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Abstract

Prostate cancer (PCa) is the most common cancer among men in the United States and the second leading cause of cancer-related deaths. Metastatic castration-resistant PCa is still a fatal disease. On the other hand, between 2016 and 2020, about 70% of PCa cases were diagnosed at a localized stage. Evolving data demonstrates that men with low-grade cancers treated with definitive therapies may now be exposed to morbidities of overtreatment and poor quality of life, with little or no benefit in terms of cancer specific mortality. Active surveillance (AS) is thus the recommended management strategy for men with low-grade disease. Although this subgroup of men have reported anxiety during the AS period, they account to be highly motivated to make positive lifestyle changes to further reduce their risk of PCa progression, underscoring the urgent need to identify novel strategies for preventing progression of localized PCa to metastatic disease through pharmacologic means, an approach termed chemoprevention. Although several promising agents and approaches have been examined over the past 2 decades, currently, there are several limitations in the approach used to systematically examine agents for chemoprevention targeting men on AS. The goal of this review is to summarize the current agents and approaches evaluated, targeting men on AS, recognize the gaps, and identify a contemporary and comprehensive path forward. Results of these studies may inform the development of phase III clinical trials and ultimately provide a strategy for clinical chemoprevention in men on AS, for whom, currently, there are no options for reducing the risk of progression to metastatic disease.

Keywords

prostate cancer clinical chemoprevention active surveillance biomarkers systematic approach % Ki-67 serum prostate specific antigen gleason score multiparametric MRI

Introduction

Prostate Cancer

It is estimated that about 299 010 new cases of prostate cancer (PCa) will be diagnosed in the US in 2024, and 35 250 deaths will occur in men with PCa (ACS 2024).¹ Since the year 2014, the incidence rate of PCa has increased by 3% per year overall and by about 5% per year for advanced-stage PCa. PCa is the most common cancer among men in the US and the second leading cause of cancer-related deaths in the US. Some of the definitive risk factors associated to PCa includes age, genetic predisposition and race.² In 2019, 37% of PCa cases were diagnosed among men aged 45 to 64 years, 43% among men aged 65 to 74 years, and 20% among men aged 75 years or older.³ Genetic predisposition for PCa is well established as a risk factor for PCa incidence and has demonstrated to increase the risk of fatal forms of PCa. The number of relatives diagnosed with PCA, age at diagnosis, grade of disease, age at death as well as if the relative was a first-degree vs second degree family member⁴ are critical factors to take into consideration. Studies have shown that siblings and sons of men with PCa have approximately a 2.5-fold increased risk of being diagnosed with PCa.⁵ In the US, Black men (BM) are disproportionally affected by PCa and a 2.2-fold higher risk of death from PCa vs White men. Compared with White men, BM are more likely to develop PCa at almost every stage of the disease as well as in every age group, including at a younger age (an average of 2 years earlier). BM have been reported to have been diagnosed with more aggressive disease and/or diagnosed at later stages, contributing to relatively fewer treatment options and higher morbidity and mortality rates.⁶

In the past, prostatectomy and radiotherapy were the standard definitive treatments for stage I–III prostate cancer patients with androgen ablation by surgical or pharmacological castration, standard for all stage IV and high-risk stage III patients. With the identification of serum prostate specific antigen (PSA) as an early surrogate biomarker for early detection of PCa, a significant increase in the detection of low-grade PCas (Gleason 6) has been reported.^7-10 In the US, between 2016 and 2020, about 70% of PCa cases were diagnosed at a localized stage.³ It is also well recognized that men with low grade cancers treated with definitive therapies may now be exposed to morbidities of overtreatment and poor quality of life such as erectile dysfunction, urinary incontinence, etc., with little or no benefit of cancer-specific survival.^9-11 Active surveillance (AS) has thus evolved as a recommended management strategy for men with low-grade disease, providing the benefit of an individualized approach of carefully monitoring disease progression using PSA kinetics and periodic multiparametric MRI (mpMRI)² guided biopsies for histologic progression, sufficient to permit timely therapeutic intervention. Prospective studies in cohorts have established relative effectiveness of this approach.^12,13 Klotz et al, (2015)¹² demonstrated a 98% disease-specific survival for low grade tumors (Gleason 3 + 3). Other large cohort prospective studies have confirmed safety and relative effectiveness of this approach.¹³ In 1 of the largest randomized studies, the ProtecT study with a comprehensive cohort follow-up, the effectiveness of conventional treatments (radical prostatectomy and radical radiotherapy) for localized prostate cancer compared to active monitoring was completed. At a median follow-up point of 10 years, prostate cancer-specific mortality was low, irrespective of the assigned treatment. Although no increased mortality was observed in the active monitoring arm, there was a higher incidence of metastatic disease and related symptoms.¹⁴ With contemporary molecular insights and the phenotypically indolent nature of low-grade, low-volume Gleason 6 prostate cancer, definitive treatment with surgical intervention is no longer recommended.¹⁵ Active surveillance (AS) has thus evolved as a recommended management strategy for men with low-grade disease, providing the benefit of an individualized approach of carefully monitoring disease progression using PSA kinetics and periodic mpMRI⁹ guided biopsies for histologic progression, sufficient to permit timely therapeutic intervention.

On the other hand, several challenges have been identified, including variation in criteria used to define men at low risk and eligible for AS in addition to undegrading.¹⁶ Based on data published by Klotz (least stringent),¹⁷ D’Amico (intermediate stringent),¹⁸ and the modified Epstein criteria (Most stringent)¹⁹ for men with PCa, 39.8% vs 28.5% vs 10.7% are determined to be low risk and eligible for AS. It has also been shown that the percentage of men placed on AS based on these criteria was 6.5%, 7.4% and 12.1%,¹⁶ demonstrating that this subset of patients continues to be overtreated in spite of the 2012 recommendations.²⁰ It has also been reported that patients report anxiety and doubts about the possible progression of the disease, depression as well as higher decisional conflict regarding selection of AS,^21,22 ultimately opting for treatment without any major change in tumor characteristics Approximately 50% of active surveillance patients are referred to definitive treatments within 5 years due to clinical cancer progression or the patient’s own request.²³ However, men on AS are a subgroup who are highly motivated and eager to make positive lifestyle changes to further reduce their risk of PCa progression.^22,24,25 If chemoprevention agents with proven efficacy gives confidence to men on active surveillance and health professionals in terms of cancer control, the rate of referral to definitive treatment may decrease. Men on AS for prostate cancer are an ideal target population for interventions for preventing progression of localized PCa to metastatic disease through pharmacological means, an approach termed “chemoprevention”^26-28.

