There's a lot of media coverage today surrounding use of 5alpha-reductase inhibitors such as finasteride (Merck) and dutasteride (GSK) and their generic equivalents for chemoprevention of prostate cancer following publication of a study on finasteride by the American Association of Cancer Research (AACR) and one earlier this year on dutasteride in the New England Journal of Medicine (see references below for sources and the journal articles).
So what do these drugs do?
The drugs in the 5alpha-reductase class were developed for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to:
- Improve symptoms
- Reduce the risk of acute urinary retention
- Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy.
Fair enough, but how does this relate to prostate cancer?
Well, testosterone is the major circulating androgen in men and is converted to the major intracellular androgen, dihydrotestosterone, by steroid 5alpha-reductase isoenzymes, designated as type 1 and type 2. Finasteride inhibits the type 2 isoenzyme, whereas dutasteride inhibits both.
Many of you will be aware that in early stage prostate cancer, most men are hormone sensitive and respond to androgen deprivation therapy (ADT), which effectively acts as chemical castration to suppress the growth of the tumour of the prostate. Later, when castration resistance sets in (CRPC), the disease is more advanced. These days, if they are asymptomatic or mildly symptomatic, then a vaccine called sipuleucel-T (Provenge) can be considered or if metastatic and symptomatic, then chemotherapy with docetaxel (Taxotere) can be considered as a first-line option or cabazitaxel (Jevtana) after docetaxel has failed.
The goal of using the 5alpha-reductase inhibitors early was therefore to prevent or at the very least delay the development of malignant prostate cancer, essentially reducing the risk of developing the disease later. Several studies have been published over the last decade to answer this question.
The big question is does this approach actually work?
My thinking was if it was that obvious, then surely urologists and primary care physicians would be rushing to prescribe either therapy? Trouble is, they're not, as this succinct AACR press release shows.
One of the problems is that the original Prostate Cancer Prevention Trial (PCPT) study back in 2003, a large randomized controlled trial consisting of 18,000 men, appeared to have conflicting results, since it showed:
- a 25 percent reduced risk of prostate cancer.
- a 27% increased risk in high-grade tumours, which was highlighted in the accompanying editorial.
This fact seems to have created doubt and concern amongst urologists and PCP's.
Subsequently, there have been other reported studies with finasteride in 2008 (reanalysis of the 2003 data) and with dutasteride in the NEJM earlier this year, suggesting in both cases that the risk did not exist. The doubt, however, still lingers as the AACR press release highlighted:
"64 percent of urologists and 80 percent of primary care physicians never prescribe finasteride for chemoprevention.
When asked for reasons for their decision, 55 percent said they were concerned about the risk of high-grade tumors and 52 percent said they did not know it could be used for chemoprevention."
Another issue is the conflicting consequence of PSA suppression, which is still used by many urologists as the main biomarker for diagnosis and ADT treatment. The NEJM editorial earlier this year noted the challenge:
"Among men without cancer, both finasteride and dutasteride treat lower urinary tract symptoms, produce dramatic prostate shrinkage, and reduce serum levels of PSA by 50% or more.
However, for the patient who believes that he is taking a drug to prevent prostate cancer, this decline in PSA level can lead to a false sense of security."
Why is this? The editorial went on to explain:
"Data from the PCPT indicate that finasteride produces a progressive suppression of PSA for the duration of treatment. To estimate what the “true” PSA level would be if finasteride were not taken, it is necessary to multiply the PSA level by 2.0 for the first 2 years, by 2.3 for years 2 through 7, and thereafter by 2.5.
However, if the PSA level ever begins to rise at all, a biopsy should be performed, because with an increase in PSA level, the risk of cancer is increased by a factor of 3 and the risk of high-grade disease is increased by a factor of 6.
In the Finnish study, men who received finasteride for more than 4 years had a risk of high-grade disease that was increased by a factor of 2.6."
After reading all of the evidence in the various studies (cited below), I can see why physicians might be:
It's hard to make solid sense of the real impact of all the research, even as an unbiased scientist given the data that has emerged. My overall takeaway from all the articles was as follows:
- Dutasteride and finasteride do not prevent prostate cancer.
- They do shrink tumours that have a low potential for being lethal.
- They do not reduce the risk of a positive biopsy in patients who have an elevated PSA level or an abnormal digital rectal examination.
- Use of these drugs for prevention may be controversial because PSA levels are suppressed, giving a false sense of security.
- If prostate cancer develops, the diagnosis may be thus delayed (by artificially low PSA levels) until they have high-grade aggressive disease that may be more difficult to cure.
My final observation is that perhaps we should be monitoring other markers of disease such as circulating tumour cells (CTCs) in the blood rather than PSA. Whether this would be a better measure of disease or not remains to be elucidated, but would certainly be worth looking at in future studies to see if it is a more accurate biomarker in early prostate cancer.
Hamilton RJ, Kahwati LC, & Kinsinger LS (2010). Knowledge and Use of Finasteride for the Prevention of Prostate Cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology PMID: 20699373
Andriole, G., Bostwick, D., Brawley, O., Gomella, L., Marberger, M., Montorsi, F., Pettaway, C., Tammela, T., Teloken, C., Tindall, D., Somerville, M., Wilson, T., Fowler, I., & Rittmaster, R. (2010). Effect of Dutasteride on the Risk of Prostate Cancer New England Journal of Medicine, 362 (13), 1192-1202 DOI: 10.1056/NEJMoa0908127
Walsh, P. (2010). Chemoprevention of Prostate Cancer New England Journal of Medicine, 362 (13), 1237-1238 DOI: 10.1056/NEJMe1001045
Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, & Coltman CA Jr (2003). The influence of finasteride on the development of prostate cancer. The New England journal of medicine, 349 (3), 215-24 PMID: 12824459
Lucia, M., Darke, A., Goodman, P., La Rosa, F., Parnes, H., Ford, L., Coltman, C., & Thompson, I. (2008). Pathologic Characteristics of Cancers Detected in the Prostate Cancer Prevention Trial: Implications for Prostate Cancer Detection and Chemoprevention Cancer Prevention Research, 1 (3), 167-173 DOI: 10.1158/1940-6207.CAPR-08-0078
Murtola, T., Tammela, T., Määttänen, L., Ala-opas, M., Stenman, U., & Auvinen, A. (2009). Prostate cancer incidence among finasteride and alpha-blocker users in the Finnish Prostate Cancer Screening Trial British Journal of Cancer, 101 (5), 843-848 DOI: 10.1038/sj.bjc.6605188