Urology
Volume 73, Issue 5, Supplement , Pages S36-S43, May 2009

Overview of Pivotal Studies for Prostate Cancer Risk Reduction, Past and Present

  • Gerald L. Andriole

      Affiliations

    • Corresponding Author InformationReprint requests: Gerald Andriole, M.D., Division of Urology, Department of Surgery, Washington University School of Medicine, Barnes-Jewish Hospital, Siteman Cancer Center, 4960 Children's Place, Campus Box 8242, St. Louis, MO 63110

Division of Urology, Department of Surgery, Washington University School of Medicine, Barnes-Jewish Hospital, St. Louis, Missouri

Received 2 February 2009; accepted 13 February 2009.

Article Outline

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.1, 2 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.3 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).4 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.

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5-ARIs and PCa 

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.5 In addition, DHT has a greater affinity to the androgen receptor,5, 6 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.5 Also, 5αR activity differs among various ethnic groups and correlates with PCa prevalence in those populations.7, 8 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.9, 10 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.10 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.10 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.11 The reduced level of type 2 5αRs in PIN tissue might explain the lack of a type 2 5αR inhibitor effect on these tissues.12 However, the inhibition of both types 1 and 2 5αRs significantly reduced the PIN volume after only 6-10 weeks.13 Type 3 5αR is a recent discovery, and its roles in the prostate and elsewhere are under study.14

Two 5-ARIs have been well studied and approved for clinical use (Table 1).15, 16 Finasteride is a selective type 2 5αR inhibitor, and dutasteride inhibits both types 1 and 2 5αR.17 In addition, dutasteride is a threefold more potent inhibitor of type 2 5αR than finasteride.18 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.15, 17 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).19 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.13

Table 1. Dutasteride and finasteride: selected comparisons
ParameterDutasterideFinasteride
Dosing, PK, and MOA
Dosage (mg/d)0.55.0
Half-life∼5wk6h⁎
5α-reductase inhibition targetTypes 1 and 2Type 2
DHT suppression (%)9570
Clinical trial endpoints†
Prostate volume reduction (%)26.7-28‡ (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 information15 and Proscar (finasteride) prescribing information.16

⁎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.

  • View full-size image.
  • Figure 1. 

    Dihydrotestosterone (DHT) reduction by dutasteride vs finasteride, baseline to end of active treatment. At therapeutic dose, from baseline to end of active treatment (24 weeks), dutasteride reduced DHT by >90%, significantly greater reduction than the 70.8% suppression observed with finasteride and with less variability. Data from Clark et al.19

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Pivotal studies of 5-ARIs in PCa 

Prostate Cancer Prevention Trial 

Study Design 

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.20

  • View full-size image.
  • Figure 2. 

    Pivotal studies with 5α-reductase inhibitors (5-ARIs), natural supplements, and combination therapies for prostate cancer. Prostate Cancer Prevention Trial (PCPT), finasteride for PCa prevention in healthy men; Selenium and Vitamin E Cancer Prevention Trial (SELECT) in men at low risk of prostate cancer; Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, Phase III prostate cancer prevention trial; Reduction by Dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial, disease progression and interval to initiation of more aggressive cancer with dutasteride in men with localized prostate cancer; and Therapeutic Assessment of Rising PSAs (TARP), effect of combination dutasteride and bicalutamide therapy on extending interval to disease progression therapy in men with asymptomatic recurrent prostate cancer after first-line androgen deprivation. Data from GlaxoSmithKline.45

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.21, 22 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%,23, 24 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.20 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).21

Results 

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).20 In the PCPT, finasteride, just as in the pivotal trial in BPH, was relatively well tolerated.20, 25 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).20

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.20 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.26

Ongoing Discussion 

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.20, 27

Recently, it has been reported that finasteride increased the sensitivity of PSA and DRE in PCa detection.28, 29 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.30 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).20 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).30 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.31 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.32

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.33 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,34 indicating that PSA values alone might be sufficient in diagnosing a patient's current risk of PCa.

