as soon as possible broadly, out of trials.


Yes, you mentioned these diseases, of course the point was made that we’re targeting a particular repair mechanism fault rather than what’s got the headlines which is breast cancer, triple negative, blah blah blah. Where do you think these lesions are going to be found that will be sitting up there waiting for the PARP inhibitor?


I think a key issue here is that we need to rethink our strategy in cancer medicine drug development and perhaps re-focus from the established geographical site of origin tumour type focus to a more genetic lesion molecular selection process for our patient selection. That has substantial implications for how we do clinical drug development and registration strategies, not only for us and our patients but also for the regulatory authorities. But this is a challenge we have to face head on and I guess one key issue, for example, is that BRCA carrier patients with cancer who are very amenable to treatment with low toxicity oral drugs, this is a rare population of patients. So perhaps if there is a very high response rate then patients that have never had a platinum treatment or a DNA damaging drug maybe should we try and consider other ways to get these drugs approved.


Now you had a nice commentary in Nature with Alan Ashworth, do you think people are going to sit up and listen to that? Or are they going to say, “Well they would say that, wouldn’t they?”?


Well, I think the community has been listening and actually not just listening but driving this forward as a community themselves. I think that it’s hard to actually change everything all at once and I think we are working hard to change things bit by bit. Data emerging on the ALK inhibitor in adenocarcinoma with the rearrangement; the MEK and BRAF inhibitors in melanoma, it’s an exciting time for our community.


But I get the impression the regulators have got to step up their educational level, they’ve got to understand what’s driving all of this and realise that these are completely new mechanisms.


I think many of the regulators do but clearly there are challenges for all of us here and the challenges are not only scientific but there are other challenges. For us, in the laboratory and the clinic, we need to really focus on developing new drugs in parallel with established, validated biomarkers and that still remains something that we could do better. But we are as a community working harder to try and make that happen.


And we’re really not going fast enough, that’s certainly my view from a pace perspective.


It can never be fast enough with patients dying of cancer.


Absolutely. The patients who are across this hall now are talking about this and they’re asking questions. Now one other drug that has been taking a long time to get anywhere, you’re talking about tomorrow, you’re giving the results of a big international study in castrate resistant prostate cancer. You can’t tell us the results but tell us about the drug.


So the first thing to say is that, as you know, prostate cancer is the commonest cancer in men and the second commonest killer from cancer in men. The two priorities in prostate cancer are to minimise over-treatment in men with good prognosis disease and to maximise aggressive treatment in men with poor prognosis disease.


So actually our key priority is treating men with advanced resistant disease and you could actually, on the fingers of one hand, count the number of advances we’ve had therapeutically in this disease; it’s really been a Cinderella cancer for so long. So the evidence has been emerging over many years, maybe even since Huggins identified a hormonal driver for this disease, that hormonal driver, that actually these cancers remain hormone dependent and certainly nuclear steroid hormone receptor dependent, even when they have progressed despite all available treatments. And there is a lot of evidence for that, we’ve published a number of papers reviewing this recently in Cancer Cell.


I think the key issue is actually recognising that; once we recognised that we were fortunate enough that chemists at our institution in a team led by Mike Jarman, who led the group including Gerry Potter and Elaine Barrie. Mike has now retired but Elaine still works with us in our institution at ECF Cancer Research and the Royal Marsden in London. They designed and actually synthesised for the first time a drug through a screen that they ran on testicular extracts, a drug that inhibits CYP17 very potently. CYP17 is very akin to aromatase in breast cancer, aromatase is CYP19; CYP17 is upstream of aromatase in the steroid synthesis pathway and blocks both androgen and oestrogen synthesis. Initial concerns that targeting this enzyme would cause adrenal failure were thankfully unfounded in that children can be born with this defect in an autosomal recessive congenital rare disease and these kids never get adrenal failure. What they do get, though, is late and actually poor sexual development at puberty; no pubertal development and some of them, but not all of them, get hypertension and hypokalemia and there’s secondary cone syndrome and fluid retention due to the ACTH drive that causes an increase in the upstream mineralocorticoids which also have gleucocorticoid effects, like a cortical steroid. So they risk adrenal function. But importantly, as we now believe that these cancers generate their own hormones and that remains a key driver, we’ve tested this drug now in a lot of patients with prostate cancer, not only in the UK, which is where the trials were first done, but also elsewhere. We’ve shown really categorically that this disease remains hormone driven.


Tell me how you pronounce the drug again?


The drug is called abiraterone.


I have real problems remembering it and I was around when Mike Jarman actually synthesised this drug, I remember it very well.


It was made in the mid-nineties and we’ve shown that the drug is safe, very well tolerated. It’s an oral drug, certainly in my experience it doesn’t have the side effects of chemotherapy. We now have patients that have been on this drug for years, I’ve got a patient who is still on the drug after over four years, 4½ years, which in the setting of resistance to multiple available agents, including Docetaxel, is really very impressive. I’ve developed many drugs and tested many drugs in prostate cancer, I have never seen a drug as active as this in this disease.


So tomorrow we present data of our phase III trial which does show a survival advantage and we’re very pleased with that result. I think, though, there are still many things that need to be addressed in prostate cancer, there is still a lot of work to do but it’s been an exciting year with Cabazitaxel, which you’ve probably seen in The Lancet a few weeks ago with the Sipuleucel-T published in the New England Journal of Medicine by Kantoff et al about a month or two ago, and now Abiraterone. So we really have had several London buses arrive at the same time after waiting for many, many years because before this there were only two treatments that improved survival and that was castration and Docetaxel. So we’ve really had a major impact this year.


Johann, congratulations on this work you’ve been doing, the leadership that you’ve shown in that group has been exemplary and you’ve re-established the Institute of Cancer Research as a powerhouse and a manufacturing house of innovative molecules and your phase unit with Stan Kaye is just remarkable. Thanks very much for giving us time.


Stan has been my mentor for twenty years and the Glasgow influence continues.


I wasn’t going to say that!