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Abiraterone acetate, trade name Zytiga™, was discovered at The Institute of Cancer Research (ICR) in what is now the Cancer Research UK Cancer Therapeutics Unit. It was first trialled at The Royal Marsden Hospital, London, UK.
The success of an anti-hormone therapy in men with late stage prostate cancer challenges conventional wisdom, opening the door to an entirely new way of treating these patients.
“Men with advanced prostate cancer have very few therapies available to them and sadly around 10,000 patients in the UK die each year from this disease,” said Chief Investigator and lead author Professor Johann de Bono from the ICR and The Royal Marsden. “We are thrilled that a drug discovered at The Institute of Cancer Research has been proven to significantly extend life for many men, giving doctors a valuable new treatment option.”
The positive study results led the US Food and Drug Administration (FDA) on April 28 to approve abiraterone acetate as a pill in combination with the steroid prednisone for men with late-stage “castration-resistant” prostate cancer who have received prior docetaxel chemotherapy.
The drug’s manufacturer Janssen Pharmaceutical Companies has also applied for regulatory agency approvals in Europe, but for now the drug is not available to patients in the UK.
Prostate cancer growth is fuelled by the male hormone testosterone. Hormone treatments that block the testes’ production of testosterone usually stop benefiting patients after a few years, leading to the assumption that as tumours progressed they developed the ability to grow independently of testosterone.
However it was known that the adrenal glands also produce testosterone, suggesting that this was providing fuel to some cancer cells. In addition, scientists elsewhere had measured higher levels of enzymes involved in testosterone synthesis inside prostate tumour tissue, giving rise to a new theory that some cancers were able to produce their own testosterone.
Professor Mike Jarman and his team in what is now the Cancer Research UK Cancer Therapeutics Unit at the ICR in Sutton, south of London, designed abiraterone acetate to have a different mechanism of action from standard hormone treatments – blocking the production of male hormones in all tissues, not just the testes, by targeting an enzyme involved in hormone synthesis called CYP17.
“From the success of this study, it’s now clear that men with advanced prostate cancer can still benefit from treatments targeting male hormones. This has corrected 40 years of misunderstanding about this disease and we hope it will lead to the development of more second-line hormone treatments for these men – much like those used successfully to treat breast cancer,” said ICR Chief Executive Professor Alan Ashworth.
The randomised, double-blind study sponsored by Ortho Biotech Oncology Research & Development, a Unit of Cougar Biotechnology, Inc., began in May 2008 and was conducted in 147 sites in 13 countries. The 1,195 men who enrolled in the trial had all stopped responding to standard hormone therapy as well as second-line treatments including the chemotherapy drug docetaxel. They were either given abiraterone acetate together with the steroid prednisone (797 men), or prednisone and a placebo (398 men).
The study was designed to assess overall survival (the “primary endpoint”) and showed that men given the placebo survived an average of 11 months, while men given abiraterone acetate survived for nearly 15 months. Pain eased during the trial for a much greater number of patients taking abiraterone acetate than the placebo (44% versus 27% in patients for whom this could be measured).
Based on results of a prespecified interim analysis of the study, the trial’s Independent Data Monitoring Committee recommended unblinding the trial and allowing anyone on the placebo arm to be offered the drug.
The scientists also examined other possible measures of a drug’s effectiveness (as “secondary endpoints”). When compared to the placebo group, patients taking abiraterone acetate were also more likely to experience a significant drop in their prostate specific antigen (PSA) levels, the standard measure of prostate cancer activity (29% versus 6%), and they had more time before their PSA level started to rise again (10.2 months versus 6.6 months). X-rays showed mean time until tumour growth among the treatment group was also longer (5.6 months versus 3.6 months).
Doctors reported that patients taking abiraterone acetate generally did not experience some of the unpleasant side effects they often observe in men being treated with chemotherapy. In this trial, patients in the abiraterone acetate group compared to the placebo group did report more side effects such as fluid retention and swelling related to elevated levels of the mineralocorticoid class of steroid hormones, but these could usually be managed.
Harpal Kumar, Cancer Research UK’s chief executive, said: “Abiraterone is the first treatment of its kind shown to be effective in men with this type of advanced prostate cancer. This could make a huge difference to the 10,000 men diagnosed with aggressive forms of the disease in the UK every year. Thanks to our supporters, Cancer Research UK was a major funder of the discovery and early development of abiraterone including the first studies in humans. It’s incredibly heartening to see this early potential being turned into a treatment capable of providing patients with valuable extra months of life.”