Chemoprevention strategies in prostate cancer

INTRODUCTION — Prostate cancer is the second most common cancer in males worldwide, according to data from the GLOBOCAN database. In the United States, there were an estimated 191,930 cases and 33,330 deaths from prostate cancer in 2020 [1].

In the United States, the incidence of prostate cancer detection dramatically rose in the early 1990s in conjunction with the increasing utilization of prostate-specific antigen (PSA) screening. After an initial peak, incidence rates fell, but they have persisted at a rate nearly twice that recorded in the pre-PSA era, suggesting that many cases are clinically indolent and would never have become clinically apparent. Despite the increase in diagnosis of early stage prostate cancer, the impact of earlier treatment on survival remains to be proven.

The implementation of the United States Preventative Services Task Force (USPSTF) guidelines assigning a recommendation level of D has reduced the number of males seeking early detection, as well as reduced the number of transrectal ultrasound (TRUS) biopsies. Some centers have reported an increase in males with more aggressive and advanced disease.

The high incidence of prostate cancer, its associated morbidity and mortality, the complications associated with its treatment, and a partial understanding of its biologic basis have led to a focus on chemoprevention strategies. The most extensive data come from the use of 5-alpha reductase (5-AR) inhibitors; other classes of agents are also being explored.

The rationale for chemoprevention, the results with 5-AR inhibitors, and the more limited data with other approaches are presented here. Screening for prostate cancer, an alternative approach that focuses on early detection to decrease morbidity and mortality, is discussed elsewhere. (See "Screening for prostate cancer".)

RATIONALE — Three factors have contributed to the rationale for prostate cancer chemoprevention in males: the long latency period between the initial evidence of prostate cancer and the development of overt or fatal disease, the androgen dependency of these tumors, and the availability of intermediate endpoints for use in clinical trials.

Long latency period — The marked discrepancy between the autopsy prevalence of occult prostate cancer and the incidence of clinically manifest disease indicates that there is a long latency phase and significant heterogeneity in the rate of progression of early neoplastic lesions. Progression to invasive cancer in males with high-grade prostatic intraepithelial neoplasia (PIN) may take 10 years or more. (See "Precancerous lesions of the prostate: Pathology and clinical implications", section on 'Prostatic intraepithelial neoplasia'.)

As a result, chemoprevention strategies that do not reverse the premalignant condition but merely delay its progression to invasive cancer may be sufficient to improve survival or avoid the complications of the disease or its treatment [2,3].

Androgen dependency — Direct or indirect androgenic influences are important in the malignant transformation of prostatic tissue. Males with 5-alpha reductase (5-AR) deficiency (the enzyme that converts testosterone to dihydrotestosterone [DHT], the most active androgen in the prostate) do not develop prostate cancer [4]. The precursor lesion, high-grade PIN, is also hormonally dependent. The atrophy and apoptotic changes that occur with androgen deprivation in normal and hyperplastic prostatic epithelium and in invasive cancers are also observed in PIN [5].

These data suggest that interference with normal androgen balance may affect prostate cancer incidence. Medical therapies directed at hormonal manipulation include estrogens, antiandrogens, gonadotropin-releasing hormone (GnRH) agonists, and 5-AR inhibitors. Most of these therapies are not candidates for use as chemopreventive agents because of potential side effects. The use of 5-AR inhibitors or antiandrogens that block the androgen receptor may be associated with fewer side effects because serum testosterone levels remain unaltered. (See "Side effects of androgen deprivation therapy".)

Clinical trials biomarkers — Development of chemopreventive agent(s) may be facilitated by the availability of biomarkers that may predict the subsequent development of prostate cancer or that can be used to define its progression and, thus, serve as intermediate endpoints for clinical trials.

●Prostatic intraepithelial neoplasia – PIN represents a spectrum of dysplastic changes that are limited to prostatic acini and do not invade the basement membrane. High-grade PIN is thought to be associated with an increased prostate cancer risk. The pathologic features of PIN and its relationship to cancer are discussed separately. (See "Precancerous lesions of the prostate: Pathology and clinical implications", section on 'Prostatic intraepithelial neoplasia'.)

●Prostate-specific antigen – Changes in serum prostate-specific antigen (PSA) concentration and its association with prostate cancer suggest that serum PSA may be a useful biomarker and that defined changes could act as intermediate endpoints in the setting of chemoprevention trials. However, serum PSA is also secreted by normal prostate tissue, and as an androgen-regulated gene, levels are incompletely correlated with tumor burden. (See "Measurement of prostate-specific antigen".)