Prostate Cancer Chemoprevention

Cancer Chemoprevention can be defined as the use of natural, synthetic, or biologic agents and vaccines to inhibit or reverse pre-invasive carcinogenesis before the development of clinical cancer, as signified by cellular invasion across the basement membrane. More recently, the term, “Cancer interception” has evolved. Cancer interception is the active way of combating cancer and carcinogenesis at earlier and earlier stages. The ultimate goal is to halt or reverse carcinogenesis.²⁹ The long latency of prostate carcinogenesis, provides for an ideal setting for interventions to mitigate risk of progression from localized to metastatic disease.³⁰ Men on AS are an ideal target for chemoprevention interventions with promising single or combination agents, to further reduce progression to later stage disease.³¹

Current Strategies for Prostate Cancer Chemoprevention

Over the past decade, there have been several attempts to identify and evaluate agents and approaches for PCa chemoprevention targeting healthy men or men at relatively higher risk for PCa (HGPIN) or early phase trials of short duration in PCa patients with localized disease during the 4-6 week pre-surgical window (Biopsy to prostatectomy). These studies evaluated soy isoflavones,^32-34 lycopene,^35-37 Selenium and Vitamin E^38,39 and resveratrol.^40,41 In spite of encouraging observations from epidemiological studies on the potential benefit of these agents in population studies, in vitro and preclinical studies, early phase clinical trials were not comprehensive nor of sufficient duration to inform well powered phase II-III clinical trials.

The goal of this report is to summarize the current chemoprevention strategies, specifically targeting men with localized PCa, identify the gaps and limitations of the data and future directions to improve quality and rigor with which these early studies should be conducted, that would inform future well-powered phase III clinical trials in targeted populations at high risk for PCa.

Selenium and Vitamin E

Several in vitro and preclinical studies have reported the effectiveness and potential mechanism with which selenium and Vitamin E^42-46 can modulate prostate carcinogenesis. Using these studies and secondary analysis from randomized clinical trials, the phase III Selenium and Vitamin E Cancer Prevention Trial (SELECT)^38,39 was undertaken^42-46 targeting a heterogenous group of men with no PCa. Long-term supplementation with the trace element Se administered in the form of selenomethionine, or vitamin E, demonstrated no benefit either individually or in combination. On the other hand, among men who were randomized to receive Vitamin E, a significant increase in PCa was observed.³⁸ The significant undertaking clearly indicates the need for utilizing the systematic approach to have comprehensive and complete data that will inform phase III clinical trials. Although there was a signal of efficacy based on the in vitro and preclinical evidence regarding the role of selenomethionine and vitamin E individually and in combination, there was no direct clinical evidence based on phase I-II clinical trials establishing dose, duration of intervention, intermediate endpoint biomarkers of safety and efficacy that would be required to inform phase III clinical trials. It was clear that the secondary analysis from other randomized clinical trials were not direct evidence that could adequately inform development of a phase III chemoprevention trial. Additionally, the target population was heterogenous and not limited to men at high risk or men with localized disease. Valuable lessons have been learnt from these earlier studies that have informed the development of rigorous design of chemoprevention approaches, including for localized PCa.

Lycopene

Lycopene has been the most prevalent carotenoid in the Western diet and identified in the human serum. It is a non-provitamin A carotenoid that ranks highest among major natural carotenoids in its capacity for quenching singlet oxygen and scavenging free radicals, and distributed primarily in the fatty tissue, liver, plasma and skin.⁴⁷ Data from epidemiological studies have reported that populations with high intake of dietary lycopene and relatively higher concentrations of plasma lycopene^48-52 have lower risk of PCa.^53-58 On the other hand, results of a large nested case-control study, found no association between serum lycopene and CaP.⁵⁹ Thus, the data regarding lyocopene and prostate cancer from epidemiological studies was mixed. On the other hand, data from in vitro studies have consistently shown that lycopene modulates several hallmarks of carcinogenesis, producing several cellular effects which are both genomic and non-genomic, relevant to preventing prostate carcinogenesis.⁶⁰ Preclinical studies of the effects of lycopene in prostate carcinogenesis in rodent models,^61-65 have reported that lycopene metabolism was modulated by androgens,^61,65 as castrated rats accumulated twice the liver lycopene compared to intact controls, interfering with local testosterone activation. Lycopene was observed to down regulated prostatic IGF-I and IL-6 expression.⁶⁴ Early clinical trials have reported a reduction in surrogate markers of prostate carcinogenesis - serum PSA^66,67 and tumor volume,^68,69 with lycopene supplementation. Results of these early clinical trials appear promising, although they have targeted varying stages of PCa, doses of lycopene, formulations, and duration of intervention. Doses ranged from 12 mg/day for 8 weeks to 150 mg/day for 7 days). In a study completed by our group, we observed increases in plasma lycopene with 45 mg lycopene-supplemented for 30 days in the lycopene treated arm compared to placebo. Additionally in the group receiving 30 mgs lycopene for the same duration, a significant reduction in serum free testosterone and increase in total estradiol (30 mg and 45 mg). However, no significant increases in serum PSA or tissue Ki-67 were observed. To date, there have been no toxicities reported with lycopene supplementation at these doses or duration of intervention.³⁶ Overall, the current evidence has not informed further evaluation of lycopene as a chemopreventive agent for prostate cancer.

