Will abiraterone impact survival in advanced prostate cancer?
Prostate cancer, the most common carcinoma in men, is characterised by malignant cells that are both androgen-dependent and androgen-independent. In the cells that are androgen-dependent, a critical level of androgen is required to activate a sufficient number of androgen receptors (ARs), so that death-signaling genes are repressed. Ninety percent of androgens are produced by the testes, with 10 percent produced by the adrenal glands or the cancer cells themselves.
Image: Two prostate cancer cells dividing from Cancer Research UK
Prostate cancer treatment is loosely divided into three phases based on the stage of disease; early stage disease, followed by a hormone therapy phase and finally an advanced cancer phase also know as stage IV, which usually leads to metastasis i.e. spread of the cancer cells to others areas of the body.
Early phase disease (stage I and II) can be picked up from an annual physical exam and involves surgical removal of the prostate gland, radiation therapy with or without hormone therapy, and "active surveillance", also known as watchful waiting.
The hormone therapy phase (stage III) is treated with primary androgen deprivation therapy, which may include castration and therapeutic disruption of the normal androgen production regulatory pathways.
Advanced metastatic prostate cancer (stage IV) is where the cancer cells can become androgen ablation insensitive (also called hormone refractory prostate cancer or HRPC). As the patient becomes insensitive to the hormone therapy, the levels of prostate specific antigen (PSA) increase. Chemotherapy is considered the standard of care for advanced stage disease. There are only three drugs approved by the FDA to treat HRPC; docetaxel, mitoxantrone, and estramustine, all of which have noticeable side effects, but show an increase in survival over best supportive care by approx. 18 months.
Recent therapies in the clinic have had a difficult time with FDA approval. Abbott's atrasentan (Xinlay) was found by the FDA advisory panel to be lacking in clear evidence that it prolonged survival despite significant drops in the PSA levels. Ditto for GPC/Spectrum's satraplatin, although it was approved by the European authorities.
More recently, Dendreon's Provenge (sipruleucel) was reviewed by the panel and more data was required because the trial just missed significance (0.052). This vaccine used a technique called Antigen Presenting Cells (APCs) to alert the patient’s T cells to attack the cancer and will likely be available for patients at some point in the next 12 months.
There are several drugs in development for prostate cancer, including AstraZeneca's endothelin receptor antagonist, Zibotentin, Genentech/Roche's Avastin and Merck/Ariad's mTor inhibitor, deforolimus.
In February this year another biotechnology company, Cougar, announced some promising data. Results of a phase II trial abiraterone in chemotherapy naiive patients demonstrated a 50 percent drop in PSA in 61 percent of patients. A phase II trial in patients having failed first-line chemotherapy with docetaxel showed 48 percent of patients having 50 percent decrease in PSA and 53 percent experiencing on-going stable disease. Additional phase I and II studies show similar promise with patients who have failed other treatment regimens including chemotherapy, leutenizing hormone analogs and other hormonal therapies. It remains to be seen, however, whether the falls in PSA will lead to a demonstrable improvement in survival (witness the atrasentan and satraplatin experiences).
So how does abiraterone work? In simple terms, it works by blocking the androgen sex hormones that fuel the cancer. Ten percent of the normal levels are produced in the adrenal glands, but theories point to cancer cells producing their own testosterone, thereby fueling the tumour's growth.
Abiraterone interferes with the cell's mechanisms for adrenal steroid synthesis through two very specific pathways, P450 enzymes 17-alpha hydroxylase and C17,20-lyase. This approach is thought to result in far fewer side effects and also inhibits androgen synthesis with tumour cells, although the data is still immature.
The latest study, reported in the Journal of Clinical Oncology, is a small one based on 21 patients with advanced, aggressive prostate cancer treated with the drug, but data has been collected on a total of 250 worldwide. It found significant tumour shrinkage, and a drop in tell-tale levels of a key protein produced by the cancer in the majority of patients.
To date, no patient has taken the drug for longer than two-and-a-half years, and so it has not been possible to determine exactly what the effect of the drug on life expectancy will be. These findings need to be reproduced in larger scale clinical trials, but the results so far look promising for advanced stage prostate cancer.
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This article is part of the Cancer Research Blog Carnival being hosted by the Sciencebase Science Blog.
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