Overview of Pivotal Studies for Prostate Cancer Risk Reduction, Past and Present
2009; Elsevier BV; Volume: 73; Issue: 5 Linguagem: Inglês
10.1016/j.urology.2009.02.017
ISSN1527-9995
Autores Tópico(s)Health Systems, Economic Evaluations, Quality of Life
ResumoProstate cancer (PCa), with its potentially long latency, generally late-age onset, and high prevalence, is an ideal target for risk reduction and disease prevention strategies. Treatment of the disease is currently associated with significant side effects and reduced quality of life. Encouraging results are emerging in PCa risk reduction with 5α-reductase inhibitors (5-ARIs). The pivotal Prostate Cancer Prevention Trial (PCPT) with finasteride established the efficacy of 5-ARIs in reducing the period prevalence of PCa. Ongoing trials that will further clarify the role of 5-ARIs in preventing and treating PCa include the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) with dutasteride in PCa risk reduction; the Reduction by Dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial on the effect of dutasteride on disease progression in low-grade localized PCa; and the Therapeutic Assessment of Rising PSAs [prostate-specific antigens] (TARP) trial on dutasteride in asymptomatic recurrent cancer. The data from these trials might initiate a paradigm shift in the attitudes of clinicians, healthcare policymakers, and patients to the benefits of PCa risk reduction strategies and their potential effect on a patient's health and quality of life. Prostate cancer (PCa), with its potentially long latency, generally late-age onset, and high prevalence, is an ideal target for risk reduction and disease prevention strategies. Treatment of the disease is currently associated with significant side effects and reduced quality of life. Encouraging results are emerging in PCa risk reduction with 5α-reductase inhibitors (5-ARIs). The pivotal Prostate Cancer Prevention Trial (PCPT) with finasteride established the efficacy of 5-ARIs in reducing the period prevalence of PCa. Ongoing trials that will further clarify the role of 5-ARIs in preventing and treating PCa include the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) with dutasteride in PCa risk reduction; the Reduction by Dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial on the effect of dutasteride on disease progression in low-grade localized PCa; and the Therapeutic Assessment of Rising PSAs [prostate-specific antigens] (TARP) trial on dutasteride in asymptomatic recurrent cancer. The data from these trials might initiate a paradigm shift in the attitudes of clinicians, healthcare policymakers, and patients to the benefits of PCa risk reduction strategies and their potential effect on a patient's health and quality of life. Prostate cancer (PCa) is the most common noncutaneous cancer, and the second leading cause of cancer death among men in the United States.1Jemal A. Siegel R. Ward E. et al.Cancer statistics, 2007.CA Cancer J Clin. 2007; 57: 43-66Crossref PubMed Scopus (7549) Google Scholar, 2Delongchamps N.B. Singh A. Haas G.P. The role of prevalence in the diagnosis of prostate cancer.Cancer Control. 2006; 13: 158-168PubMed Google Scholar Its incidence increases as age increases, with detection beginning around 45-54 years of age, and nearly 40% of men diagnosed before the age of 65 years.3Ries L. Melbert D. Drapcho M. et al.SEER cancer statistics review (based on November 2007 SEER data submission, posted to the SEER Web site, 2008).http://seer.cancer.gov/csr/1975_2005/Google Scholar The traditional treatment choices are associated with significant adverse events, and negatively affect the quality of life of both patients and their families (see also the report by Gomella in this supplement).4Sanda M.G. Dunn R.L. Michalski J. et al.Quality of life and satisfaction with outcome among prostate-cancer survivors.N Engl J Med. 2008; 358: 1250-1261Crossref PubMed Scopus (1846) Google Scholar However, the negative effects of the treatments, potentially long latency of the disease, late-age onset (given the long lifespan of today's male population), and high prevalence make PCa an ideal target for risk reduction and disease prevention. To this