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Transforming prostate cancer treatment

We transformed care for advanced prostate cancer, by validating inhibitors of androgen production as an effective cancer treatment, and discovering and developing abiraterone, a life-extending prostate cancer drug.

De bono prostate cancer article (Mateus Crespo/Prof Johann de Bono, the ICR)
Image of prostate cancer cells courtesy of Mateus Crespo/Professor Johann de Bono

The discovery and development of abiraterone is one of our biggest success stories. It was the first treatment shown to be effective in men with advanced prostate cancer and is now used as standard treatment for prostate cancer after chemotherapy, extending the lives of thousands of men in the UK with advanced prostate cancer.

Abiraterone’s journey began in the 1990s, when a team of scientists at The Institute of Cancer Research began to look for ways of shutting off production of male androgen sex hormones. Prostate cancer relies on testosterone to grow, so one of the main ways doctors treat the disease is by blocking its action. Over time most patients’ cancers stop responding to standard hormone treatments and many scientists believed the cancers had learned how to grow without testosterone.

An alternative theory

The ICR’s Professor Mike Jarman, and colleagues Dr Elaine Barrie and Professor Gerry Potter, began investigating an alternative theory – that these prostate cancers were using testosterone from elsewhere in body to grow, and might therefore still be treated by disrupting testosterone synthesis. They began investigating an existing antifungal drug called ketoconazole – an inhibitor of an enzyme called CYP17, which plays a key role in the production of androgens – and found that it could prevent the growth of prostate cancer cells.

Ketoconazole was not very potent or specific, and was quickly broken down by the body, making it unsuitable for use in patients. The team searched for alternative CYP17 inhibitors, aided by three-dimensional computer models created by colleagues at the ICR. Using this technique, the team identified a compound which specifically and irreversibly blocked CYP17, and prevented testosterone being made anywhere in the body. They confirmed that the drug switched off production of testosterone in both cancer cells and in mice.

Developing abiraterone

The ICR collaborated with the British Technology Group, an international specialist healthcare company, to further develop this compound, abiraterone. Read more about how we worked with commercial partners to develop abiraterone.

The early clinical trials of abiraterone were sponsored by the Cancer Research Campaign (now Cancer Research UK), led by Professor Ian Judson and carried out with our partner hospital, The Royal Marsden NHS Foundation Trust. They showed that the drug could impact its target when administered for a few days. The first continuous dosing Phase I trial was led by the ICR’s Professor Johann de Bono whose team showed abiraterone to be both safe and effective with impressive and durable antitumour activity. This then led to a large phase III trial led by Professor Johann de Bono which showed that prostate cancer patients given abiraterone lived on average for 15.8 months, compared with 11.2 months for men taking a placebo.

Based on this study, the drug received approval from the US Food and Drugs Administration and from the European Medicines Agency in 2011, marketed under the trade name Zytiga. In 2012, NICE announced that abiraterone would be made available on the NHS for patients with advanced metastatic prostate cancer.

References

O’Donnel et al. (2004) Hormonal impact of the 17α-hydroxylase/C17,20-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer 
British Journal of Cancer, 90, p2317–2325.  doi:10.1038/sj.bjc.6601879

Attard et al. (2008) Phase I Clinical Trial of a Selective Inhibitor of CYP17, Abiraterone Acetate, Confirms That Castration-Resistant Prostate Cancer Commonly Remains Hormone Driven. Journal of Clinical Oncology vol 26 no 28 p4563-4571 doi: 10.1200/JCO.2007.15.9749

de Bono et al., (2011) Abiraterone and Increased Survival in Metastatic Prostate Cancer, N Engl J Med 2011; 364:1995-2005 doi: 10.1056/NEJMoa1014618

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