5 -Alpha Reductase Inhibitors

One of the well-established drivers of prostate carcinogenesis is via the androgen receptor pathway and a known target for the treatment of PCa. Testosterone, the most abundant androgen in circulation can be converted to the more potent androgen, dihydroxytestosterone (DHT) by 5-alpha reductase enzymes.⁷⁰ Reducing the level of androgens via chemical or surgical castration and reducing the levels of androgen has remained the first line therapy for PCa. The rationale for utilizing the 5-alpha reductase inhibitors for PCa chemoprevention to reduce exposure to dihydrotestosterone (DHT) is a valid approach to reduce progression of localized PCa to later stages of disease. Previous chemoprevention strategies for PCa have included large phase III trials with 5-alpha-reductase inhibitors, finasteride and dutasteride.^71-73 The magnitude of the prevention effect of finasteride on prostate cancer was then evaluated across risk based on a predictive logistic model and PSA strata. Reports based on initial observations indicated that 5-alpha-reductase inhibitors (5-ARIs) significantly reduced the risk of PCa progression. However, an association with increased detection of high-grade disease was also reported, limiting their clinical adoption.⁷² In a follow up study, the team examined the association between serum finasteride concentrations and the risk of prostate cancer in the treatment arm of the PCPT and determined factors involved in modifying drug concentrations. The association of serum finasteride concentrations with prostate cancer risk was determined by logistic regression. Results of this study indicated that finasteride exposure may reduce prostate cancer risk and concentrations of finasteride are affected by genetic variations in genes responsible for altering its metabolism pathway.⁷⁴ In a 4-year, multicenter, randomized trial targeting men 50 to 75 years of age, with a PSA of 2.5 to 10.0 ng per milliliter with 1 negative prostate biopsy researchers determined whether dutasteride reduces the risk of incident prostate cancer. Subjects underwent follow up biopsies at 2 and 4 years. Two-sided P values of 0.01 or less were considered to indicate statistical significance in the assessment of the superiority of dutasteride over placebo. Results indicated that dutasteride reduced the risk of incident prostate cancer detected on biopsy and improved the outcomes related to benign prostatic hyperplasia.⁷¹

In a more recent report⁷⁵ to determine whether men taking 5-ARIs with regular health care access have increased PCa mortality, the team conducted 2 analyses in the Health Professionals Follow-up Study examining 5-ARI use in a cohort of 38 037 cancer-free men from 1996 - 2017 for PCa incidence and mortality through 2019. A case-only analysis followed 4383 men with localized/locally advanced PCa for mortality over a similar period. Results demonstrated that men using 5-ARIs underwent more PSA testing, prostate exams and biopsies. Among men who were initially free of PCa and using 5-ARI received more follow up care, specific to PCa (Serum PSA, biopsies and prostate exams) and were not at higher risk for lethal disease or cancer specific deaths after diagnosis. In the 20 follow-up years, 509 men developed lethal PCa.⁷⁵ The key to their findings is the that these results were observed in a cohort of men who had health care access (frequent monitoring of serum PSA, prostate exam and biopsies) including surveillance to detect PCa at an early stage. These studies are informative and continues to demonstrate that the 5-ARIs are a promising agent that should be further evaluated in men with localized disease or in men at elevated risk for PCa, who are monitored closely. These studies also provide evidence for the need to improve access to health care in high-risk and localized PCa patients, to ensure that they are monitored closely to prevent progression to metastatic disease.

Green Tea Catechins (GTC)

GTC include (−)-epigallocatechin-3-gallate (EGCG), (−)-epicatechin (EC), (−)-epigallocatechin (EGC), and (−)-epicatechin-3-gallate (ECG). Twenty percent of green tea is consumed in Asian countries where PCa mortality rates are among the lowest in the world. 4 The risk of PCa has been shown to increase among Asian men who abandon their original dietary habits upon migrating to the U. S.⁷⁶ However, case-control and cohort studies addressing the relationship between Green Tea Catechins (GTC) consumption and PCa risk have been mixed, potentially attributed to varying formulations and forms of catechins evaluated.^77,78

Laboratory studies have identified EGCG as the most potent modulator of multiple molecular pathways relevant in prostate carcinogenesis.^76-80 In cell culture systems, several cancer-related proteins have been reported to be modulated by EGCG, including p27, Bcl-2 or Bcr-Abl oncoproteins, Bax, matrix metalloproteinases (MMP-2 and MMP-9) the androgen receptor, EGF receptor, Activator proteins 1(AP1) as well as cyclin kinase inhibitor WAF-1/p21.⁷⁹ These result in induction of apoptosis and cell growth inhibition, relevant to chemoprevention. Adami et al also observed the EGCG treatment of LNCaP cells resulted in induction of genes that exhibit the growth-inhibitory effects and repression of genes that belong to the G-protein signaling network.⁸¹ Our team reported that EGCG potently and selectively inhibits the proteasome activity in intact human cells leading to the accumulation of IkB-α and p27 proteins resulting in growth arrest.^82-86 We showed that GTC preferentially inhibits the proteasomal chymotrypsin-like activities with an IC50 value for trypsin-like activity that we observed was above 100 μM.^82-86 Inhibition of the proteasome activity by EGCG in GTC, and the consequent increase in apoptosis and antiproliferation effects, may contribute to the chemopreventive effect of GTC. Thus, the cumulative data from our work demonstrated that the proteasome is a PCa-related molecular target of GTC.^27,79,82,83 Others have observed that EGCG influences T-cell proliferation and inhibits the activation of NF-ĸB and neuroprotective properties by acting as a free radical scavenger^87,88 thus demonstrating both anti-inflammatory and anti-oxidant properties.

