` Our milestones: the birth of a new prostate cancer
`drug
`Category: Science blog September 21, 2015 Henry Scowcroft2 comments
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`This entry is part 24 of 25 in the series Our milestones
`In the latest in Our milestones, we look back to the 1990s, and to our ‘first-in-man’ trial of prostate
`cancer drug abiraterone – a vital step in the drug’s development that set the scene for its
`progression through to routine use on the NHS.
`“The mid-90s was a dark time for prostate cancer trials,” recalls Cancer Research UK’s expert
`Professor Malcolm Mason. “The disease had a much lower profile, and we only had limited tools to
`help men with advanced disease: hormone therapy, and radiotherapy to control pain and other
`symptoms.
`“Things like chemotherapy weren’t really taken seriously”, he says, “as the limited clinical evidence
`we had led us to think it wouldn’t make much of a difference when the disease had already spread”.
`The situation got worse when a large UK prostate cancer trial failed to recruit enough patients: “We
`were very disheartened. The generally accepted view was that there wasn’t much point in setting up
`more,” he recalls.
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`Today, this picture is almost unrecognisable, with several new treatments now available, together
`with a new optimism in the field.
`But how did we get here? In this blog post, we’ll look at how – thanks to research – that picture
`began to change, and how the outlook for men with the disease is now improving year on year.
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`A new dawn
`Prostate cancer is the most common cancer among UK men, affecting nearly 42,000 each year. And
`although it can be cured if diagnosed early, the picture changes if it starts to spread.
`Since the 1940s, the mainstay for treatment for men with advanced prostate cancer has been to
`block the action of their male sex hormones (collectively called ‘androgens’) – so-called androgen
`deprivation therapy – halting the disease in its tracks.
`But after months or years, the cancer almost inevitably starts growing again. And from there, things
`generally only have one outcome.
`At the beginning of the 1990s, however, UK scientists started to become more optimistic. There was
`a new dawn in understanding hormone biology, and the molecules involved in hormone-linked
`prostate cancer growth were being isolated and understood.
`And at our Cancer Therapeutics Unit at London’s Institute of Cancer Research (ICR), a team led by
`Professor Mike Jarman and Elaine Barrie were developing drugs to try to shut down the production
`of the hormones that fuel prostate cancer’s growth, rather than merely block their action.
`And they were zeroing in on a promising-looking compound: abiraterone acetate.
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`From bench to bedside
`By the mid-90s, Jarman, Barrie and their colleagues had proven that abiraterone worked in cancer
`cells in the lab, and then in animals with prostate cancer – a story we’ve detailed previously.
`It was time for the crucial test – to see if the drug could shut off testosterone production in patients.
`Through the Cancer Research UK Centre for Drug Development (formerly our Drug Development
`Office), a small series of trials was conducted at several hospitals, led by Professor Ian Judson at
`the Royal Marsden in London.
`Judson recalls: “We were looking to see if we could either completely suppress hormone levels in
`men who hadn’t begun treatment yet, or have an extra effect, over and above current hormone
`drugs, in men who were currently being treated.”
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`“It was a simple but absolutely vital study” – Professor Malcolm Mason
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`“It was a very simple but absolutely vital study,” says Mason, whose patients at Cardiff’s Velindre
`Cancer Centre took part in the trial. “Our idea was to see if a single tablet of abiraterone could
`produce the sort of impact that the lab studies suggested it should.”
`It was a classic example of a ‘phase I’ trial – the search for simple answers to fundamental biological
`questions. Does this drug do what we think it should? At what dose? And – just as important – does
`it do anything we didn’t anticipate?
`Over six months in the late 90s, Judson, Mason and their team recruited 26 volunteers with early-
`stage prostate cancer, who were either waiting for surgery to remove their cancer, or having
`hormone treatment.
`At first, men on hormone treatment received a single dose of abiraterone, and over the next few
`days, gave blood samples to see what happened to their hormone levels.
`Ultimately, they found that a 500mg dose of abiraterone could indeed reduce a man’s androgen
`levels to unprecedented lows, for several days, without any short term side-effects.
`“It worked exactly as we expected,” says Mason.
`Over the next few months the team carried out further studies, to see what happened in men with
`normal androgen levels given the drug for 12 days. Although things were slightly less clear cut, the
`hormone levels fell in these men too.
`But when the trial team convened to what to do next, the story took an unexpected step backwards.
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`Back on the shelf
`“We had a teleconference to decide what to do,” recalls Mason. “And we really struggled to come to
`any sort of conclusion.”
`The issue was not that the drug worked: it was who to give it to.
`“We couldn’t agree on who would benefit most,” says Mason. “Should we give it early on? Or as a
`first line hormone therapy? Or after current hormone treatments? It wasn’t clear cut, and we couldn’t
`agree.”
`This dilemma was because, at that time, no-one really understood exactly how hormones fuelled
`prostate cancer.
`Mason explains: “About 90 per cent of a man’s testosterone is produced by his testicles. But as
`researchers in the late 80s had worked out, the rest is produced by various other tissues – notably
`the adrenal glands.
`“And at that time we already used a combination of drugs, which suppressed both testosterone
`production by the testicles, and also the extra 10 per cent of testosterone produced elsewhere. We
`rather optimistically called this ‘Maximal Androgen Blockade’”.
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`They saw it as old-hat. No-one wanted an ‘old-fashioned’ hormone blocker.
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`– Prof Ian Judson
`“But the extra gain in survival with this combination, compared with suppressing testicular
`testosterone alone, was very small. So we wondered how a single drug that effectively did the same
`as this combination, would give any greater benefit than what we had already.”