5-ALPHA REDUCTASE INHIBITORS — The 5-alpha reductase (5-AR) inhibitors finasteride and dutasteride are used primarily for treatment of benign prostatic hyperplasia. They improve lower urinary tract symptoms by blocking the conversion of testosterone into the more potent androgen dihydrotestosterone (DHT).

Androgens are a key driver of prostate carcinogenesis. There are data from at least two randomized trials that support a reduced risk of prostate cancer in males receiving 5-AR inhibitors; however, no survival benefit has been shown in either trial, and both raised concerns about a possible increased risk of high-grade prostate cancer. The US Food and Drug Administration (FDA) has not approved the use of these agents for prostate cancer prevention, and in 2011, it issued a safety warning about the elevated risk of high-grade cancers, stating that one additional high-grade cancer would occur for every three to four lower grade cancers that would be prevented [6]. Although a subsequent analysis of data from the Prostate Cancer Prevention Trial (PCPT) found that finasteride increased the detection rate of high-grade prostate cancer by shrinking the prostate, thereby introducing a potential detection bias [7], and the clinical significance of this finding remains unclear, concerns remain, and these drugs are not widely used for prostate cancer chemoprevention.

For most males, we suggest not using chemopreventive therapy with a 5-AR inhibitor. However, chemopreventive therapy with a 5-AR inhibitor in conjunction with monitoring serum prostate-specific antigen (PSA) may be appropriate for those who place a higher value on preventing cancer than on the side effects associated with such therapy and the uncertainties as to benefits and risks.

Guidelines from an expert panel of the American Society of Clinical Oncology (ASCO) and the American Urological Association (AUA) identified key issues that clinicians and males should discuss when deciding whether or not to use a 5-AR inhibitor for prostate cancer chemoprevention [8,9]. These include the following:

●5-AR inhibitors decrease, but do not eliminate, the risk of prostate cancer.

●An elevated rate of high-grade prostate cancers has been observed in patients taking finasteride [10] and dutasteride [11], although the significance of these observations remain unclear.

●There is scant information about whether these agents decrease the risk of death from prostate cancer or affect overall survival. In at least one analysis using data from 89,227 males diagnosed with prostate cancer between 2007 and 2016 derived from the Prostate Cancer Data Base Sweden, the risk of prostate cancer death for all cases, including males with high-risk disease, was similar among 5-AR inhibitor users and nonusers [12]. The median years of follow-up for these males ranged from 5.2 to 6.7 years. There is no information about the effects of use beyond seven years.

●Side effects of these agents include gynecomastia, decreased libido, erectile dysfunction, and decreased ejaculate volume. At the same time, these agents may decrease urinary tract symptoms due to benign prostatic hyperplasia.

●5-AR inhibitors reduce serum PSA levels by an average of 50 percent, which can affect the use of serum PSA for prostate cancer detection in males treated with these agents [13-15].

Finasteride: PCPT — In the Prostate Cancer Prevention Trial (PCPT), 18,882 males were randomly assigned to finasteride (5 mg/day) or placebo between 1994 and 1997 [10,16].

Males were considered at elevated risk of prostate cancer based on age ≥55 years, African-American ethnicity, or having a first-degree relative with prostate cancer. All had a normal digital rectal examination (DRE) and a serum PSA ≤3 ng/mL.

Prostate biopsy was recommended if the annual PSA level, adjusted for the effect of finasteride (which decreases the serum PSA by approximately 50 percent), was ≥4 ng/mL or if the DRE became abnormal. In addition, all males were offered a prostate biopsy at the end of study (seven years).

The PCPT was closed early because the primary study endpoint (ie, a decrease in the prevalence of biopsy-proven prostate cancer in the finasteride population compared with placebo) was met. The initial analysis found a 25 percent decrease in the incidence of prostate cancer with seven years of finasteride, but there was also an observed increase in the absolute number and proportion of high-grade prostate cancers (ie, Gleason score ≥7) [10].

A long-term follow-up of this study (up to 18 years of follow-up), which included the identification of 187 additional cases of prostate cancer, analyzed overall survival data through October 2011 [16]:

●There was a statistically significant decrease in the incidence of prostate cancer in males assigned to finasteride compared with placebo (10.5 versus 14.9 percent, relative risk [RR] 0.70, 95% CI 0.65-0.76).

●There remained a small but statistically significant increase in the risk of high-grade prostate cancer (Gleason score ≥7) with finasteride (3.5 versus 3.0 percent, RR 1.17, 95% CI 1.00-1.37, p = 0.05).

●The 15-year overall survival rates for the finasteride and placebo groups were 78.0 and 78.2 percent, respectively (unadjusted hazard ratio [HR] 1.02, 95% CI 0.97-1.08).