Preclinical studies of GTC,^88-92 have demonstrated significant reductions in tumor size and multiplicity in the TRAMP mouse models. Similarly, evaluating the effects of GTC in a TRAMP mouse model, Gupta et al,⁸⁸ demonstrated that oral infusion of GTP extract at a human achievable dose (6 cups of green tea per day) significantly delayed primary tumor incidence and tumor burden, decreased prostate (64% of baseline) and Genitourinary (72%) weight. Compared with water-fed TRAMP mice, the results of these preclinical studies showed that GTC inhibited serum insulin-like growth factor-I (IGF-I) and restoration of insulin-like growth factor binding protein-3 levels (IGFBP-3), and produced marked reduction in the protein expression of Proliferating Cell Nuclear Antigen (PCNA) in the prostate. GTP consumption resulted in apoptosis, reduced dissemination of cancer cells, contributing to inhibition of development, progression and metastasis to distant organ sites. Oral administration of GTPs (vs pure EGCG) administered to TRAMP mice demonstrated greater bioavailability^81,84,89-91 compared to EGCG alone.⁹¹ Our team evaluated the safety and efficacy of GTC (200, 500, and 1000 mg EGCG in GTC/kg/day), in reducing the progression of PCa in a TRAMP mouse model. The number and size of tumors in treated TRAMP mice were significantly decreased compared with untreated animals. Furthermore, treatment with GTC significantly inhibited metastasis in a dose-dependent manner (P = 0.0003). Long-term (32 weeks) treatment with standardized GTC formulation was safe and well-tolerated with no evidence of toxicity in C57BL/6J mice. Our findings provide additional evidence for the safety and chemopreventive effect of GTC in preventing metastatic progression of PCa.⁹²

Phase I/II studies^91,93-103 have demonstrated bioavailability and tolerability at doses ranging from 200 to 1200 mg EGCG per day. Similarly, early phase I trials of Sunphenon® E have demonstrated increasing plasma EGCG with increasing dose of GTC.^104-107 Oral intake of Sunphenon® D, a standard formulation of GTC, targeting healthy subjects and containing doses of EGCG 225, 375, and 525 mg, demonstrated a significant, and dose-dependent increase in plasma concentrations of EGCg to 657, 4300, and 4410 pmol EGCg/ml, respectively.¹⁰⁶ Plasma EGCg increased significantly with consumption of Sunphenon® D containing 246 mgs EGCg and highly correlated with a marker of antioxidant capacity, as indicated by the attenuation of plasma phospahtidycholine hydoperoxide levels.¹⁰⁷ Relatively grater concentrations of EGCG in plasma occurs when GTC are consumed in a fasting state⁹³ as opposed to a fed state. On the other hand, increased toxicity has been reported when GTC is taken in a fasting state. Similarly, multiple dosing schedule compared to a single daily dose of EGCG has been reported to increase bioavailability and tolerance in phase II trials.^{91,93,100,108} Our team¹⁰¹ and others^91,93,94 have shown that a daily administration of GTC in a standardized formulation for 12 months in divided doses, with meals (non-fasting), accumulates in plasma, produces no toxicities, reduces serum PSA and the cumulative rate of progression to PCa.^91,93,101

Nuclear staining of NF-κB was significantly decreased in radical prostatectomy tissue of men consuming GTC (P = 0.013) but not black tea (P = 0.931) compared to water control. Catechins were detected in the prostate tissue in 32 of 34 men consuming green tea but not in the other arms of the study. Reduced urinary 8OHdG, an indicator of a systemic antioxidant effect was observed only with green tea consumption (P = 0.03).¹⁰⁸ In randomized trials targeting men with localized PCa, prior to prostatectomy, administration of GTC containing 800 mgs of EGCG, produced no toxicities.^108-110 These trials reported a reduction in serum PSA was observed in these trials.^108,109 Additionally, Nguyen et al,⁸⁴observed a trend towards a greater decrease in Gleason score between biopsy and surgical specimens in the GTC arm, although these observations were not statistically significant for the duration of intervention. In addition to statistically significant decreases in serum PSA, Fib B in radical prostatectomy tissue (P = 0.013) a systemic antioxidant effect, decreases in HGF, and VEGF.GTC was observed in the treated arm compared to controls.¹⁰⁸ McLarty et al,¹⁰⁹ showed a significant reduction in serum levels of PSA, HGF, and VEGF in men with PCa after treatment with 800 mgs EGCG with no elevation of liver enzymes. In summary, the in vitro, preclinical and phase I-II trials of GTC, completed by our group and others have demonstrated bioavailability, safety and effectiveness to modulate clinical and biological intermediate endpoint biomarkers implicated in prostate carcinogenesis, establishing the evidence needed to further test this agent in the AS population. However, since more recent data has indicated that higher doses of GTE (defined as 800 mgs or higher) may be associated with moderate to severe abnormalities in liver function tests (LFTs) during the intervention period, it may be important to incorporate strict criteria for inclusion as well as a robust monitoring of liver function throughout future clinical interventions. Currently, 2 phase II clinical trials are evaluating the safety, effectiveness and potential molecular mechanism by which EGCG in GTC can modulate PCa progression in men on AS for PCa. (Clinical trials.gov: NCT04300855 and NCT04597359). If the results of these trials demonstrate safety and efficacy, they should further inform future phase III clinical trials in this target population.

Dietary Interventions (The Men’s Eating and Living (MEAL) Study)

In a 24-month dietary intervention randomized phase III clinical trial, Parsons et al¹¹¹ tested the effectiveness of a high-vegetable diet to prevent progression in patients with PCa on AS (AS) between 2011 and 2015. Men on AS were randomized to a counseling behavioral intervention by telephone promoting consumption of 7 or more daily vegetable servings (MEAL intervention; n = 237) or a control group of men who received written information about diet and PCa (n = 241). The study demonstrated feasibility and acceptance of a dietary intervention to reduce PCa progression. However, no significant differences in time to progression was observed with the 24-month intervention with the 24-month Kaplan-Meier progression-free percentages were 43.5% and 41.4% for the intervention and control groups, respectively (difference, 2.1% [95% CI, −8.1% to 12.2%].

The research team concluded that among men with early-stage PCa managed on AS, a behavioral intervention that increased vegetable consumption did not significantly reduce the risk of PCa progression. This was the first randomized clinical trial to evaluate the indirect evidence from population studies that phytochemical-rich vegetables may promote genomic stability, induce expression of cytoprotective enzymes, and decrease the risk of lethal PCa.^112-115 In the absence of preliminary evidence in preclinical models as well as early phase clinical interventions using varying doses that can modulate relevant intermediate biomarkers of clinical significance, the arbitrary recommendation of 7 servings of vegetables may not have been adequate (dose) nor duration of intervention to modulate changes in clinical outcomes evaluated. Additionally, the study may have been underpowered to identify a clinically important difference. These preliminary studies may be informative to future nutritional intervention and other lifestyle interventional approaches and must precede phase III clinical trials.

