Advanced Prostate Cancer – The Need for New Treatments
Cancer of the prostate is one of the most common malignancies in men in both the USA and Europe. Despite the majority of patients having a good prognosis (outlook), there is still a high incidence of incurable metastatic disease. Most patients respond to androgen blocking treatments, but many develop progressive disease that is resistant to androgen ablation and is referred to variously as castration-resistant prostate cancer (CRPC), androgen-independent prostate cancer (AIPC) or hormone-refractory prostate cancer (HRPC). Many of these patients have no clinical symptoms, but have raised prostate-specific antigen (PSA) levels. The survival time for patients with CRPC is about one to two years. Up until recently, therapy options for progressive disease were limited to docetaxel-based chemotherapy but recent advances have provided new experimental treatments for advanced prostate cancer.
Androgen Ablation and Chemotherapy
Administration of the drug abiraterone in CRPC patients post-chemotherapy has been shown to improve survival. This is a CYP17 lyase inhibitor, with reduces androgen synthesis. Common side-effects include hypertension and fluid overload but this can be controlled by administration of prednisone. Other clinical studies have indicated that the addition of bevacizumab to the docetaxel/prednisone combination does not further increase survival rates.
MDV3100 is an androgen receptor antagonist which has been reported to cause decline in prostate-specific antigen (PSA) levels and objective clinical responses.
The drug Cabazitaxel, when given to patients with metastatic CRPC after docetaxel has shown a survival benefit.
Immunotherapy for Prostate Cancer
Multiple strategies have been used to stimulate immune mediated killing of prostate cancer cells. These include Prostvac, ipilimumab, GVAX and APC8015 (sipuleucel-T, Provenge), the latter two showing the greatest development.
Provenge is an autologous cell vaccine utilizing a prostatic acid phosphatase and GM-CSF fusion protein, which has demonstrated extended survival times in metastatic CRPC patients.
The GVAX therapy consists of tumor cells genetically modified to express an immunostimulatory cytokine, GM-CSF. However, when tested in phase III clinical trials this vaccine gave disappointing results.
Primary prostate tumors often metastasize (spread) to the bones, hence new agents that reduce skeletal fractures and bone pain are beneficial to patients. There is some data to suggest that bisphosphonates such as zoledronic acid benefit prostate cancer patients in this way. In addition, Denosumab has been shown to support bone density in patients who respond to androgen ablation.
Future Treatment of Prostate Cancer
CRPC is a highly variable malignancy, its management is challenging and most disease is not curable. Improved understanding of the basic biology of prostate cancer is likely to point to further experimental treatments for advanced prostate cancer. Many new drugs are entering the clinic and are likely to complement or replace older treatments, hopefully reducing the morbidity and mortality of this disease.
Novel agents and new therapeutics in castration-resistant prostate cancer. Y. Wu Y, J.E Rosenberg & M.E. Taplin. Curr Opin Oncol. 2011 Feb 9
Update on castrate-resistant prostate cancer: 2010. By K.Lassi, N.Dawson. In Current Opinion in Oncology. 2010, Vol 22, P263-7.
Advances in the Treatment of Castration-resistant Prostate Cancer by I.Davis, Asia-Pacific Oncology & Hematology, 2008, Vol 1, P54-7