●Among males who subsequently developed prostate cancer, there were no significant differences in the 10-year overall survival rates in males assigned to finasteride or placebo. For males with low-grade prostate cancer (Gleason score ≤6), the 10-year overall survival rates were 83.0 and 80.9 percent, respectively, and for those with high-grade prostate cancer (Gleason score ≥7), the 10-year overall survival rates were 73.0 and 73.6 percent, respectively.

At 20+ years of follow-up, the HR for prostate cancer-specific death with finasteride versus placebo was 0.75 (95% CI 0.50-1.12) [17].

Long-term benefit after discontinuation of finasteride was also explored in a subsequent analysis linking PCPT clinical records to the participants' Medicare claims data [18]. Throughout the entire course of follow-up (median 16 years), finasteride participants maintained a 21 percent reduction in the risk of prostate cancer (HR 0.79, 95% CI 0.74-0.84). However, the protective effect was significant only through year 7.5 (HR 0.71, 95% CI 0.66-0.77) and not afterwards (HR 1.10, 95% CI 0.96-1.26).

The observed increase in the number of patients with high-grade cancers dampened enthusiasm for the use of finasteride as a chemopreventive agent [19], even though several subsequent analyses suggested that the observed increase in high-grade lesions did not represent a true alteration in the biology of the disease and, instead, likely indicated detection bias attributed to the fact that finasteride shrinks the prostate, thereby increasing the detection of high-grade disease [20-24].

Nevertheless, in our view, the absence of a difference in overall or prostate cancer-specific survival with longer follow-up provides clear evidence that an increase in high-grade prostate cancer is not a major factor affecting overall survival and that chemoprevention using finasteride may safely decrease the incidence of low-grade prostate cancers [16].

Dutasteride: REDUCE trial — The effects of dutasteride on the incidence of prostate cancer were evaluated in the double-blind Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, in which 8336 males were randomly assigned to dutasteride (0.5 mg/day for four years) or placebo [11]. All males were considered at increased risk for prostate cancer based on age and serum PSA level, and all had a single negative prostate biopsy within six months prior to protocol entry. Males 50 to less than 60 years of age had a baseline serum PSA of 2.5 to 10 ng/mL, while those 60 to 75 years of age had a PSA 3 to 10 ng/mL. The protocol called for repeat 10-core biopsies at two and four years after treatment initiation.

Key findings included:

●The incidence of prostate cancer was significantly reduced in males assigned to dutasteride compared with placebo (25.1 versus 19.9 percent, RR reduction 23 percent).

●The decrease in incidence was limited to cancers with a Gleason score of 5 or 6, which constituted 70 percent of all cases diagnosed. There was no statistically significant reduction in risk of prostate cancer with Gleason scores of 7 to 10. Overall, in years 1 through 4, there were 220 Gleason score 7 to 10 tumors diagnosed in the dutasteride group and 233 in the placebo group, a difference that was not significant (6.7 versus 6.8 percent, p = 0.81). Mortality rates were similar in both groups, and no deaths were attributed to prostate cancer in either group.

Other data — Additional data on the impact of 5-AR inhibitors on the risk of prostate cancer are available from a Swedish population-based cohort study of all males over the age of 40 who had at least one PSA test in Stockholm County between 2007 and 2018 [25]. Of the 349,152 in the cohort, 26,190 had been prescribed a 5-AR inhibitor at some time during the study period. With a median follow-up of 8.2 years, prostate cancer was diagnosed in 0.4 versus 4.1 percent of the individuals treated with versus without a 5-AR inhibitor, and despite the association of 5-AR inhibitor use with higher PSA levels, larger prostates, higher Gleason score, and a higher TNM stage at diagnosis, treatment with a 5-AR inhibitor decreased the risk of prostate cancer mortality, with a larger effect seen with longer duration of exposure. With 0.1 to 2 years of exposure, the adjusted HR was 0.89 (95% CI 0.0.64-1.25); at 2 to 4 years, adjusted HR was 0.54 (95% CI 0.37-0.78); at 4 to 6 years, adjusted HR was 0.72 (95% CI 0.52-1.01); at 6 to 8 years, adjusted HR was 0.51 (95% CI 0.33-0.79); >8 years, HR was 0.44 (95% CI 0.27-0.74). (See 'Finasteride: PCPT' above.)

These data provide some reassurance that treatment with a 5-AR inhibitor for lower urinary tract symptoms in males is safe with regard to prostate cancer risk. An important point is that, because 5-AR inhibitors reduce the serum concentration of PSA by approximately 50 percent, clinicians should use adjusted levels of PSA when screening males who are receiving these drugs for prostate cancer; otherwise, the diagnosis may be delayed and result in worse cancer-specific outcomes [26]. (See "Measurement of prostate-specific antigen", section on 'Medications'.)