Pomegranate Fruit Extract

Pomegranate (Punica granatum L.) and its extracts contain phenolic acids, tannins, and flavonoids.¹¹⁶ Cell line studies as well as preclinical studies have demonstrated that pomegranate extracts have shown antiproliferative and proapoptotic effects in cell lines and animal models, relevant to prostate carcinogenesis, that have informed early phase trials. Although pomegranate extract has been shown to target multiple signaling pathways, specific to PCa, it has been shown to inhibit STAT3 phosphorylation and NFκB activation,^117-119 inhibits IGF-1/AKT/mTOR signaling,^120,121 inhibit androgen biosynthesis enzymes such as 5α-reductase type I and 3β-hydroxysteroid dehydrogenase type II,¹²² inhibit CYP1B enzyme activity/expression¹²³ and decrease serum PSA levels.¹²⁴

In an early phase randomized clinical chemoprevention trial of 1 -year duration, Jarrad D et al (2021)¹²⁵ evaluated pomegranate extract, targeting a cohort of men on AS. The goal was to evaluate the feasibility of the target population to adhere to the trial requirements as well as to observe the ability of pomegranate extract to modulate serum and prostate tissue. Men on AS for PCa were randomly assigned to receive pomegranate fruit extract (PFE) 1000 mg (n = 15) or placebo (n = 15) once daily for 12 months. Twenty none subjects (29) completed the 1-year intervention. Results indicated that metabolites such as urolithin A and urolithin A-gluc were detected more frequently in subjects in the PFE arm in both urine and plasma (P < .001 and P = .006, respectively). Reduction in 8-OHdG (a DNA damage marker) (P = .01) and androgen receptor expression (P = .04) in prostate tumor from baseline to end of intervention associated with PFE treatment compared to placebo was observed, informing further investigation in this target population.

In a double-blind phase II, dose-exploring trial to evaluate (CJ Pallar, 2015)¹²⁶ the biological activity of 1 or 3 g of pomegranate extract (POMx) in men with recurrent PCa, Pallar et al used changes in PSADT as the primary outcome. The target population were men with a rising PSA and without metastases, stratified by baseline serum PSA doubling time (PSADT) and Gleason score. One hundred and four (104) subjects were recruited and completed 18 months of intervention. Results demonstrated an increase in the length of time for median PSADT from 11.9 months at baseline to 18.5 months after treatment (P < 0.001). PSADT lengthened in the low-dose group from 11.9 to 18.8 months and 12.2 to 17.5 months in the high-dose group. However, due to rising PSA, 42% of patients discontinued treatment before meeting the protocol-definition of PSA progression (18 months). They concluded that POMx treatment was associated with ≥6 month increases in PSADT in both treatment arms without adverse effects, establishing the preliminary data needed to conduct a well-powered clinical trial.

In a double-blinded randomized trial (2:1 randomization) of 183 to evaluate the effects of pomegranate extract, juice (vs placebo) on PSA doubling times (PSADT) targeting men with rising PSA levels after primary therapy for PCa, Pantuck AJ et al (2015),¹²⁷ pomegranate extract did not significantly prolong PSADT in PCa patients with rising PSA after primary therapy, compared to placebo. However, greater PSADT lengthening on the pomegranate extract arm was observed in a subgroup of men with the manganese superoxide dismutase (MnSOD) AA genotype.

Freedland SJ (2013) et al,¹²⁸ randomized 70 men to 2 tablets, POMx or placebo, daily up to 4 weeks in a pre-surgical trial, prior to radical prostatectomy. POMx was associated with 16% lower benign tissue 8-OHdG (P = 0.095), which was not statistically significant. The study team observed urolithin A in 21/33 patients in the POMx group vs 12/35 in the placebo group (P = 0.031). Changes in other markers evaluated in prostate tissue such as Cancer pS6 kinase, NF-κB, Ki67, and serum PSA were similar between the treated and placebo arms. The study may be considered preliminary, “window of opportunity” trial with a short duration of intervention (4 weeks) and a single dose of study extract. These early observations may require further investigation in a well-powered trial of longer duration.

The agent has been well characterized, the molecular mechanism has been delineated in vitro and preclinical studies. Early phase clinical trials have identified safety of dose that can modulate PSADT, although other surrogate IEBs such as serum PSA, urolithin A and urolithin A-gluc in urine and plasma or other mechanistic markers resulting in proliferation and apoptosis (%Ki-67, apoptosis) have not been identified nor validated in these early phase trials. Thus, there are still gaps in our knowledge of the effectiveness of pomegranate extract and its role in PCa chemoprevention.

1α-hydroxyvitamin D2

Vitamin D in circulation is present in the form of 25-hydroxyvitamin D3 [25(OH)D3]. Other than from dietary sources, this prohormone can be produced endogenously from exposure to sunlight.¹²⁹ Data from population studies¹³⁰ noted that some of the major risk factors implicated in prostate carcinogenesis such as increasing age, being Black are associated with low serum levels of vitamin D.^130,131 Other observations in a cohort by Corder et al,¹³² reported an inverse relationship between pre-diagnostic vitamin D levels and subsequent development of PCa. Ahonen et al,¹³³ reported that men with higher serum concentrations of vitamin D were at reduced risk of PCa. On the other hand, others have shown increased risk of PCa for men both at the highest and lowest concentrations of serum vitamin D.¹³⁴

In vitro studies of prostate cells have shown that they can convert 25(OH)D₃ to 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], the biologically active form. 1,25(OH)₂D₃ plays a part in modulating cellular differentiation, proliferation, and apoptosis in PCa cell lines.^135-142 Several Vitamin D analogues as well as 1,25(OH)2D3 have been shown to inhibit the growth of androgen responsive cells.^143,144 However, the challenges with hypercalcemia with 1,25(OH)₂D₃ has limited potential for clinical translation requiring development of Vitamin D analogues that are less calcemic and yet retain anticarcinogenic properties. Based on these caveats, the effectiveness of a less calcemic formulation of a vitamin D analog 1α-hydroxyvitamin D₂ [1α-OH-D₂]^145,146 administered for 28 days was evaluated in patients with HG PIN and localized PCa undergoing radical prostatectomy. Although well tolerated with no hypercalcemia for the duration of intervention, results indicated that the only biomarker that was modulated with this intervention was TGF-ß2. However, the study was underpowered, evaluating a single dose and of short duration with only 31 subjects completing the 28 day intervention.

