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Turning the tide

An array of drug classes under assessment could change the course of prostate cancer treatment

Tide Prostate cancer is one of the most common cancers among men, occurring at varying rates in different countries. More prevalent in the US and Europe than in Asia, the risk of prostate cancer is multifactorial, with both genetics and diet playing a role in its development. While the incidence of prostate cancer is low in Japan, Japanese immigrants in the US have a similar risk of prostate cancer to the general US population.

Prostate cancer is generally a slow-growing disease, occurring mainly in patients over the age of 50. The cancer itself is not often fatal, with death often the result of age-related illness. Also, prostate cancer does not generally produce clinically significant symptoms until quite late in the disease course. Prostate cancer can, however, have a significant effect on quality of life, with the primary tumour causing pain, urinary and sexual dysfunction, among other symptoms. Also, like other cancers, prostate cancer can spread, commonly to bone.

The mainstays of prostate cancer treatment are surgery and radiotherapy, aimed at removing or destroying the tumour. Due to the slow disease course, treatment of prostate cancer is often aimed at maintaining a balance between beneficial effects and the impact of treatment on quality of life, for example, prostatectomy – while able to effectively remove a localised tumour – runs the risk of destroying nerves vital for normal sexual function.

Hormonal therapy slows tumour growth by starving the tumour of testosterone. The action of testosterone is targeted in two ways: castration, either by physically removing the testes or stopping production of testosterone using gonadotropin-releasing hormone analogues, or by blocking testosterone receptors. Gonadotropin-releasing hormone analogues, such as goserelin (Zoladex; AstraZeneca) act to stop the production of testosterone in the testes, while testosterone antagonists, such as bicalutamide (Casodex; AstraZeneca) block the action of testosterone on prostate tissue.

Unfortunately, the main problem with these therapies is that they remain effective only while growth of the cancer is hormone-driven. As such, the need still exists for drugs aimed at treating advanced, aggressive or hormone-refractory prostate cancers.

Angiogenesis inhibitors
Angiogenesis inhibitors act to stall tumour growth by preventing the growth of new blood vessels that supply tumours with nutrients and oxygen. A number of angiogenesis inhibitors are in development for the treatment of prostate cancer, of which two leading candidates are sunitinib (Sutent; Pfizer) and bevacizumab (Avastin; Genentech). Both drugs act to inhibit vascular endothelial growth factor (VEGF), an important signalling molecule for blood vessel growth.

A phase III trial assessing the efficacy of bevacizumab in combination with docetaxel and prednisone in patients with metastatic hormone-refractory prostate cancer began in 2005, with regulatory filings for the indication expected sometime after 2010.

Results from a phase II study (CALGB 90006) assessing combination therapy with bevacizumab, docetaxel and estramustine appeared encouraging, with the authors noting that the regimen produced high response rates and had an acceptable tolerability profile. Pfizer began a phase III trial of sunitinib in patients with metastatic hormone-refractory disease in July 2008. Results of a phase II trial assessing combination therapy with sunitinib, docetaxel and prednisone were presented at ASCO 2008, with the authors commenting that prostate specific antigen and objective response rates were encouraging.

Other antiangiogenic treatments in development for prostate cancer include thalidomide and lenalidomide (Revlimid; Celgene Corporation). Both drugs have been launched for the treatment of multiple myeloma, and are currently in phase II trials assessing their efficacy in patients with prostate cancer.

Apoptosis stimulants
Apoptosis is the process by which cells 'self-destruct,' allowing unnecessary or damaged cells to be removed without causing collateral damage due to inflammation. Apoptosis is a promising target for the treatment of cancer, as disruption of cellular communication cascades leading to activation of apoptosis is one of the factors contributing to cancer cells immortality. A variety of apoptosis stimulants are undergoing clinical trials to assess their effectiveness for the treatment of prostate cancer.

A phase II trial began in May 2005 to assess the efficacy of DMXAA (Antisoma) in combination with docetaxel for the treatment of hormone-refractory prostate cancer. Preliminary results suggest that the addition of DMXAA to docetaxel is considerably more effective than docetaxel alone in this patient group, though Antisoma has stated that longer-term data is needed to assess the full potential of this regimen.

Other apoptosis stimulants currently in development include idronoxil and eribulin, which are being assessed in phase II trials sponsored by Marshall Edwards and Eisai, respectively.

Platinum drugs
Platinum drugs were one of the earliest classes of anticancer drugs to be discovered, acting to cross-link DNA strands resulting in reduced DNA replication and disruption of cell replication. Unfortunately, the use of platinum drugs is limited by their toxicity, the requirement for intravenous administration and the development of platinum-resistant tumours. Picoplatin (Poniard Pharmaceuticals) is currently in phase II trials, in combination with docetaxel and prednisone.

Initial results appear to indicate that picoplatin is well tolerated and effective for the treatment of hormone-refractory disease. Satraplatin (Orplatna; Bristol-Myers Squibb) is the first orally bioavailable platinum drug. Results from the phase III SPARC (Satraplatin and Prednisone Against Refractory Cancer) trial, which assessed the efficacy and tolerability of satraplatin in combination with prednisone, indicate that satraplatin is well tolerated and significantly improves progression-free survival. However, satraplatin did not appear to have any significant benefits with regards to overall survival.

Promising candidates
Though drugs such as bevacizumab, sunitinib and satraplatin may lead the fight against prostate cancer in the near future, they are by no means the only candidates to treat this disease. The huge array of drugs being assessed to treat prostate cancer includes improved hormonal therapies, such as the gonadotropin-releasing hormone analogue ozarelix, currently being developed by Spectrum Pharmaceuticals and Æterna Zentaris.

Other drug classes being assessed include anti-cytotoxic T-lymphocyte antigen 4 monoclonal antibodies, such as Bristol-Myers Squibb's ipilimumab, vaccines such as Dendreon Corporation's sipuleucel-T and immunotherapies, such as Merck Serono's adecatumumab. Coupled with improved screening and earlier detection of this silent killer, the armamentarium that could soon be available may turn the tide on prostate cancer.

The Author
Pipeline was written by Bernard Kerr of Adis International - Wolters Kluwer Health - using data derived from Adis R&D Insight and Clinical Trials Insight. For further information on Adis services, please contact Camille Scot-Smith on +44 (0)20 7981 0733

12th December 2008


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