end, recent studies assessing the effect of pharmacologic intervention by 5α-reductase inhibitors (5-ARIs) in reducing the risk of PCa have shown promising results. Studies addressing the utility of these agents and others in the treatment of PCa and in the reduction of disease incidence are underway. With progress in the understanding of the biology of PCa, multiple signaling targets have been identified that are involved in the development and progression of the disease (see report by Crawford in this supplement). Although testosterone is the main circulating androgen in men, dihydrotestosterone (DHT) is the primary prostatic androgen.5Marks L.S. 5α-reductase: history and clinical importance.Rev Urol. 2004; 6: S11-S21Google Scholar In addition, DHT has a greater affinity to the androgen receptor,5Marks L.S. 5α-reductase: history and clinical importance.Rev Urol. 2004; 6: S11-S21Google Scholar, 6Wilbert D.M. Griffin J.E. Wilson J.D. Characterization of the cytosol androgen receptor of the human prostate.J Clin Endocrinol Metab. 1983; 56: 113-120Crossref PubMed Scopus (134) Google Scholar making it the predominant agonist of the androgen receptor pathway that leads to prostate maintenance and growth. The conversion of testosterone to DHT is regulated by the enzyme 5α-reductase (5αR) in prostate cells.5Marks L.S. 5α-reductase: history and clinical importance.Rev Urol. 2004; 6: S11-S21Google Scholar Also, 5αR activity differs among various ethnic groups and correlates with PCa prevalence in those populations.7Ross R.K. Bernstein L. Lobo R.A. et al.5-Alpha-reductase activity and risk of prostate cancer among Japanese and US white and black males.Lancet. 1992; 339: 887-889Abstract PubMed Scopus (405) Google Scholar, 8Ntais C. Polycarpou A. Tsatsoulis A. Molecular epidemiology of prostate cancer: androgens and polymorphisms in androgen-related genes.Eur J Endocrinol. 2003; 149: 469-477Crossref PubMed Scopus (67) Google Scholar These and other data have led scientists to study the role of 5αR inhibition in reducing PCa occurrence and progression. Three isoforms of 5αR have been identified. Type 1 is most prevalent in extraprostatic tissues, such as the skin and liver, and plays a role in regulating androgen metabolism and protecting against hormone excess in peripheral tissues, and type 2 is the predominant isoform in the prostate.9Jin Y. Penning T.M. Steroid 5α-reductases and 3α-hydroxysteroid dehydrogenases: key enzymes in androgen metabolism.Best Pract Res Clin Endocrinol Metab. 2001; 15: 79-94Abstract Full Text PDF Scopus (109) Google Scholar, 10Thomas L.N. Lazier C.B. Gupta R. et al.Differential alterations in 5α-reductase type 1 and type 2 levels during development and progression of prostate cancer.Prostate. 2005; 63: 231-239Crossref PubMed Scopus (155) Google Scholar Type 1 is expressed in the prostate when benign prostatic hyperplasia (BPH) is present, and its expression increases greatly in various stages of PCa, especially high-grade tumors.10Thomas L.N. Lazier C.B. Gupta R. et al.Differential alterations in 5α-reductase type 1 and type 2 levels during development and progression of prostate cancer.Prostate. 2005; 63: 231-239Crossref PubMed Scopus (155) Google Scholar The upregulation of type 1 5αR in the prostate might have significance in PCa development. The expression of type 2 5αR is decreased in prostatic intraepithelial neoplasia (PIN) tissue and primary PCa compared with its expression in BPH tissues but is again highly elevated in recurrent and metastatic cancer tissue.10Thomas L.N. Lazier C.B. Gupta R. et al.Differential alterations in 5α-reductase type 1 and type 2 levels during development and progression of prostate cancer.Prostate. 2005; 63: 231-239Crossref PubMed Scopus (155) Google Scholar Therefore, comprehensively inhibiting both 5αR isoforms might be a rational approach to impair PCa development. PIN, characterized by precancerous cellular proliferations in the prostate, is regarded as a likely precursor of PCa.11Bostwick D.G. Prostatic intraepithelial neoplasia is a risk factor for cancer.Semin Urol Oncol. 