[Dutasteride in the treatment of hormone refractory prostate cancer]

Most patients with advanced prostate cancer respond to androgen inhibition with or without antiandrogens. Progression to androgen-independent prostate cancer takes 5-7 years and is characterized by biochemical or diagnostic changes, despite testosteronemia levels similar to those after castration. Dutasteride, a 5-alfa-reductase types 1 and 2 inhibitor, is used in the treatment of benign prostatic hyperplasia (BPH). In prostate cancer, 5-alfa-reductase type 1 expression is greater than in BPH, but no differences in 5-alfa-reductase type 2 expression have been observed between metastatic prostate cancer and BPH. The higher levels of the two isozymes in metastatic and in recurrent prostate cancer after androgen withdrawal may reflect a selective adaptive mechanism to the amplification of remaining androgen signals. The aim of this prospective study was to evaluate the clinical utility of dutasteride in the treatment of hormone refractory prostate cancer.

Between March 2005 and December 2007, 8 patients with hormone refractory prostate cancer were evaluated prospectively. Following antiandrogen withdrawal and subsequent increase in PSA, 5 patients received docetaxel plus prednisone and 3 received ketoconazole plus hydrocortisone. The regimen was a single administration of 2 tablets of 0.5 mg dutasteride/die. Therapeutic response was defined as a >50% reduction in PSA or a 75% reduction at 4 weeks after the start of therapy.

The mean duration of follow-up was 9 months (range, 21-24 months). A reduction >50% or >75% in PSA was noted in 4 and 6 patients, respectively. Bone scintigraphy detected no normalization of bone lesions; computed tomography scanning showed no partial response to treatment. The mean duration of response was 6.9 months (range, 0-21 months). Two (25%) of the 8 patients died at 6 and 10 months, respectively, neither of which had responded to dutasteride treatment. Only 1/8 patients reported experiencing dyspepsia during the study period.

The activity of 5-alfa-reductase types 1 and 2 is expressed in the epithelial cells of the prostate, the stroma, and the prostate tumor. The genetic expression of fatty acid synthesis is influenced by dutasteride, which inhibits it by blocking the pathway that regulates sterol protein binding which, in turn, regulates androgen stimulation. The addition of a dual inhibitor of 5-a-reductase types 1 and 2 to antiandrogen therapy may further inhibit tumor growth, thus reducing the concentration of intracellular dihydrotestosterone, which is the primary androgen mediator of PSA gene expression in prostate tumor cell lines. These data support the rationale for the use of dutasteride in the treatment of hormone refractory prostate cancer. The study findings show that dutasteride is useful in the treatment of hormone refractory prostate cancer.