Reduction by Dutasteride of Prostate Cancer Events Trial 

Rationale 

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,10, 19 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.35

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).36 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.37 In the subsequent 2-year extension period, the incidence of most drug-related sexual adverse events continued to decrease.38 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.37

Study Design 

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 50-60 years or 3.0-10 ng/mL in those aged >60 years, and a single negative biopsy result within 6 months of enrollment at baseline.39 The requirement for a negative biopsy was instituted to enroll a high-risk population of men with an elevated serum PSA level who did not have PCa or had clinically undetectable disease.40 This requirement was also intended to decrease the for-cause biopsy rate and the number of refusals for follow-up biopsies, because the men would be accustomed to the technique. Men with evidence of high-grade PIN or atypical small acinar proliferation, prostate volume >80 cm3 or an International Prostate Symptom Score >25 were excluded. After screening, eligible subjects were required to complete a 4-week placebo run-in and then be randomized in a 1:1 ratio stratified by center. Those in the dutasteride group took 0.5 mg dutasteride daily for 4 years and those in the placebo group took matching pills. The study participants were to return for assessment and PSA measurement every 6 months throughout the study. For the dutasteride group, the PSA level was adjusted by doubling the actual value to maintain the study blinding. Mandated 10-core biopsies were to be performed at 2 and 4 years. In addition, for-cause biopsies could be performed as clinically indicated by the treating physician at any time. All biopsy samples underwent pathology review, and the rates of PCa in each treatment group were measured.41 The trial was to be completed in early 2009.

The primary endpoint was biopsy-detectable PCa at 2 and 4 years of treatment. The secondary endpoints, in addition to overall survival, included the Gleason score of cancer at diagnosis, high-grade PIN at biopsy, the number of cancer-positive cores, the percentage of cores with cancer at diagnosis, the treatment alteration score, and the incidence of interventions for PCa.39, 40

A major difference in the study designs of the PCPT and REDUCE trial was the risk profile of the subjects. Although the PCPT recruited men at low risk of PCa (PSA <3.0 ng/mL, negative DRE findings), the REDUCE trial examined high-risk patients (PSA ≥2.5 ng/mL; Table 2), who might be better candidates for population-based screening for cancer risk reduction therapy.

Table 2. Comparison of PCPT and REDUCE studies
VariablePCPTREDUCE
Study drugFinasteride (5 mg/d)Dutasteride (0.5 mg/d)
Trial duration (y)74
Subjects (n)18 882 total enrollment⁎8200 (estimated enrollment)
ScopeUnited StatesInternational
Age (y)≥55≥50
Entry PSA level (ng/mL)<3.02.5-10.0
Baseline biopsynone1, with negative findings
Follow-up biopsy (y)7†2 and 4†
Cores taken at biopsy (n)610

PCPT, Prostate Cancer Prevention Trial; REDUCE, Reduction by Dutasteride of Prostate Cancer Events; PSA, prostate-specific antigen.

Data from Thompson et al.20 and Andriole et al.40

⁎Included in final analysis: 4368 in finasteride arm and 4692 in placebo arm.

†In addition to for-cause biopsies.

Reduction by Dutasteride of Clinical Progression Events in Expectant Management Trial 

Rationale 

Although the findings from the REDUCE trial are expected to shed light on the effect of dutasteride on reducing the risk of PCa in men at high risk, the possibility that 5-ARIs could also be effective in delaying disease progression in men who already have localized PCa is also of great interest. In a study of the effect of dutasteride on markers of tumor regression in PCa, 46 men with localized PCa were randomized to receive dutasteride 5 mg/d or placebo for 6-10 weeks before RP. In the dutasteride group, a significant increase in apoptosis and a trend toward decreased microvessel density in cancer tissues were observed.13 Among the dutasteride-treated patients, a smaller mean volume of cancer, demonstrated by a 37% reduction in mean percentage of involvement by cancer and an increase in the percentage of atrophic epithelium, were also reported.42 These histologic observations provided the rationale for additional study of the effect of dutasteride on disease progression.