1999; 17: 187-198PubMed Google Scholar The reduced level of type 2 5αRs in PIN tissue might explain the lack of a type 2 5αR inhibitor effect on these tissues.12Cote R.J. Skinner E.C. Salem C.E. et al.The effect of finasteride on the prostate gland in men with elevated serum prostate-specific antigen levels.Br J Cancer. 1998; 78: 413-418Crossref PubMed Scopus (62) Google Scholar However, the inhibition of both types 1 and 2 5αRs significantly reduced the PIN volume after only 6-10 weeks.13Andriole G.L. Humphrey P. Ray P. et al.Effect of the dual 5α-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer.J Urol. 2004; 172: 915-919Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar Type 3 5αR is a recent discovery, and its roles in the prostate and elsewhere are under study.14Uemura M. Tamura K. Chung S. et al.Novel 5 α-steroid reductase (SRD5A3, type-3) is overexpressed in hormone-refractory prostate cancer.Cancer Sci. 2008; 99: 81-86PubMed Google Scholar Two 5-ARIs have been well studied and approved for clinical use (Table 1).15Avodart® (dutasteride) prescribing information GlaxoSmithKline, Research Triangle Park, NC2008Google Scholar, 16Proscar® (finasteride) Prescribing Information Merck & Company, Whitehouse Station, NJ2007Google Scholar Finasteride is a selective type 2 5αR inhibitor, and dutasteride inhibits both types 1 and 2 5αR.17Bramson H.N. Hermann D. Batchelor K.W. et al.Unique preclinical characteristics of GG745, a potent dual inhibitor of 5AR.J Pharmacol Exp Ther. 1997; 282: 1496-1502PubMed Google Scholar In addition, dutasteride is a threefold more potent inhibitor of type 2 5αR than finasteride.18Gisleskog P.O. Hermann D. Hammarlund-Udenaes M. et al.A model for the turnover of dihydrotestosterone in the presence of the irreversible 5α-reductase inhibitors GI198745 and finasteride.Clin Pharmacol Ther. 1998; 64: 636-647Crossref Scopus (59) Google Scholar In both animal models and humans, dutasteride has a much longer terminal half-life than finasteride. Dutasteride has a half-life of approximately 5 weeks in humans, and the half-life of finasteride is 6-8 hours.15Avodart® (dutasteride) prescribing information GlaxoSmithKline, Research Triangle Park, NC2008Google Scholar, 17Bramson H.N. Hermann D. Batchelor K.W. et al.Unique preclinical characteristics of GG745, a potent dual inhibitor of 5AR.J Pharmacol Exp Ther. 1997; 282: 1496-1502PubMed Google Scholar At the 0.5-mg therapeutic dose, dutasteride reduces serum DHT by >90%, a significantly greater reduction than the 70.8% suppression observed with finasteride and with less variability (Fig. 1).19Clark R.V. Hermann D.J. Cunningham G.R. et al.Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5α-reductase inhibitor.J Clin Endocrinol Metab. 2004; 89: 2179-2184Crossref PubMed Scopus (382) Google Scholar Although both drugs have been approved for the treatment of BPH, only dutasteride is currently under investigation for its effect in reducing the risk of developing PCa.13Andriole G.L. Humphrey P. Ray P. et al.Effect of the dual 5α-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer.J Urol. 2004; 172: 915-919Abstract Full Text Full Text PDF PubMed Scopus (136) Google ScholarTable 1Dutasteride and finasteride: selected comparisonsParameterDutasterideFinasterideDosing, PK, and MOA Dosage (mg/d)0.55.0 Half-life∼5 wk6 h⁎Increased to 8 h (range 6-15) for men aged ≥70 years. 5α-reductase inhibition targetTypes 1 and 2Type 2 DHT suppression (%)9570Clinical trial endpoints†From randomized controlled clinical trials of men with benign prostatic hyperplasia symptoms. Prostate volume reduction (%)26.7-28‡Range reflects differences in mean baseline prostate volume in clinical trials. (at 2 y)17.9 (at year 4) Increase in urinary flow (mL/s)1.8 (at 2 y)1.9 (at 1 y) Reduction in risk of AUR (%)57 (at 2 y)57 (at 4 y)PK, pharmacokinetics; MOA, mechanism of action; DHT, 5α-dihydrotestosterone; AUR, acute urinary retention.Data from Avodart (dutasteride) prescribing information15Avodart® (dutasteride) prescribing information GlaxoSmithKline, Research Triangle Park, NC2008Google Scholar and Proscar (finasteride) prescribing information.16Proscar® (finasteride) Prescribing Information Merck & Company, Whitehouse Station, NJ2007Google Scholar Increased to 8 h (range 6-15) for men aged ≥70 years.† From randomized controlled clinical trials of men with benign prostatic hyperplasia symptoms.