Androgen deprivation and other treatments for advanced prostate cancer

Among the issues discussed at this year's meeting on prostate cancer in Vail, Colorado, were several that specifically relate to the patient with advanced disease. Dr. E. David Crawford addressed the issue of the timing of hormone therapy, specifically reviewing several important trials that give a glimpse at the potential outcome of aggressive treatment in stage D1.5. The efficacy of antiandrogens, flutamide, bicalutamide, and nilutamide, when combined with chemical or surgical castration, was reviewed. Dr. Arturo Mendoza-Valdes reviewed the rationale behind intermittent (versus continuous) total androgen blockade, especially as related to quality of life. Dr. Paul Miller gave an update on the role of bisphosphonates as adjuvant therapy for prostate cancer. Also discussed was an important new agent for androgen deprivation, Abarelix, a sustained-release GnRH antagonist with low histamine-releasing potential which avoids testosterone and other hormone surge and flare.     

Effective Testosterone Suppression for Prostate Cancer: Is There a Best Castration Therapy?

Achieving and maintaining effective suppression of serum testosterone levels in men treated with androgen ablation is one of the essential strategies in the management of prostate cancer. Historically, a serum testosterone below 50 ng/dL was considered to be the castrate level. Current data suggest that the new target for either surgical or chemical castration is a serum testosterone level of lower than 20 ng/dL in an attempt to maximize therapeutic outcomes. Testosterone breakthrough and the acute-on-chronic effects of administration of a luteinizing hormone-releasing hormone analogue may cause testosterone levels to periodically rise, sometimes to noncastrate levels. The goal of androgen ablation is to identify those agents that will most consistently achieve and maintain the lowest testosterone levels possible.Key words: Prostate cancer, Androgen ablation, LHRH analogues, LHRH antagonists, TestosteroneThe cornerstone of understanding the basic biology of prostate cancer relies upon the important discovery that prostate cancer is a hormonally responsive tumor. The current use of androgen ablation therapy in prostate cancer includes treatment based on serum prostate-specific antigen (PSA) only or local recurrence; neoadjuvant or adjuvant treatment of high-risk disease, usually in combination with radiation therapy; and treatment of patients with metastatic disease regardless of symptoms. The American Society of Clinical Oncology (ASCO) 2007 guidelines and National Comprehensive Cancer Network (NCCN) 2009 guidelines recommend either luteinizing hormone-releasing hormone (LHRH) agonists or bilateral orchiectomy as first-line therapy for men with advanced prostate cancer.^1,2Medical or chemical castration is almost exclusively performed by the use of injectable LHRH analogues, with a minor role for estrogen and limited experience with LHRH antagonists. Surgical castration through bilateral orchiectomy is infrequently used today.Intermittent hormonal therapy (IHT) is being investigated as an alternative to continuous hormonal therapy with a potential for reduced morbidity and a delay of the progression to hormone-refractory disease.³ Although intermittent therapy may rely upon restoring a normal testosterone level, it is believed that the testosterone level should be as low as possible when the patient is on treatment, thus generating the lowest serum PSA level possible and likely improving outcome.⁴ Although the data on IHT are promising, trials reported thus far are relatively small and somewhat underpowered, and it is likely that its use will increase in the future as trials mature.There is growing recognition that many men may not achieve acceptable levels of testosterone using androgen ablation. This has led to a renewed interest in the significance of the testosterone level in the modern era of prostate cancer management. Can we define the best castration therapy for prostate cancer? Is this the therapy that provides the lowest and most consistent levels of testosterone suppression? To quote Dr. Claude Schulman in a recent editorial: “less is more.”⁵     

Immediate Treatment with Bicalutamide, 150 mg/d, Following Radiotherapy in Localized or Locally Advanced Prostate Cancer

Previous studies and meta-analyses have made it clear that some subgroups of prostate cancer patients who have received radiotherapy should benefit from immediate adjuvant hormonal therapy. A cohort totaling 1370 patients who received radiotherapy for early nonmetastatic prostate cancer is currently enrolled in three ongoing, randomized, double-blind, placebo-controlled trials investigating the role of bicalutamide ('Casodex') 150 mg/d as adjuvant to standard care (the bicalutamide Early Prostate Cancer program). At preliminary analysis, conducted after a median follow-up of 3 years, adjuvant therapy with bicalutamide 150 mg/d significantly reduced the risk of objective progression by 37% compared with radiotherapy alone (HR 0.63, 95% CI, 0.46-0.85, P = .0024). Initial results demonstrate that bicalutamide 150 mg/d given as immediate adjuvant therapy following radiotherapy in men with early nonmetastatic prostate cancer has benefits over radiotherapy alone.     

Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer

Prostate cancer is the most frequently diagnosed non-cutaneous tumor of men in Western countries. While surgery is often successful for organ-confined prostate cancer, androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. Shortening the period of androgen ablation therapy may benefit prostate cancer patients. Intermittent Androgen Deprivation therapy improves quality of life, reduces toxicity and medical costs, and delays disease progression in some patients. Cell culture and xenograft studies using androgen receptor (AR)-positive castration-resistant human prostate cancers cells (LNCaP, ARCaP, and PC-3 cells over-expressing AR) suggest that androgens may suppress the growth of AR-rich prostate cancer cells. Androgens cause growth inhibition and G1 cell cycle arrest in these cells by regulating c-Myc, Skp2, and p27^Kip via AR. Higher dosages of testosterone cause greater growth inhibition of relapsed tumors. Manipulating androgen/AR signaling may therefore be a potential therapy for AR-positive advanced prostate cancer.     

Prostate cancer risk in testosterone-treated men

Men with classical androgen deficiency have reduced prostate volume and blood prostate-specific antigen (PSA) levels compared with their age peers. As it is plausible that androgen deficiency partially protects against prostate disease, and that restoring androgen exposure increases risk to that of eugonadal men of the same age, men using ART should have age-appropriate surveillance for prostate disease. This should comprise rectal examination and blood PSA measurement at regular intervals (determined by age and family history) according to the recommendations, permanently revisited, published by ISSAM, EAU, Endocrine Society….

Testosterone replacement therapy is now being prescribed more often for aging men, the same population in which prostate cancer incidence increases; it has been suggested that administration in men with unrecognised prostate cancer might promote the development of clinically significant disease. In hypogonadal men who were candidates for testosterone therapy, a 14% incidence of occult cancer was found. A percentage (15.2%) of prostate cancer has been found in the placebo group (with normal DRE and PSA) in the prostate cancer prevention study investigating the chemoprevention potential of finasteride.

The hypothesis that high levels of circulating androgens is a risk factor for prostate cancer is supported by the dramatic regression, after castration, of tumour symptoms in men with advanced prostate cancer. However these effects, seen at a very late stage of cancer development, may not be relevant to reflect the effects of variations within a physiological range at an earlier stage.

Data from all published prospective studies on circulating level of total and free testosterone do not support the hypothesis that high levels of circulating androgens are associated with an increased risk of prostate cancer. A study on a large prospective cohort of 10,049 men, contributes to the gathering evidence that the long standing “androgen hypothesis” of increasing risk with increasing androgen levels can be rejected, suggesting instead that high levels within the reference range of androgens, estrogens and adrenal androgens decrease aggressive prostate cancer risk. Indeed, high-grade prostate cancer has been associated with low plasma level of testosterone. Furthermore, pre-treatment total testosterone was an independent predictor of extraprostatic disease in patients with localized prostate cancer; as testosterone decreases, patients have an increased likelihood of non-organ confined disease and low serum testosterone levels are associated with positive surgical margins in radical retropubic prostatectomy.

A clinical implication of these results concerns androgen supplementation which has become easier to administer with the advent of transdermal preparations (patch or gel) that achieve physiological testosterone serum levels without supra physiological escape levels. During the clinical development of a new testosterone patch in more than 200 primary or secondary hypogonadal patients, no prostate cancer was diagnosed.     

