The Prostate 66:1674 ^1685 (2006) The Effects of the Dual 5a-Reductase Inhibitor Dutasteride on Localized Prostate CanceröResults From a 4-Month Pre-Radical Prostatectomy Study M. Gleave,1* J. Qian,2 C. Andreou,3 P. Pommerville,4 J. Chin,5 R. Casey,6 G. Steinhoff,7 N. Fleshner,8 D. Bostwick,2 L. Thomas,9 and R. Rittmaster10 on behalf of the ARI40010 Study Team{ 1Prostate Centre at Vancouver General Hospital,Vancouver,British Columbia,Canada 2Bostwick Laboratories,Inc.,Glen Allen,Virginia 3Surrey Memorial Hospital, Surrey,British Columbia,Canada 4Can-Med Clinical Research, Inc.,Victoria, British Columbia,Canada 5London Health Sciences Centre, London,Ontario,Canada 6The Female/Male Health Centre, Oakville, Ontario,Canada 7Dr. Steinhoff Clinical Research,Victoria, British Columbia,Canada 8Division of Urology,Princess Margaret Hospital,Toronto,Ontario,Canada 9Department of Biochemistryand Molecular Biology,Dalhousie University,Halifax, Nova Scotia,Canada 10Research and Development,GlaxoSmithKline, ResearchTriangle Park, North Carolina BACKGROUND. As dihydrotestosterone (DHT) is the most potent androgen in the prostate, inhibition of the 5a-reductase isoenzymes, which convert testosterone to DHT, could be an appropriate target for the treatment of prostate cancer. METHODS. Eighty-one men with clinically localized prostate cancer received daily dutaste- ride 3.5 or 0.5 mg, or no therapy for 4 months before radical prostatectomy. Histopathological assessments were conducted on prostatectomy specimens. RESULTS. Treatment with dutasteride was associated with reductions in serum and intraprostatic DHT of 90%, and a decrease in total prostate and tumor volumes. No effect of dutasteride was noted on Gleason grade. Histopathological effects on benign tissue were similar but less prominent than those seen with androgen ablation, whereas there was no significant difference in cancer histology among the groups. CONCLUSIONS. Dutasteride treatment results in similar but less marked changes compared with androgen ablation. Prostate 66: 1674–1685, 2006. # 2006 Wiley-Liss, Inc. KEY WORDS: 5 alpha reductase; prostate cancer; treatment; Gleason score; apoptosis; proliferation {ARI40010 Study Team Members: Lorne E Aaron, Charalambous Grant sponsor: GlaxoSmithKline. Andreou, Richard W. Casey, Joseph L. Chin, Angelo De Marzo, *Correspondence to: M. Gleave, MD, Prostate Centre at Vancouver Russell B. Egerdie, Neil E. Fleshner, Martin E. Gleave, Antonio General Hospital, D9 Heather Pavillion 2733 Heather Street, Hurtado-Coll, Lawrence Klotz, Jay C-H. Lee, M. Scott Lucia, Chris Vancouver, British Columbia, Canada V5Z 3J5. GL. Morash, PFA. Mulders, Indrani Nandy, Peter Nelson, Peter J. E-mail: [email protected] Pommerville, Nadia Romano, Fred Saad, Thomas Sebo, Darlene Received 9 June 2006; Accepted 13 July 2006 Steele-Norwood, Gary EJ. Steinhoff, Lynn Thomas, Donald Tindall, DOI 10.1002/pros.20499 Catherine Too, Lawrence True, Timothy Wilson. Published online 22 August 2006 in Wiley InterScience (www.interscience.wiley.com). 2006Wiley-Liss,Inc. The Effects of Dutasteride on Prostate Cancer 1675 INTRODUCTION with 5 mg daily dutasteride versus placebo [17,18]. The objective of the current study was to further explore From the late nineteenth century it has been these findings by assessing the effect of 4 months hypothesized that ‘testicular factors’ promoted benign therapy with dutasteride before radical prostatectomy prostatic growth [1]. In the early 1940s, serum acid compared with surgery alone on histopathological phosphatase levels were demonstrated to be decreased assessments of prostatic tissue in men with biopsy- by castration and increased by androgens [2], and proven, clinically localized prostate cancer. castration was shown to result in clinical and serolo- gical improvements in men with prostate cancer [3]. Clinical studies have since established androgen MATERIALS AND METHODS ablation as a key component of prostate cancer Study Population management. Given the knowledge that dihydrotes- tosterone (DHT) and not testosterone is the most potent Eligible men for this study were aged 45 and androgen in the prostate [4], inhibition of the 5a- 80 years with a serum PSA of 2.5–10 ng/ml and reductase isoenzymes could be an appropriate target biopsy-proven, localized prostate cancer (clinical stage for the treatment of prostate cancer. T1c–T2b, N0/NX, M0) with a Gleason score 7. Those A number of lines of evidence support this hypoth- who had received prior treatment for prostate cancer esis. Firstly, studies with 5a-reductase inhibitors have were excluded. Other principal exclusion criteria inclu- demonstrated that they inhibit proliferation of human ded the use of 5a-reductase inhibitors or agents with LNCaP and PC-82 prostate cancer cells