‡ Range reflects differences in mean baseline prostate volume in clinical trials. Open table in a new tab PK, pharmacokinetics; MOA, mechanism of action; DHT, 5α-dihydrotestosterone; AUR, acute urinary retention. Data from Avodart (dutasteride) prescribing information15Avodart® (dutasteride) prescribing information GlaxoSmithKline, Research Triangle Park, NC2008Google Scholar and Proscar (finasteride) prescribing information.16Proscar® (finasteride) Prescribing Information Merck & Company, Whitehouse Station, NJ2007Google Scholar The Prostate Cancer Prevention Trial (PCPT) was the first large-scale PCa risk reduction study (Fig. 2). It was a 7-year randomized, double-blind, placebo-controlled trial of finasteride for PCa risk reduction in healthy men. Participants in the study were healthy men with a low risk of PCa as determined by a prostate-specific antigen (PSA) level of ≤3.0 ng/mL and normal digital rectal examination (DRE) findings at enrollment. After a 3-month placebo run-in, 18 882 men ≥55 years old were randomized to receive 5 mg/d finasteride (n = 9423 men, with 4368 men included in the final analysis) or placebo (n = 9459 men, with 4692 men included in the final analysis). Annual PSA measurements and DREs were performed to determine whether for-cause biopsy was necessary. At the end of the seventh year, all participants who had not been diagnosed with PCa were recommended for an end-of-study biopsy.20Thompson I.M. Goodman P.J. Tangen C.M. et al.The influence of finasteride on the development of prostate cancer.N Engl J Med. 2003; 349: 215-224Crossref PubMed Scopus (2338) Google Scholar Although survival would be the reference standard for such a study, the long latency of the disease makes such a goal problematic, and other established surrogate endpoints were used. The primary endpoint was the period prevalence of biopsy-detected cancer to include the development of PCa diagnosed during the study period, as well as the detection of PCa by biopsy at the end of 7 years.21Feigl P. Blumenstein B. Thompson I. et al.Design of the Prostate Cancer Prevention Trial (PCPT).Control Clin Trials. 1995; 16: 150-163Abstract Full Text PDF PubMed Scopus (107) Google Scholar, 22Higgins B. Thompson I.M. The Prostate Cancer Prevention Trial: current status.J Urol. 2004; 171: S15-S17Abstract Full Text Full Text PDF Scopus (14) Google Scholar Histologic cancer is a necessary step in the natural history of cancer development, and its prevalence and biopsy detectability are therefore relevant to the ultimate goal of cancer prevention. Because finasteride reduces the serum PSA level by 50%,23Guess H.A. Heyse J.F. Gormley G.J. et al.Effect of finasteride on serum PSA concentration in men with benign prostatic hyperplasia: results from the North American phase III clinical trial.Urol Clin North Am. 1993; 20: 627-636PubMed Google Scholar, 24Andriole G.L. Guess H.A. Epstein J.I. et al.Proscar Long-term Efficacy and Safety Study, PLESS Study GroupTreatment with finasteride preserves usefulness of prostate-specific antigen in the detection of prostate cancer: results of a randomized, double-blind, placebo-controlled clinical trial.Urology. 1998; 52: 195-201Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar the PSA cutoff was adjusted in the treatment group so that similar proportions of participants in the finasteride group and placebo group would be recommended for for-cause biopsy according to a serum PSA level of >4.0 ng/mL.20Thompson I.M. Goodman P.J. Tangen C.M. et al.The influence of finasteride on the development of prostate cancer.N Engl J Med. 2003; 349: 215-224Crossref PubMed Scopus (2338) Google Scholar At that time, the effect on biopsy of the prostate shrinkage caused by finasteride was not known and, for the purposes of the study, no effect was assumed (this was also the assumption with respect to any effect of increased DRE sensitivity related to finasteride therapy).21Feigl P. Blumenstein B. Thompson I. et al.Design of the Prostate Cancer Prevention Trial (PCPT).Control Clin Trials. 