OTHER AGENTS — A number of other agents are being studied to prevent prostate cancer. All of them remain experimental.

Statins — Multiple studies have looked at the relationship between statin use and prostate cancer. Although the data regarding an impact on the incidence are equivocal, epidemiologic findings suggest that statin use may have a beneficial effect on the risk of prostate cancer progression and death. Prospective trials are needed to validate the importance of these agents. (See "Overview of cancer prevention", section on 'Statins'.)

Metformin — Epidemiologic studies have suggested that diabetic patients using metformin have a decreased incidence of a variety of malignancies other than prostate cancer compared with those not being treated with metformin. No prospective trials support these observations, and caution is advised. (See "Overview of cancer prevention", section on 'Metformin'.)

Metformin does not appear to have a substantial impact on the overall incidence of prostate cancer. As an example, in a study of over 119,000 males ≥66 years old with incident diabetes, prostate cancer was subsequently diagnosed in 5306 [27]. There was no difference in the risk of prostate cancer (adjusted odds ratio [OR] 1.03, 95% CI 0.96-1.1).

Metformin may have an effect on the progression of disease in diabetic patients with prostate cancer. In a study that included 3837 patients older than 66 years with a new diagnosis of diabetes who were subsequently diagnosed with prostate cancer, prostate cancer-specific mortality was significantly decreased in those treated with metformin [28]. The decrease in mortality with metformin use was proportional to the cumulative duration of metformin use (hazard ratio [HR] for prostate cancer-specific mortality 0.76 for each additional six months of use of metformin). This effect was not observed with other diabetic medications. These observations require confirmation.

Vitamins and micronutrients — The available data on vitamins and dietary supplements for chemoprevention are extensive and difficult to interpret. Currently, available data have not established a role for any of these agents in the prevention of prostate cancer.

The most extensively studied agents are vitamin E (alpha-tocopherol) and selenium.

Vitamin E — Males should avoid vitamin E supplementation at doses that exceed dietary intakes. Current evidence does not support a role for vitamin E supplementation in the prevention or treatment of cancers, cardiovascular disease, dementia, or infection. (See "Vitamin intake and disease prevention", section on 'Vitamin E' and "Overview of vitamin E".)

Two randomized trials, the alpha-tocopherol beta-carotene (ATBC) intervention trial [29-31] and the Heart Outcomes Prevention Evaluation – The Ongoing Outcomes (HOPE-TOO) trial [32], provided conflicting evidence regarding the incidence of prostate cancer as a secondary outcome.

Two randomized trials specifically designed to study the impact of vitamin E on prostate cancer incidence failed to provide any evidence supporting a chemopreventive role:

●The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was designed to study the role of selenium and vitamin E as agents to decrease the incidence of prostate cancer. In this trial, 35,533 males were randomly assigned to selenium (200 mcg/day), vitamin E (400 international units/day), both, or neither with appropriate placebos [33]. This trial was stopped in October 2008 after an independent data safety monitoring committee found no evidence of a decrease in the incidence of prostate cancer. Dietary supplementation with vitamin E significantly increased the incidence of prostate cancer, and there were nonsignificant increases with selenium and the combination of vitamin E plus selenium compared with placebo (HR for developing prostate cancer 1.17, 1.09, and 1.05, respectively) [34,35].

●The Physicians' Health Study II (PHS II) was a double-blind, placebo-controlled trial in which 14,641 male clinicians ages 55 years and older were randomly assigned to beta-carotene, vitamin E, ascorbic acid, and/or a multivitamin [36]. One of the primary endpoints of this study was the prevention of prostate cancer. The incidence of prostate cancer was not significantly reduced with any of the agents, including vitamin E (HR 0.97, 95% CI 0.85-1.09) [37].

Selenium — The relationship between prostate cancer and selenium intake and level is complex. (See "Risk factors for prostate cancer", section on 'Selenium and vitamin E'.)

However, there is no evidence to support a chemopreventive effect from selenium supplementation [35]. The effect of selenium supplementation was directly evaluated in SELECT, which included 35,533 males at risk for prostate cancer. The incidence of prostate cancer was nonsignificantly increased with selenium alone or in combination with vitamin E (HR 1.09 and 1.05, respectively). Further subsequent analyses found that selenium supplementation did not benefit males with low selenium status but increased the risk of high-grade prostate cancer among males with high selenium status [38].