In another randomized clinical trial, Jarrad et al¹⁴⁷ proposed that with the effect of vitamin D on prostate epithelial cell proliferation and differentiation well established, augmenting this effect with genistein which has been shown to inhibit the CYP24 enzyme, critical for intracellular vitamin D metabolism. Genistein and vitamin D have also been shown to inhibit the intraprostatic synthesis of a mediator of inflammation -prostaglandin E2. Men undergoing prostatectomy were randomized to (1) cholecalciferol (vitamin D3) 200 000 IU as 1 dose at study entry plus genistein (G-2535), 600 mg daily (n = 7) or (2) placebo cholecalciferol day 1 and placebo genistein PO daily (n = 8) for 21-28 days prior to radical prostatectomy. All 15 subjects completed the trial with no side effects. A significant increase in in AR expression (P = 0.04) and a trend toward increased TUNEL staining (P = 0.1) in PCa tissues in men randomized to receive VD + G compared to placebo was observed. This study was limited in the number of subjects, duration of intervention requiring further confirmatory studies of these initial observations.

Several studies have indicated the role of polyunsaturated fatty acids-omega-6 and omega-3 as modulators of prostate carcinogenesis.^148-151 Sixty-eight (68) patients with very low risk or low risk PCa were administered Omega-3 PUFAs 720 mg (3/day); curcumin 2000 mg/day; vitamin D3 dose titrated to achieve serum level of 60 ng/mL; and vitamin B-complex 1000 mg (4 times weekly). Subjects in this trial who had higher baseline vitamin D levels were twice as likely to have a downward PSA trend (OR = 2.04, 95% confidence interval 1.04-4.01, P = .04). Fifty-five patients who were followed to 9 months at follow-up biopsy demonstrated no disease progression. Some of the adverse events observed were loose bowel movements requiring adjustment of dose.¹⁵² Although the rationale for including curcumin and vitamin B-complex is not well rationalized, the study provided some evidence of the role of vitamin D and PUFAs in reducing an intermediate endpoint biomarker (serum PSA) implicated in PCa. Future well-powered trials designed to specifically target men with localized disease, evaluating safety and effectiveness in addition to including a well rationalized approach for the combination of the agents, dose and duration of administration to modulate both IEBs and cancer outcomes may be valuable to the field.

Discussion

Currently, there is a paucity of research that systematically examines agents for chemoprevention targeting men on AS, underscoring the need to identify novel agents for PCa chemoprevention in this target population. To date, there is minimal evidence available of any 1 agent or approach that has been found to be effective for chemoprevention for men on AS for PCa. Although the agents summarized appear promising, there are several gaps in the current literature that has limited readiness for phase III clinical trials and ultimately translation for clinical application.

Some of the limitations of previous studies includes a lack of a systematic approach, similar to the rigorous approach that is required to discover any drug used for a therapeutic purpose. Similar to most cancer, PCa is a heterogeneous disease with several drivers implicated in disease progression. Some or several of these drivers are in play during prostate carcinogenesis and can include acquisitions of distinct and diverse sets of hallmark capabilities, an atypical functioning of androgen receptor signaling, deregulation of vital cell physiological processes, inactivation of tumor suppressive activity and disruption of prostate gland specific cellular homeostasis. These complexities thus provide a justification for concurrent inhibition of multiple hallmark -associated pathways.^153,154 Targeting single albeit relevant pathways may thus be an inadequate PCa chemoprevention strategy.

Based on these caveats, the goal for PCa chemoprevention should be to utilize a systematic, broad spectrum approach¹⁵⁵ that involves using an agent or agents that has been (a) well characterized; (b) as a single or combination agent - enhance bioavailability and half-life; (c) have an excellent safety profile; (d) produce robust and concurrent inhibition of multiple hallmark-associated pathways in target tissue/microenvironment, addressing the underlying biology of prostate carcinogenesis; (e) modulates relevant intermediate endpoint biomarkers implicated in clinical progress of PCa - an approach that may be more effective than agents evaluated to date (Ref).

Preliminary studies in vitro to understand the molecular mechanism by which the agents modulate PCa carcinogenesis; (d) validating the results in relevant preclinical models (establish preclinical bioavailability, route of administration, duration of intervention, half-life, safety, efficacy)to inform translation; (e) early phase trials (phase I-II) to establish preliminary safety, efficacy, bioavailability, dose, route, frequency (based on half-life) at which modulation of the relevant biomarkers implicated in prostate carcinogenesis is observed; and (f) information on duration of intervention required to modulate IEBs relevant to clinical outcome. These data must precede and inform the design of phase III clinical trials. Since most patients with low grade/localized PCa will be followed by their community urologists, early phase trials must involve and collaborate with community urologists in the early phase trials. These trials must be designed to in consultation with the community medical community including research methods that can be easily performed not only at academic but also non-academic institutions.

Early phase trials must include objective markers of compliance to study agent throughout the trial, in addition to pill counts and self-reported daily study-agent intake logs. Standardized methods to evaluate compliance using plasma, serum or tissue concentrations of study agent will provide an objective measure of compliance. Since most cancer patients may use multivitamins/minerals or other supplements, it may be important to check if these supplements contain the active agent used in the trial in addition to evaluating these agents with competing or concomitant effects.

The potential adverse events reported should be taken into consideration and if a subgroup of subjects may be at high risk for toxicity or adverse events, these subjects can be excluded based on the criteria for inclusion and exclusion. Safety labs such as metabolic screening by CMP and CBC must be performed at baseline for determination of eligibility prior to starting on study agent, at mid-point and at end of study for safety monitoring. Assessment of the safety of GTC (vs Placebo) by evaluating incidence of adverse events and toxicities, monitored using Common Toxicity Criteria version 5.0 and concomitant medications, both during scheduled visits in the clinic as well as via telephone, while patients are on trial. Patient reported outcomes on improvement in symptoms of the lower urinary tract and quality of life must be included.