1995; 16: 150-163Abstract Full Text PDF PubMed Scopus (107) Google Scholar The study was terminated 15 months before the original 9-year schedule owing to overwhelming evidence that the primary objective had been met, and the results were reported in 2003. A 24.8% (P < .001) reduction in PCa prevalence during the 7-year period was observed, with 803 of 4368 men (18.4%) in the finasteride group having biopsy-detected PCa compared with 1147 of 4692 men (24.4%) in the placebo group. Unexpectedly, more high-grade tumors (defined as Gleason score 7-10) were found on biopsy in the finasteride group (6.4%) than in the placebo group (5.1%; P = .005).20Thompson I.M. Goodman P.J. Tangen C.M. et al.The influence of finasteride on the development of prostate cancer.N Engl J Med. 2003; 349: 215-224Crossref PubMed Scopus (2338) Google Scholar In the PCPT, finasteride, just as in the pivotal trial in BPH, was relatively well tolerated.20Thompson I.M. Goodman P.J. Tangen C.M. et al.The influence of finasteride on the development of prostate cancer.N Engl J Med. 2003; 349: 215-224Crossref PubMed Scopus (2338) Google Scholar, 25Gormley G.J. Stoner E. Bruskewitz R.C. et al.Finasteride Study GroupThe effect of finasteride in men with benign prostatic hyperplasia.N Engl J Med. 1992; 327: 1185-1191Crossref PubMed Scopus (984) Google Scholar The main side effects were in sexual function, but urinary function generally improved. A reduced volume of ejaculate, erectile dysfunction, loss of libido, and gynecomastia were more common in the finasteride group than in the placebo group (P < .001), but urinary urgency or frequency, urinary retention, urinary tract infection, and prostatitis were greater in the placebo group (P < .001).20Thompson I.M. Goodman P.J. Tangen C.M. et al.The influence of finasteride on the development of prostate cancer.N Engl J Med. 2003; 349: 215-224Crossref PubMed Scopus (2338) Google Scholar A sound safety profile is essential for long-term use of drugs in cancer prevention. For example, sexual function side effects might not be acceptable to otherwise healthy men. In the PCPT, the reported incidence of sexual function side effects was what would be expected in men of this age group who had been followed up and questioned repeatedly for 7 years on this subject.20Thompson I.M. Goodman P.J. Tangen C.M. et al.The influence of finasteride on the development of prostate cancer.N Engl J Med. 2003; 349: 215-224Crossref PubMed Scopus (2338) Google Scholar In another analysis of the sexual side effects reported throughout the PCPT, sexual dysfunction was found to increase only slightly in the finasteride group and to diminish with time.26Moinpour C.M. Darke A.K. Donaldson G.W. et al.Longitudinal analysis of sexual function reported by men in the Prostate Cancer Prevention Trial.J Natl Cancer Inst. 2007; 99: 1025-1035Crossref PubMed Scopus (67) Google Scholar Despite the significant reduction in PCa incidence, the use of finasteride in PCa risk reduction has not been extensively adopted since the publication of the PCPT results. Heated debate has occurred concerning the incidence of high-grade PCa (HGPCa) observed on biopsy in the finasteride group. The main question is whether finasteride causes more aggressive tumors or whether the observation reflected artifactual changes on prostate morphology or volume induced by finasteride administration. If finasteride induced the development of HGPCa, it would be expected that this effect would "accelerate," such that a continuous increase in the ratio of HGPCa incidence in the finasteride group to the HGPCa incidence in the placebo group would be observed during the 7-year period. However, the ratio was greatest in the first 2 years.20Thompson I.M. Goodman P.J. Tangen C.M. et al.The influence of finasteride on the development of prostate cancer.N Engl J Med. 2003; 349: 215-224Crossref PubMed Scopus (2338) Google Scholar, 27Mellon J.K. The finasteride Prostate Cancer Prevention Trial (PCPT)—what have we learned?.Eur J Cancer. 