Androgen deprivation therapy (ADT), or hormone therapy, can lead to long-term remission. But most men will eventually build up a resistance. This is due to a complex series of changes in gene structure and expression that help cancer cells survive. When resistance occurs, the disease progresses despite the absence of androgens. This is called castration-resistant prostate cancer, or CRPC (a term now thought to be more accurate than hormone-
resistant prostate cancer).
In the past, most treatments for CRPC (chemotherapy with mitoxantrone, bisphosphonates, radioactive isotopes) have been approved to relieve symptoms. Only docetaxel (a chemotherapy drug called a taxane) was shown to improve overall survival, but the effect isn’t lasting. More recently, cabazitaxel (a new taxane) given with prednisone (a steroid) as second-line therapy after docetaxel, and sipuleucel-T given before docetaxel were reported to extend survival by several months. Both drugs have recently received regulatory approval in the United States for treatment of CRPC.
This article looks at some promising targeted therapies that are improving the outlook for men with CRPC.
Stopping androgen receptors
Androgens attach themselves to a specific androgen receptor on prostate cells; the receptor then travels into the nucleus of the cell and binds to DNA, where it can “turn on” signals that fuel cancer cell division and growth. Most prostate cancers require continued activation of the receptor by androgens in order to grow. Antiandrogen therapies work by stopping androgens from binding to receptors. In many cases, the androgen receptor can eventually switch on a different set of signals to nourish cancer cells without testosterone.
Several new classes of drugs that target the androgen receptor directly are now being developed, including CYP17 inhibitors, stronger androgen receptor antagonists and drugs that target molecular chaperones, which will be discussed later.
CYP17 inhibitors
A drug called abiraterone blocks CYP17, which is key to testosterone production. It has been shown to reduce PSA, shrink tumours and improve symptoms. Phase I and II studies have reported that abiraterone is well tolerated and effective in CRPC for men with or without previous chemotherapy. Other encouraging studies are showing significant PSA declines using abiraterone with prednisone. A multicentre phase III trial is now comparing abiraterone to placebo both before chemotherapy and as second-line treatment after docetaxel chemotherapy.
Second-generation antiandrogens
MDV3100 is a new drug that stops testosterone from binding to the receptor and blocks the androgen receptor from binding to DNA. A phase I/II study showed that MDV3100 reduced PSA by more than 50% in almost half of the patients examined. The drug was well tolerated and none of the patients experienced disease progression. A phase III trial called AFFIRM is examining the use of MDV3100 in patients previously treated with docetaxel.
Blocking new blood vessels
Tumours use blood vessels to obtain oxygen and nutrients and to remove waste products. Angiogenesis — the formation of new blood vessels by tumours — represents a promising area of cancer treatment research. Adding drugs that inhibit angiogenesis may also make some chemotherapy drugs more effective.
Clinical trials are evaluating more than 20 antiangiogenic agents. These include antibodies such as bevacizumab that specifically block VEGF — a growth factor important in angiogenesis — and small molecules that hinder the activity of the VEGF receptors, such as sunitinib.
Initial studies combining bevacizumab with docetaxal showed significant PSA improvements. One trial, CALGB 90401, compared the effect of docetaxel/prednisone with or without bevacizumab on survival in 1,020 men with CRPC. Although recent results with the combined bevacizumab therapy demonstrated some benefits, it fell short of prolonging survival in patients.
Interestingly, thalidomide is a drug known to impair angiogenesis. It causes cell death and reduces angiogenesis factors such as VEGF. Initial studies have shown positive effects on PSA levels and progression-free survival. Other studies have looked at giving docetaxel with estramustine (another chemotherapy agent) and thalidomide. The positive results led to the development of lenalidomide, similar in structure to thalidomide but with higher potency and fewer side effects.
Focus on bone tumour interactions
Bone is the tissue most frequently involved in CRPC, and thus of great interest for interventions. In prostate cancer patients with bone metastases, bisphosphonates such as zoledronic acid reduce fractures and spinal cord compression, lessen pain and improve quality of life. Another newer drug called denosumab appears to decrease bone loss, increase bone mineral density and lower the incidence of spinal fractures. A placebo-controlled trial is studying its effect on bone metastasis-free survival.
Researchers are also investigating endothelins, molecules that affect various aspects of tumour progression and bone remodelling (the process by which bone is broken down and new bone formed) in metastatic disease. Blocking endothelin receptors with drugs such as atrasentan can reduce the formation of bone metastases. Initial studies with atrasentan suggest that it decreases PSA levels and cancer-related bone pain. A phase III study compared atrasentan to placebo in 809 men with metastatic CRPC. Based on bone scans after 12 weeks, atrasentan did not delay disease progression. However, an analysis performed on men with metastases confined to bone showed a delay in disease progression in those treated with atrasentan, suggesting it may be better suited to this particular patient group.
ZD4054 (zibotentan), an endothelin receptor antagonist that has shown a survival benefit in phase II studies when compared to best supportive care, is currently being evaluated in several phase III trials.
Targeting molecular chaperones
Molecular chaperones are proteins that protect cells under conditions of environmental stress. Proteins such as clusterin (CLU), Hsp27 and Hsp90 can interfere with anticancer treatments. CLU and Hsp27 are found at high levels in prostate cancer and increase after hormone treatment or chemotherapy. All three molecular chaperones are associated with cancer progression and treatment resistance.
OGX-011, or custirsen, is a drug that can resensitize cancer cells to therapy by reducing the production of CLU. A phase II randomized trial assigned 81 men with CRPC who had never had chemotherapy to receive docetaxel/custirsen or docetaxel alone. In those treated with docetaxel/custirsen, median survival was prolonged by seven months and death rates reduced by about 40%. It has also been shown to reduce PSA levels and improve pain symptoms in men after previous chemotherapy. Encouragingly, these results are better than the usual response rates for men receiving second-line chemotherapy, warranting further studies.
OGX-427 is a drug designed to reduce levels of Hsp27. A randomized phase II trial testing OGX-427 against prednisone will begin to enroll patients across Canada in September 2010. The experimental drug 17-AAG, made from the antibiotic geldanamycin, blocks Hsp90. Both drugs are the subject of ongoing investigation as a result of hopeful preliminary results from studies in CRPC.
Recruiting the immune system
Another attractive approach to treating CRPC is stimulating a patient’s immune system to fight the cancer. Sipuleucel-T is a “custom-made” vaccine obtained by combining some of a person’s immune cells with a substance called GM-CSF. The vaccine helps the body’s immune system to recognize cancer cells as a threat, and thereby launch an attack. Recent phase III studies showed that, compared to placebo, sipuleucel-T prolonged survival in metastatic CRPC, leading to approval in the US in 2010.
The future
Significant advances have been made in treatment options for men with CRPC. One challenge is being able to accurately gauge patients’ response to therapy. A promising avenue is the measurement of circulating tumour cells from a patient’s blood. However, their numbers can be very small and these cells are not easily detected.
Another difficulty is tailoring therapy based on the unique molecular characteristics of each individual cancer. Better identification of the most effective strategies for a particular patient could bring major breakthroughs and provide invaluable progress in this challenging area. The quest continues!
Dr. Martin E. Gleave is Director of the Vancouver Prostate Centre and Distinguished Professor at the University of British Columbia (UBC).
Dr. Anthony Koupparis is a Uro-oncology Fellow at UBC, Department of Urologic Sciences.
Clinical trials in Canada |
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*metastatic castration-resistant prostate cancer