In patients on AS, mpMRI has emerged as a useful adjunct tool in the detection of PCa. Several studies have shown that suspicious findings on MRI predict a greater risk of reclassification during AS.^156-161 Two of the large prospective AS programs report their indications for use of mpMRI. MRI is currently used in men indicated for closer monitoring, such as those with adverse PSA kinetics.¹⁶² At the Royal Marsden, baseline and surveillance mpMRI for all men on AS.¹⁶³ Although the long-term data on the performance of mpMRI during AS is still pending from these large prospective cohorts, mpMRI during AS has demonstrated potential to (a) identify higher-grade cancers and (b) to evaluate targeted lesions during confirmatory prostate biopsy. mpMRI-targeted biopsies have improved the diagnosis of significant anterior tumors^160,164-167 mpMRI has improved the diagnostic performance of biopsies, enabling surgeons to switch from blind systematic TRUS-guided biopsies to targeted biopsies to reduce the amount of biopsies required and reduce the diagnostic rate of clinically insignificant cancers. mpMRI have also led to diagnostic improvements by providing information regarding size and location but also tumor aggressiveness. Most importantly, mpMRI has proven to be the most reliable non-invasive technique to be able to exclude patients with clinically significant cancer and thus gain acceptance in AS protocols during selection, confirmation and follow-up of AS patients.¹⁶⁸ Given the importance of these capabilities in the AS setting, mpMRI is a critical part of the AS program.

Other biomarkers of outcome in this target population of men with low grade disease can include change with intervention in stage and volume. Expert recommendations include assignment of individual Gleason scores to separate prostate needle core biopsies.¹⁶⁹ On prostate needle biopsies, the Gleason score is based on the predominant pattern plus the highest-grade pattern. Minor high-grade patterns are defined as < 5% tumor volume and do not change the Grade Groups. Gleason score 6 (Grade Group 1) is the lowest grade currently reported. Gleason score 7 is not homogenous. Gleason score 4 + 3 = 7 (Grade Group 3) has a significantly worse prognosis than Gleason score 3 + 4 = 7 (Grade Group 2); therefore, separating these grades into different prognostic and treatment strategies, particularly in patients treated with radiation therapy. Gleason scores 8-10 are considered high-grade disease. Grade Group 4 (Gleason score 8) vs Grade Group 5 (Gleason scores 9-10) stratifies patients into various treatment strategies as well.¹⁶⁹ WHO (World Health Organization) 2016 recommends reporting of percentage of pattern 4 for Gleason score 7, adenocarcinoma.¹⁷⁰ For select patients, depending on their age, comorbidity, extent of cancer, MRI findings and patient preference, these patients may be candidates for AS if their reported Gleason score 7 (3 + 4) contains limited pattern 4, particularly if pattern 4 is <10%.^171,172 Percentage of Gleason pattern 4, may also be beneficial in guiding radiation therapy.¹⁷³ Borderline pattern 4 percentages may prompt clinicians to utilize other additional factors such as serum PSA, number of cores positive for carcinoma and imaging studies for guiding therapy. Indolent PCa should be organ-confined. Using current clinical definitions, indolent PCa is considered low-risk (Gleason ≤6, cT1c-cT2a, PSA ≤10 ng/mL) or very low-risk disease (Gleason ≤6, cT1c, PSAD ≤0.15 ng/mL/mg, and involvement of no more than 2 cores and ≤50% of each core, including the non-neoplastic intermediate segments).¹⁷⁴

While PSA testing, Gleason score, clinical and pathological tumor staging remain routinely used methods for clinical diagnosis and management of PCa, studies conducted as early as the 1990s have also explored the prognostic utility of intermediate endpoint biomarkers of proliferation such as % Ki67 expression.^175,176 Immunohistochemistry detection of Ki-67, a nuclear protein, is expressed in all phases of the cell cycle except the resting G0 phase.¹⁷⁷ The evaluation of the magnitude of its expression provides insights into the aggressiveness and the invasiveness of the tumor.¹⁷⁷ Additionally, it provides data on progression of indolent variants in addition to aggressive PCAs.^176,178,179 Ki67 expression has been shown to be highly expressed in prostatic carcinoma and remains low in benign and normal prostatic cells. In their systematic literature review, Carneiro et al (2018)¹⁷⁵ demonstrated an association between elevated Ki67 and aggressiveness (P = 0.037) as well as shorter tumor-specific survival (P = 0.0007).¹⁷⁵ In a systematic review, Berlin et al (2017)¹⁸⁰ reported that elevated % Ki67 expression was significantly associated with decreased survival outcomes. On the other hand, low % Ki-67 expression tumors showed significantly higher odds of disease-free survival at 5 (OR = 0.32, CI = 0.23-0.44, P < 0.00001) and 10 years (OR = 0.31, CI = 0.20-0.48, P < 0.00001) compared to high % Ki67 expression tumors.¹⁸⁰ Similarly, Berney et al¹⁸¹ reported that a % Ki67 expression (cut off value 5.42%) staining as a significant prognostic factor for cancer-specific (HR = 1.09 (1.07-1.10), P < 0.001) and overall survival (HR = 1.06 (1.05-1.07), P < 0.001) in a cohort of men on AS. % Ki67 expression was reported as a significant prognostic marker for cancer-specific survival in men with intermediate (P = 0.049) and high-risk PCa (P = 0.001) by their group. In a follow-up study, Fisher et al (2013),¹⁸²evaluated in the same cohort of conservatively managed men utilized needle biopsy specimen and showed % Ki67 expression (cut off value 10%) as a significant, independent prognostic marker of PCa death both in univariate (HR = 3.42 (1.76, 6.62), χ2 (1 df) = 9.8, P = 0.0002) and multivariate analysis (HR = 2.78 (1.42, 5.46), χ2 (1 df) = 7.0, P = 0.008).¹⁷⁶ Additionally, in a study conducted by Nagao et al,¹⁸³ it was found that % Ki67 expression (cut off value = 4.1) levels were significantly valuable in distinguishing clinically significant and insignificant PCas as defined by Epstein and PRIAS criteria. They also reported significant association between elevated % Ki67 expression and increasing PSA levels (P < 0.05) as well with increasing Gleason score (P < 0.01).¹⁸³ Their findings corroborated with a study conducted by Zellweger et al, in 2009,¹⁸⁴ where they had prospectively analyzed needle and radical prostatectomy for a cohort of 279 patients, and reported a significant association between elevated levels of % Ki67 (cut off = 10%) expression and advancing tumor stage (P = 0.036), lymph node involvement (P < 0.001), seminal vesicle infiltration (P < 0.001) and large tumor diameter (P = 0.039).¹⁸⁴ They also stated in their research the significant (P < 0.01) prognostic utility of % Ki67 expression in low grade PCas (Gleason score <7), and PCas with only 1 tissue core positive (P < 0.01). Thus, in summary, findings from the literature have highlighted the predictive role for Ki-67 expression in low and intermediate risk to high-risk PCas, indicating that increased tumor proliferation is correlated with disease aggressiveness and adverse clinical outcomes. Change in % Ki67 expression in a biopsy core positive for cancer with intervention can serve as an intermediate endpoint biomarker of disease progression.