2005; 41: 2016-2022Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Recently, it has been reported that finasteride increased the sensitivity of PSA and DRE in PCa detection.28Thompson I.M. Tangen C.M. Goodman P.J. et al.Finasteride improves the sensitivity of digital rectal examination for prostate cancer detection.J Urol. 2007; 177: 1749-1752Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 29Thompson I.M. Chi C. Ankerst D.P. et al.Effect of finasteride on the sensitivity of PSA for detecting prostate cancer.J Natl Cancer Inst. 2006; 98: 1128-1133Crossref PubMed Scopus (262) Google Scholar This might partially explain the increased detection of HGPCa in the for-cause biopsies, especially during the early years of the study period, although the extent of progression of the HGPCa cases in the finasteride group was lower than in the placebo group.30Lucia M.S. Epstein J.I. Goodman P.J. et al.Finasteride and high-grade prostate cancer in the Prostate Cancer Prevention Trial.J Natl Cancer Inst. 2007; 99: 1375-1383Crossref PubMed Scopus (214) Google Scholar However, the bias introduced by increased PSA and DRE sensitivity would have been neutralized by the end-of-study biopsy. That the increase in HGPCa on biopsy continued to be seen in the for-cause and end-of-study biopsies combined requires additional explanation. In the PCPT, the median prostate volume at biopsy was 24.1% lower in the finasteride group (25.5 vs 33.6 cm3, P < .001).20Thompson I.M. Goodman P.J. Tangen C.M. et al.The influence of finasteride on the development of prostate cancer.N Engl J Med. 2003; 349: 215-224Crossref PubMed Scopus (2338) Google Scholar Thus, a greater proportion of the prostate was sampled in the finasteride arm, which might have increased the chance of detecting PCa of all grades. To evaluate such an effect, the Gleason grades of tissue samples from radical prostatectomy (RP) can be used as the standard for the labeling of HGPCa. The evaluation of RP specimens from 25% of patients in the PCPT showed that more men in the placebo arm were "upgraded" at RP, with the result that the finasteride-associated increase compared with placebo in HGPCa at biopsy (42.7% finasteride vs 25.4% placebo) was reduced at RP (46.4% finasteride vs 38.6% placebo).30Lucia M.S. Epstein J.I. Goodman P.J. et al.Finasteride and high-grade prostate cancer in the Prostate Cancer Prevention Trial.J Natl Cancer Inst. 2007; 99: 1375-1383Crossref PubMed Scopus (214) Google Scholar When the RP data were extrapolated to all men in the PCPT, the rate for true HGPCa was estimated at 3.9% in the finasteride arm and 4.6% in the placebo arm.31Pinsky P. Parnes H. Ford L. Estimating rates of true high-grade disease in the Prostate Cancer Prevention Trial.Cancer Prev Res. 2008; 1: 182-186Crossref Scopus (70) Google Scholar These results suggest that the observed increase in HGPCa on biopsy in the PCPT resulted from the bias introduced by the increased biopsy sensitivity in the finasteride arm. In a second model that adjusted further for biases in the RP participants, the HGPCa rate was estimated at 6.0% in the finasteride arm and 8.2% in the placebo arm.32Redman M.W. Tangen C.M. Goodman P.J. et al.Finasteride does not increase the risk of high-grade prostate cancer: a bias-adjusted modeling approach.Cancer Prev Res. 2008; 1: 174-181Crossref PubMed Scopus (174) Google Scholar One of the key points that emerged from analysis of the placebo arm of the PCPT was the predictive utility of PSA measurements in diagnosing a patient's current risk of developing PCa. A statistically significant relationship between the PSA level and the risk of PCa (P < .001), with greater PSA levels consistently associated with an increased PCa risk, was demonstrated within the placebo-treated control population. This relationship between PSA and cancer risk was correlative with regard to both PCa overall and high-grade disease.33Thompson I.M. Ankerst D.P. Chi C. et al.Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial.J Natl Cancer Inst. 2006; 98: 529-534Crossref PubMed Scopus (766) Google Scholar A prediction model using these same data found that the addition of other risk factors—age, DRE, and previous biopsy—did not have a large effect on risk prediction. Although reaching the threshold of statistical significance (P < .05), the difference in magnitude between PSA measurement alone and PSA measurement with additional risk factors was, at 3%, not considered clinically significant,34Pepe M.S. Feng Z. Huang Y. et al.Integrating the predictiveness of a marker with its performance as a classifier.Am J Epidemiol. 