in vitro [5,6], as androgenic or anti-androgenic properties within the well as tumor growth in the Dunning rat model [7–9]. last 12 months, recent use of selenium (>75 mg), vitamin Secondly, several small-scale studies of finasteride in E(>100 IU) or Saw Palmetto (a washout period men with advanced prostate cancer demonstrated of 2 weeks was acceptable for the latter two), or serological improvements, albeit without evidence of prior prostatic surgery (including minimally invasive tumor regression or prevention of recurrence [10,11]. techniques). Lastly, the Prostate Cancer Prevention Trial (PCPT) demonstrated that daily therapy with finasteride Study Design significantly reduced the prevalence of prostate cancer versus placebo over a 7-year period [12]. Given that the This was a randomized, parallel-group study rates of prostate cancer in men treated with finasteride (Fig. 1). Prior to randomization, baseline assessments and placebo diverged early in the study, it seems were conducted including examination of prostate plausible that finasteride treated sub-clinical, micro- biopsy cores to confirm Gleason score (for comparison scopic tumors that were not clinically apparent at with prostatectomy specimens), medical history, phy- baseline [12]. sical examination, and free and total serum PSA levels. If 5a-reductase inhibitors confer a treatment benefit Following a screening visit, subjects were randomized in prostate cancer, an in vitro effect at the histological, to one of three treatment arms in a 1:1:1 ratio: 0.5 mg as well as clinical level, would be expected. A number dutasteride once daily for 4 months after a loading dose of studies have examined the effects of 5a-reductase of 7 mg (to ensure that steady-state was achieved more inhibitors on the histology of the benign and hyper- rapidly), 3.5 mg dutasteride once daily for 4 months, or plastic human prostate [13], but data on their effects in surgery alone at the earliest convenient time. The prostate cancer are less comprehensive. For the Type 2- 0.5 mg dose is the approved dose for the treatment of selective agent finasteride, a single needle biopsy study benign prostatic hyperplasia, and is also being exam- failed to demonstrate any effect beyond atrophy [14], ined in the REDUCE prostate cancer prevention study while two radical prostatectomy studies demonstrated [19]. The 3.5 mg dose was chosen to evaluate whether apoptosis and atrophy: [15] the effects of finasteride a larger dose of dutasteride would have more pro- were similar but less pronounced than those of nounced anti-tumor effects. leuprolide and flutamide [16]. For subjects receiving dutasteride, the subjects and A prospective, randomized pilot study in men investigators were blinded as to dutasteride dose. with prostate cancer undergoing radical prostatectomy For those randomized to surgery without dutasteride has also examined the histological effects of the dual therapy, patients and investigators were aware of treat- 5a-reductase inhibitor dutasteride. This study demon- ment allocation. Subjects randomized to dutasteride strated significantly increased atrophy and decreased were required to return to the clinic for clinical tumor volume, trends towards increased apoptosis and assessments at 2 weeks (Visit 3), 2 months (Visit 4), a higher treatment alteration score, and decreased and 4 months (Visit 5) after randomization. The microvessel density, for men treated for 6–10 weeks 4-month post-randomization visit (Visit 5) occurred The Prostate DOI 10.1002/pros 1676 Gleave et al. Fig. 1. Summary of study protocol. within 1 week before radical prostatectomy. At undergoing apoptosis as assessed by tissue transglu- surgery, prostatectomy samples were obtained for taminase (tTG) staining [20], which was conducted histological analysis. All subjects returned for a using unstained slides cut from blocks of prostate tissue follow-up visit 4 months after prostatectomy (Visit 6). taken on the day of surgery. In addition to tTG staining, All laboratory and histological assessments were TUNEL staining (percentage of prostatic cells per unit conducted in a blinded fashion. area undergoing apoptosis) was also conducted, and further assessments of proliferation, atrophy, micro- Serum and Intraprostatic Androgen vessel density, tumor grade (Gleason score), nuclear and PSA Measurements and architectural changes (none, mild, moderate, or severe), stromal/epithelial ratio, and prostate cancer Serum levels of DHT, testosterone, and PSA were lesion number and size were also performed on all measured at Visits 2, 4, 5, and 6. Intraprostatic DHT and prostatectomy specimens. These are summarized in testosterone were measured in the benign portion of the Table I. resected prostate tissue. Androgens were measured by