Prostate cancer is one of the most common forms of cancer in men. As a hormone-dependent cancer, treatment typically involves some way of blocking the activation of androgen receptors in the prostate, whether this is with luteinising hormone releasing hormone agonists, chemical castration or even surgical castration, all of which reduce the amount of androgen hormones such as testosterone that are in the system.
If this does not work and the cancer progresses regardless, the next mode of attack involves antiandrogen drugs such as bicalutamide, but even these tend not to work for prolonged periods as they also have some agonist activity. However, it has been shown that even in castration-resistant prostate cancer, androgen-dependent androgen receptor target gene expression still continues,1 so drugs that are either more effective at reducing the production of androgens or better at blocking their binding to androgen receptors should still be of therapeutic benefit.
One such drug is MDV-3100, an antiandrogen that was discovered by Medivation and is being co-developed with Astellas.2 It prevents androgens from binding to the androgen receptor, and also stops nuclear translocation and co-activator recruitment of the ligand–receptor complex, as well as inducing apoptosis in tumour cells. Unlike earlier antiandrogens like bicalutamide, it has no agonist activity.
In a Phase I/II study in 140 patients with progressive, metastatic castration-resistant prostate cancer, the subjects were given oral daily starting doses of 30mg of the drug, and then the doses were escalated in various cohorts, with the final doses ranging from 30mg to 600mg.3 Antitumour effects were seen at all doses, and more than half of the patients had a decrease in serum prostate-specific antigen of at least 50%. Other positive findings were a soft tissue response in 13 of 59 patients, stabilised bone disease in 61 of 109 patients, and a conversion to favourable from unfavourable circulating cell counts in 25 of 51 patients. The median time to progression was 47 weeks, and the maximum tolerated dose for sustained treatment 240mg. The most common serious adverse events were dose-dependent fatigue. This usually improved after the dose was reduced.
Recently, scientists announced that they had seen positive preclinical results in breast cancer, which showed that the drug appears to suppress androgen-driven breast cancer cell growth and, to their surprise, also oestrogen-driven breast cancer cell growth.4
references
1. E.A. Mostaghel et al. Cancer Res. 2007, 67, 5033
2. M.E. Jung et al. J. Med. Chem. 2010, 53, 2779
3. H.I. Scher et al. Lancet 2010, 375, 1437
4. J. Richer, Department of Defense Breast Cancer Research Program's 2011 Era of Hope Conference (August 2011, Orlando)