2008; 167: 362-368Crossref Scopus (220) Google Scholar indicating that PSA values alone might be sufficient in diagnosing a patient's current risk of PCa. Another 5-ΑRI, the dual inhibitor dutasteride, is currently in a Phase III PCa risk reduction trial (Fig. 2). Because of the increased expression of type 1 5αR in various PCa stages and the greater suppression of DHT by a dual 5-ΑRI,10Thomas L.N. Lazier C.B. Gupta R. et al.Differential alterations in 5α-reductase type 1 and type 2 levels during development and progression of prostate cancer.Prostate. 2005; 63: 231-239Crossref PubMed Scopus (155) Google Scholar, 19Clark R.V. Hermann D.J. Cunningham G.R. et al.Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5α-reductase inhibitor.J Clin Endocrinol Metab. 2004; 89: 2179-2184Crossref PubMed Scopus (382) Google Scholar dutasteride might prove to be more effective than finasteride in PCa risk reduction. This hypothesis has been further supported by in vitro data showing that dutasteride, but not finasteride, enhanced cell death, possibly through apoptosis, in the LNCaP PCa cell line.35Lazier C.B. Thomas L.N. Douglas R.C. et al.Dutasteride, the dual 5alpha-reductase inhibitor, inhibits androgen action and promotes cell death in the LNCaP prostate cancer cell line.Prostate. 2004; 58: 130-144Crossref PubMed Scopus (70) Google Scholar An analysis of the pooled data from 3 identical Phase III clinical trials of dutasteride as BPH treatment revealed that dutasteride significantly lowered the cumulative incidence of PCa vs placebo at 24 months (1.1% vs 1.9%, P = .025) and 27 months (1.2% vs 2.5%, P = .002).36Andriole G.L. Roehrborn C. Schulman C. et al.Effect of dutasteride on the detection of prostate cancer in men with benign prostatic hyperplasia.Urology. 2004; 64: 537-541Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar This is the most important clinical evidence supporting the potential for dutasteride to reduce PCa risk. However, these studies were not designed to study risk reduction, and the diagnosis of PCa was reported as an adverse event. Randomized trials to study dutasteride in PCa risk reduction are needed. Dutasteride is well tolerated. In the pooled BPH studies discussed, daily use of dutasteride for 2 years showed a safety profile similar to that of placebo, with the exception of a modestly elevated incidence (each <5%) of impotence, ejaculation disorders, decreased libido, and gynecomastia. Most drug-related adverse events occurred within the first 12 months of treatment and diminished over time.37Andriole G.L. Kirby R. Safety and tolerability of the dual 5α-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia.Eur Urol. 2003; 44: 82-88Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar In the subsequent 2-year extension period, the incidence of most drug-related sexual adverse events continued to decrease.38Debruyne F. Barkin J. Van Erps P. et al.Efficacy and safety of long-term treatment with the dual 5α-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia.Eur Urol. 2004; 46: 488-494Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar In a large direct comparison study, the safety profile of dutasteride did not differ from that of finasteride. Because type 1 5αR is also located in the liver and skin, it is important to note that dutasteride does not differ significantly from either placebo or finasteride with respect to clinical laboratory parameters, including the results of liver function tests. Furthermore, in healthy volunteers, dutasteride administered daily for 1 year did not significantly affect bone metabolism markers, bone mineral density, or the lipid profile.37Andriole G.L. Kirby R. Safety and tolerability of the dual 5α-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia.Eur Urol. 2003; 44: 82-88Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial is an ongoing 4-year, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of oral dutasteride 0.5 mg/d in PCa risk reduction. It was initiated in 2004, recruiting approximately 8000 men 50-75 years of age, with a PSA level of 2.5-10 ng/mL in those aged 5
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