Vitamin D analogs — A link between vitamin D levels and prostate cancer risk has been suggested, mainly based on the association of vitamin D deficiency with epidemiologic risk factors such as age, African-American race, and geographic area of residence [39-46]. Preclinical studies support an antiproliferative, antimetastatic, and differentiating effect of vitamin D and its analogues in prostate cancer, providing a rationale for the consideration of these compounds as potential chemopreventive agents. No prospective trials have confirmed this effect.

Retinoids — Retinoids are metabolites and analogs of vitamin A that are required for the proper differentiation of various epithelial tissues, and they play a regulatory role in the activation of cytokines and the extracellular matrix. Chemoprevention trials are ongoing with retinoids in lung cancer, breast cancer, and head and neck cancer. (See "Chemoprevention and screening in oral dysplasia and squamous cell head and neck cancer".)

Fenretinide, a synthetic retinoid, has been evaluated in males with prostate cancer in preliminary studies [47-49]. However, these trials have not yielded evidence of activity, and this class of agents is not under active investigation for chemoprevention against prostate cancer.

Dietary factors — A number of dietary factors have been analyzed for their association with the risk of prostate cancer. Although information from these studies may be useful in defining new approaches to chemoprevention, none of these has an established role in prostate cancer chemoprevention. (See "Risk factors for prostate cancer", section on 'Diet'.)

Phytoestrogens (flavones, isoflavones, lignans) are naturally occurring plant compounds that have estrogen-like activity. Genistein and daidzein, the predominant isoflavones in human nutrition, are derived mainly from soybeans and other legumes.

Phytoestrogens may reduce prostate cancer risk either via their inherent estrogenic properties (which favorably alter the hormonal milieu) or by inhibition of 5-alpha reductase (5-AR), which decreases concentrations of the more prostate-active androgen dihydrotestosterone (DHT). The higher intake of soy products among Asian males has been hypothesized to be one reason for their generally lower incidence of prostate cancer.

The most provocative data linking soy or phytoestrogen exposure to a reduced prostate cancer risk come from animal studies [50-52]. In humans, most of the case-control studies have shown a modest protective benefit of soy on prostate cancer risk. (See "Risk factors for prostate cancer", section on 'Soy intake'.)

In one randomized trial, 310 males with high-grade prostatic intraepithelial neoplasia were randomly assigned to a combination of vitamin E, soy, and selenium or to placebo. There was no evidence that the combination prevented progression to prostate cancer [53]. Several other randomized, placebo-controlled clinical trials evaluating soy protein in males with treated prostate cancer who are at high risk for recurrence are ongoing.

LIFESTYLE FACTORS — Potentially modifiable lifestyle factors, particularly smoking and obesity, have been shown to increase the risk of prostate cancer, particularly for aggressive or advanced disease [54]. Factors such as diet that are associated with good cardiovascular health may also contribute to preventing the initiation and progression of prostate cancer. (See "Risk factors for prostate cancer", section on 'Cigarette smoking' and "Risk factors for prostate cancer", section on 'Obesity' and "Healthy diet in adults".)

SUMMARY AND RECOMMENDATIONS

●The high incidence of prostate cancer, its associated morbidity and mortality, and its hormone dependency all have made prostate cancer an important target for chemopreventive strategies. (See 'Rationale' above.)

●In randomized trials, 5-alpha-reductase (5-AR) inhibitors have been shown to significantly decrease the incidence of prostate cancer. However, no trials have demonstrated an impact on prostate cancer mortality. With long-term follow-up of the randomized trials, there is no clear evidence that these agents increase the incidence of higher grade prostate cancer or are associated with increased prostate cancer-specific mortality. (See '5-Alpha reductase inhibitors' above.)

The potential side effects (gynecomastia, decreased libido, erectile dysfunction), benefits (decreased symptoms from benign prostatic hyperplasia), and areas of persisting uncertainty (long-term side effects) should be explained to males considering chemopreventive therapy. For most males, we suggest not using chemopreventive therapy with a 5-AR inhibitor (Grade 2B). However, chemopreventive therapy with a 5-AR inhibitor in conjunction with monitoring serum prostate-specific antigen (PSA; with levels adjusted for the use of the 5-AR inhibitor) may be appropriate for those who consider preventing cancer more important than the side effects associated with such therapy. (See '5-Alpha reductase inhibitors' above.)

There are no data that support the use of vitamin E, selenium, or other agents for routine use, and such agents remain experimental. (See 'Other agents' above.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledge E David Crawford, MD, who contributed to an earlier version of this topic review.

We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate gratefully acknowledges Dr. Vogelzang's role as Section Editor on this topic, and his dedicated and longstanding involvement with the UpToDate program.