Therefore, the Reduction by Dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial is currently underway to evaluate whether dutasteride treatment of men with localized cancer will delay PCa progression or the interval to the initiation of more aggressive cancer (Fig. 2). Traditional treatment of PCa (ie, RP, radiotherapy) is associated with significant side effects, and untreated men with low-grade cancer can often live as long as those without PCa. In addition, the widespread use of PSA screening has dramatically increased the identification of low-grade PCa. To delay the potential negative side effect of aggressive treatment, men with low-grade, localized PCa often undergo expectant management, defined as active monitoring of the disease course with the expectation of intervention on evidence of progression.43

Study Design 

REDEEM is a 3-year, North American, multicenter, randomized, double-blind placebo-controlled trial of men 50-80 years old, with a life expectancy of >5 years. All subjects had low-grade, low-risk, localized PCa (clinical stage T1c-T2a, Gleason score ≤6, PSA level of ≤10 ng/mL). Men with a prostate volume >80 cm3 or International Prostate Symptom Score of ≥25 (or ≥20 if taking an α-blocker) were excluded. The enrollment was initiated in August 2006 and completed within 8 months. A total of 302 subjects were randomized to dutasteride 0.5 mg/d or placebo. Follow-up visits occurred every 3 months for the first year and every 6 months thereafter. At 1.5 and 3 years, mandated transrectal ultrasound-guided, 12-core biopsies will be taken. The PSA value for the dutasteride arm was not adjusted. The actual values are to be provided to physicians and subjects for effective expectant management.43

The primary endpoint was the interval to disease progression, defined as the earlier of either initiation of primary therapy for PCa or pathologic progression. The secondary endpoints included the interval to primary therapy, interval to pathologic progression, total length of cancer on repeat biopsy cores, percentage and number of positive cores, absence of cancer on repeat biopsies, change in Gleason score or clinical stage of cancer, and change in anxiety score and quality-of-life measures.43

If shown to be effective, dutasteride could provide a safe option for patients undergoing expectant management. The primary and secondary evaluation data are expected in 2010. The REDEEM study reports on the effect of dutasteride on existing PCa should complement the data from the ongoing REDUCE trial focused on the effectiveness of dutasteride in reducing the risk of PCa development and progression.

Therapeutic Assessment of Rising PSAs Study 

Rationale 

The DHT binding to the androgen receptor is about 50 times greater than that of bicalutamide.44 By blocking conversion of testosterone to DHT, dutasteride can remove the competition from DHT and make bicalutamide a more effective anti-androgen. Prolonging the clinical effect of bicalutamide in asymptomatic men (ie, no detectable metastatic disease) might delay the need for more aggressive treatment.45

The Therapeutic Assessment of Rising PSAs (TARP) study is a U.S. multicenter, randomized, double-blind, placebo-controlled trial to evaluate the effect of combination dutasteride and bicalutamide therapy on extending the interval to disease progression in men with asymptomatic recurrent PCa in whom first-line androgen deprivation therapy has failed (Fig. 2). Bicalutamide is a hormonal therapy drug that binds and blocks androgen receptors in PCa cells. TARP is an 18-month study with a 2-year extension phase.45 The target enrollment for TARP is 150 men, aged 40-85 years, who are asymptomatic but have disease progression during androgen deprivation therapy, as defined by 3 increases in PSA measured ≥4 weeks apart within the previous year. The participants must have a serum PSA level of 2-20 ng/mL, serum testosterone <50 ng/mL, no evidence of metastatic cancer, as confirmed by bone scan within 8 weeks of screening, and a life expectancy of >2 years. The eligible men must be chemotherapy naive for PCa treatment, although previous prostatectomy or radiotherapy is allowed. Patients who have undergone prostate surgery within 2 months before enrollment are not eligible for the study. Men who have received additional hormonal therapy or have taken the 5-ARIs finasteride or dutasteride, anabolic steroids within the past 6 months, or oral glucocorticoids within 3 months before randomization were also excluded.45

After initial screening and randomization, the subjects in the dutasteride group will take dutasteride 3.5 mg and bicalutamide 50 mg daily for 18 months. The placebo group will take matching placebo and bicalutamide 50 mg/d. The study participants are to return for assessment and PSA testing every month during the first 18 months, then every 3 months for the 2-year extension period. The primary endpoint is the time to disease progression with treatment up to 18 months. The secondary endpoints include the time to treatment failure, change in PSA value from baseline, and percentage of subjects who develop metastatic disease within 18 months. All endpoints will also be evaluated in subjects treated for ≤42 months (including the 2-year extension). The 18-month results are expected in 2010.45