More recently genomic biomarkers in combination with clinical and pathological variable have become useful tools to inform stratification of patients to low or high risk and guide personalized treatment decisions. Although several predictive tissue-based markers have continued to provide encouraging results and better than conventional parameters, there continues to be a need for further well-designed large, multicenter, prospective trials to avoid common bias and clinical validation.^131,132 Some of the key challenges in developing tissue-based assays include the heterogeneous nature of the disease and the very small quantity of tissue available from prostate needle biopsies at diagnosis.

PSA and PSA Kinetics (PSA, PSA Doubling Time, PSA Velocity, Prostate Health Index (phi) and PSA Density)

Virtually all AS programs continue to monitor PSA serially. PSA kinetic measurements such as PSA velocity (PSAV) and PSA doubling time (PSADT) have been extensively evaluated as predictors of progression.^28,185 In several AS programs, PSA kinetics were historically used as a trigger for intervention with a significant association between PSA kinetics and progression to treatment.^186,187 However, studies have shown that PSA kinetics are not a reliable predictor of biopsy reclassification during AS.^188,189 As a result, PSA kinetics is now considered trigger for further diagnostic evaluation rather than as a trigger for intervention.¹⁹⁰ Patel et al,¹⁹¹ showed that men with multiple successive PSAV measurements >0.4 ng/mL/year have a significantly greater risk of biopsy reclassification beyond the first 2 years of AS. Thus, men with stable disease on AS for several years may benefit from the use of PSA kinetics.^185,192,193 Other PSA measurement such as PSA density (PSAD) at the time of diagnostic biopsy can be used to predict progression and is predictive of biopsy reclassification at subsequent surveillance,¹⁹⁴ and can thus be used to predict progression during AS. Approved by the FDA in 2012 as an aid in early PCa detection.¹⁹⁵ The Prostate Health Index (phi) is an adjunctive PSA-based measurement combining total, free, and [-2] proPSA using a mathematical formula and has been shown to outperform PSA and free PSA for identifying clinically significant PCa, and a predictor of biopsy reclassification.^87,196 Additional studies are needed to identify how phi can be best utilized, possibly in conjunction with imaging, to help monitor men during AS. However, studies have shown that PSA kinetics are not a reliable predictor of biopsy reclassification during AS.^188-190 Most AS programs use PSA kinetics as a trigger for further diagnostic evaluation rather than a trigger for intervention.¹⁹⁰ Overall, it is clear that monitoring changes in serial PSA measurements can be utilized as a surrogate endpoint biomarker of disease progression in early phase clinical trials.

Future Directions

Currently, there are several limitations in the approach used to systematically examine agents for chemoprevention targeting men on AS for PCa.¹⁹⁷ Although the agents included in this summary appear promising, there are several gaps in the current research that has limited information needed and readiness for phase III clinical trials and ultimately translation to clinical application. As noted, unlike the rigorous approach that is required to discover any drug used for a therapeutic purpose, most of the previous studies have failed to use a systematic approach in the evaluation of agents. Informed by epidemiology, promising agents must be tested rigorously in the laboratory to understand the molecular mechanisms relevant to their choice to target specific carcinogenic pathways. Additionally, PCa is a complex heterogeneous disease which demands for concurrent inhibition of multiple hallmark -associated pathways. Targeting single albeit relevant pathways may thus be inadequate and not representative chemoprevention strategy. The observations of these mechanisms must be validated in a relevant preclinical model in addition to evaluating safety and efficacy parameters, prior to translating this evidence to early phase clinical trials. Based on these caveats, the goal for PCa chemoprevention should be to utilize a systematic, broad spectrum approach 26 that involves using an agent or agents that has been (a) well characterized; (b) as a single or combination agent - enhance bioavailability and half-life; (c) have an excellent safety profile; (d) produce robust and concurrent inhibition of multiple hallmark-associated pathways in target tissue/microenvironment, addressing the underlying biology of prostate carcinogenesis; (e) modulates relevant intermediate endpoint biomarkers implicated in clinical progression of PCa - an approach that may be more effective than agents evaluated to date. Results of these studies may inform development of phase III clinical trial and ultimately provide a strategy for chemoprevention in men on AS, for whom, currently, there are no options for reducing risk of progression of their risk PCa.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The work was supported by grant from the NIH-NCI: (R01 CA235032-01A1) and (5UG1 CA189828-08).

Ethicsl Statement

ORCID iD

Nagi B Kumar

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Contemporary Strategies for Clinical Chemoprevention of Localized Prostate Cancer

Abstract

Keywords

Introduction

Prostate Cancer

Prostate Cancer Chemoprevention

Current Strategies for Prostate Cancer Chemoprevention

Selenium and Vitamin E

Lycopene

5 -Alpha Reductase Inhibitors

Green Tea Catechins (GTC)

Dietary Interventions (The Men’s Eating and Living (MEAL) Study)

Pomegranate Fruit Extract

1α-hydroxyvitamin D2

Discussion

PSA and PSA Kinetics (PSA, PSA Doubling Time, PSA Velocity, Prostate Health Index (phi) and PSA Density)

Future Directions

Footnotes

Declaration of Conflicting Interests

Funding

Ethicsl Statement

ORCID iD

References