`On top of this, drug companies weren’t terribly interested in the idea. “They saw it as old-hat:
`yesterday’s chemistry, yesterday’s drugs”, recalls Judson. “The flavour of the month was so-called
`‘targeted’ therapy, aimed precisely at genetic faults in cancer.
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`“No-one wanted an ‘old-fashioned’ hormone blocker.”
`This attitude was reflected in the struggle to get the trial results published. “I’ve still got a rejection
`letter in a box file somewhere,” says Judson. “The reviewers asked, ‘Why would anyone think that
`further suppression of testosterone would be effective in prostate cancer that has already become
`resistant?’”
`Abiraterone’s development ground to a halt, and the trial data were not to surface until 2004, when
`the paper was finally published in the British Journal of Cancer.
`“This was because we were lacking what, in retrospect, was a crucial piece of biological information
`– something that wouldn’t be uncovered for a few more years,” Mason says.
`This was the discovery, in the early 2000s in US laboratories, that as prostate cancers grow, they
`can acquire a new trick: they begin producing their own testosterone.
`And this allows them to fuel their own growth, even in the presence of hormone-blocking drugs.
`“It was a game-changer,” recalls Mason.
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`Sex addicts
`Before this discovery, when a man’s prostate cancer had come back after hormone treatment, it was
`said to be “hormone-independent” (or, hormone-‘resistant’) – the cancer no longer seemed to rely on
`hormones to grow.
`This had been shown to be completely wrong. “Far from being hormone-‘resistant’, these prostate
`tumours are completely addicted to male sex hormones,” says Mason.
`The ‘resistance’ theory had been turned on its head.
`In characteristic dry, scientific fashion, the conclusion of one these research papers reads:
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`New agents that target androgen receptor directly, and prevent formation of androgens within
`prostate cancer tissue, may offer the most effective approach to prolong remission of
`recurrent prostate cancer.
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`In other words, the discovery signalled clearly that drugs designed to directly shut off hormone
`production could prove highly effective.
`Abiraterone, languishing at the back of a dusty shelf in The ICR, was back in the spotlight.
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`Rapid process
`Armed with the knowledge that abiraterone could target these addicted prostate cancer cells, the
`drug gained a new lease of life.
`Through Cancer Research UK’s commercial arm, Cancer Research Technology, the rights to
`develop the drug were licensed to pharmaceutical company Cougar Biotherapeutics (now part of
`Janssen Pharmaceuticals).
`The rest is history: with backing from Cougar, The ICR’s Professor Johann de Bono spearheaded
`the clinical trials in the 2000s and 2010s, proving it could extend men’s life for vital months after
`hormone therapy and chemotherapy.
`In late 2012, it was finally approved for use across the NHS for treating these men. And in 2016, it
`was approved by NICE for use before chemotherapy, making it availabe to even more men.
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`“Today, abiraterone is incredibly important for patients with advanced prostate cancer and their
`families,” said de Bono, who is now, with support from Cancer Research UK and others, trialling
`abiraterone in combination with other drugs. “We at the ICR are proud to have led its development.”
`But none of this would have been possible without that early Cancer Research UK-funded ‘first-in-
`man’ study in the mid 90s. “It was a pivotal trial, and laid the foundations for everything that
`happened subsequently,” says Mason.
`It’s also a salient example of why laboratory research is fundamental to the success of clinical
`studies, and why we are so passionate about funding and integrating both types of research.
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`Winning combinations
`So what next for abiraterone?
`It’s not a cure for prostate cancer. But in combination with other drugs, it’s starting to turn the tables
`on the disease. Alan is 72, and is now on his third prostate cancer trial, having first been diagnosed
`back in 2005.
`He’s been treated with surgery, chemotherapy, radiotherapy and hormone therapy. And, in May last
`year, he enrolled on a phase I trial of abiraterone – this time in combination with another drug
`developed by Cancer Research UK-funded scientists: olaparib.
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`“My energy levels and general well-being have been good since I started on the trial” – Alan
`“Since starting on this trial my PSA level has to-date dropped by half – so I certainly think that this
`combination of drugs is doing some good work,” he told us. “I’m feeling fine. My energy levels and
`general well-being have been good since I started on the trial, and I haven’t had any side effects at
`all.”
`Alan – a grandfather of four – acknowledges that it is hard to ascribe the benefits to any particular
`part of the treatment (as part of his treatment he’s also taking the steroid prednisolone). But at 72,
`ten years after his diagnosis, he’s still walking the dogs and playing golf three times a week,
`“weather permitting”.
`And abiraterone’s not the only new kid on the block – in 2013 another hormone-targeting
`drug, enzalutamide, was also licensed for use. So the challenge in the immediate future is to work
`out how best to use these new drugs – at what stage, in what order, or which combination
`(something our STAMPEDE trial is now focusing on).
`“It’s a far cry from the pessimism of the 90s,” says Professor Mason. “The huge leap forward in our
`understanding of the disease has turned into a series of new drugs, and we’re finally seeing the sort
`of progress in prostate cancer that other cancers have seen in recent decades.”
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`Survival rates for prostate cancer have improved hugely over the last few years, thanks to
`researchers like the team at the ICR and the hospitals where the trials take place. And, of course,
`because of patients like Alan, who volunteer to take part in them.
`But we’ve got so much further to go – the disease still claims more than 10,000 UK men each year.
`So while we’re on the cusp of great things, there’s still much more work to do.
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