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Pivotal study of dietary supplement in PCa risk reduction 

Rationale 

PCa development is a complicated process, involving multiple cell signaling pathways and a myriad of molecular components. In addition to the action of 5-ARIs through the androgen receptor pathway, some dietary items have shown potential in PCa risk reduction, according to evidence from secondary analyses of large-scale trials of other potential risk reduction agents for other cancers. In the Nutritional Prevention of Cancer study of the effect of selenium on skin cancer, the patients in the selenium group had a statistically significant lower incidence (37%) of PCa, although selenium therapy had no effect on the primary endpoint.46 Similarly, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study was designed to determine whether vitamin E and/or β-carotene supplements could reduce the risk of lung cancer. A subsequent analysis of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention trial showed that the incidence of PCa was reduced by 32% and PCa mortality by 41% among vitamin E recipients.47

Study Design 

The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a large-scale, Phase III, randomized, double-blind, placebo-controlled, population-based clinical trial with a 2 × 2 factorial design, was designed to examine the efficacy of vitamin E and selenium alone and in combination for PCa risk reduction. As in the PCPT study, SELECT focused on men at low risk of PCa, as defined by an entry PSA level of ≤4 ng/mL and nonsuspicious DRE findings (Fig. 2). Men aged ≥55 years (≥50 years for black men) with no history of PCa or high-grade PIN were eligible. As of April 2004, 32 400 participants had been enrolled and randomized equally among the 4 study arms, selenium (l-selenomethionine 200 μg/d), vitamin E (racemic α-tocopheryl 400 mg/d), selenium (200 μg/d), and vitamin E (400 mg/d), with an optional multivitamin containing no selenium or vitamin E. The primary endpoint was the clinical incidence of PCa determined by routine clinical care. The secondary endpoints included PCa-free survival, all-cause mortality, and the incidence and mortality of other cancers and diseases.48

Results 

Although the final results of the study were slated to be released in 2013,48 the recent initial, independent review of the study data in October 2008 revealed that selenium and vitamin E supplements, taken either alone or together for an average of 5 years, did not prevent PCa.49 In addition, 2 concerning trends were observed: a small, but not statistically significant, increase in the number of PCa cases among study subjects taking only vitamin E and a small, but not statistically significant, increase in the number of cases of adult-onset diabetes in men taking only selenium. Because this was preliminary analysis of the data, neither of these findings proves an increased risk from the supplements and both might have been due to chance. However, the trial was stopped, and the participants were asked to stop taking their study supplements. Health monitoring of the subjects (including possible regular DREs and PSA tests to detect PCa) by the investigators is planned for 3 years to determine the long-term effects of having taken either supplement or placebo.49 The final analysis of these data will, it is hoped, provide insight regarding the role of these dietary supplements in the progression of PCa, as well as furthering the understanding of the disease mechanism.

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Conclusions 

In the past decade, significant strides have been made in our understanding of PCa development and progression. The results from the PCPT, the first large-scale, long-term, prospective PCa risk reduction clinical trial, have established the promise of 5α-reductase inhibitors in reducing PCa events.

Dutasteride, a potent, dual 5-ΑRI, is being investigated for PCa risk reduction in the REDUCE trial. Large prospective studies are also underway to determine the effect of dutasteride on PCa progression in low-grade localized cancer (REDEEM study) and in asymptomatic recurrent cancer (TARP trial).

The data from these ongoing clinical trials will generate a great amount of information regarding the benefits of PCa risk reduction strategies and their potential effect on a patient's health and quality of life, as well as on current public health policies. The findings of these trials could initiate a paradigm shift in the treatment of PCa from a focus on early detection programs to an emphasis on risk reduction strategies and implementation.

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 G. L. Andriole serves as a consultant to Aeterna Zentaris, Nema Steba, Onconome, and GlaxoSmithKline and has received research funding from Envisioneering, Ferring Pharmaceuticals, GlaxoSmithKline, Veridex, Viking Medical, and Zeneca.

PII: S0090-4295(09)00238-6

doi:10.1016/j.urology.2009.02.017

Refers to erratum:

Urology
Volume 73, Issue 5, Supplement , Pages S36-S43, May 2009

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