The treatment of hormone-refractory prostate cancer: docetaxel and beyond

Two randomized clinical trials demonstrated a survival benefit of 20% to 24% with docetaxel-based therapy when compared with survival with mitoxantrone and prednisone after failure of androgen ablation therapy. These studies supported the approval of docetaxel-based therapy for the treatment of metastatic hormone-refractory prostate cancer by the US Food and Drug Administration in May 2005. Clinical trials in hormone-refractory prostate cancer are now focused on building on the survival improvement seen with docetaxel-based therapy. This article presents a summary of some of the more promising treatments and regimens for advanced prostate cancer.     

P450-dependent enzymes as targets for prostate cancer therapy

Metastatic prostate adenocarcinoma is a leading cause of cancer-related deaths among men. First line treatment is primarily aimed at blocking the synthesis and action of androgens. As primary endocrine treatment, androgen deprivation is usually achieved by orchidectomy or LHRH analogues, frequently combined with androgen receptor antagonists in order to block the residual adrenal androgens. However, nearly all the patients will eventually relapse. Available or potential second line therapies include, among others, alternative endocrine manipulations and chemotherapy.

Cytochrome P450-dependent enzymes are involved in the synthesis and/or degradation of many endogenous compounds, such as steroids and retinoic acid. Some of these enzymes represent suitable targets for the treatment of prostate cancer.

In first line therapy, inhibitors of the P450-dependent 17,20-lyase may achieve a maximal androgen ablation with a single drug treatment. Ketoconazole at high dose blocks both testicular and adrenal androgen biosynthesis but its side-effects, mainly gastric discomfort, limit its widespread use. A series of newly synthesized, more selective, steroidal 17,20-lyase inhibitors related to 17-(3-pyridyl)androsta-5,16-dien-3β-ol, may open new perspectives in this field.

In prostate cancer patients who relapse after surgical or medical castration, therapies aiming at suppressing the remaining adrenal androgen biosynthesis (ketoconazole) or producing a medical adrenalectomy (aminoglutethimide + hydrocortisone) have been used, but are becoming obsolete with the generalization of maximal androgen blockade in first line treatment. The role of inhibition of aromatase in prostate cancer therapy, which was postulated for aminoglutethimide, could not be confirmed by the use of more selective aromatase inhibitors, such as formestane.

An alternative approach is represented by liarozole fumarate (LIA), a compound that blocks the P450-dependent catabolism of retinoic acid (RA). In vitro, it enhances the antiproliferative and differentiation effects of RA in cell lines that express RA metabolism, such as F9 teratocarcinoma and MCF-7 breast carcinoma cells. In vivo, monotherapy with LIA increases RA plasma levels and, to a greater extent, endogenous tissue RA levels leading to retinoid-mimetic effects. In the rat Dunning prostate cancer models, it inhibits the growth of androgen-independent as well as androgen-dependent carcinomas relapsing after castration. Concurrently, changes in the pattern of cytokeratins characteristic of increased differentiation were observed. Early clinical trials show that LIA, in second or third line therapy in metastatic prostate cancer, induces PSA responses in about 30% of unselected patients. In some patients regression of soft tissue metastasis has been observed. In a subgroup of patients, an important relief of metastatic bone pain was also noted.     

Fundamental aspects of hypogonadism in the aging male

With aging in men, serum testosterone levels decline progressively and the prevalence of hypogonadism increases; these changes are associated with alterations in androgen-regulated physiological functions. In young hypogonadal men, similar alterations improve with testosterone replacement. In older men, short-term testosterone treatment trials suggest benefits (eg, on body composition and bone mineral density), without significant adverse effects. Therefore, androgen deficiency may contribute to physiological decline with aging, and testosterone therapy is reasonable for older men with clinical manifestations of androgen deficiency and low testosterone levels. However, the long-term benefits and potential risks (eg, for prostate disease) of testosterone treatment in older men are unknown.     

Rationale for the Radiation Therapy Oncology Group Study RTOG P-0014

Chemotherapy currently has an established role in the treatment of hormonerefractory prostate cancer. There is strong evidence that combined-modality treatment, using androgen ablation in addition to radiotherapy, provides a benefit above and beyond radiotherapy alone in patients with a poor prognosis, perhaps due to the effect of androgen ablation on subclinical distant disease. Several clinical trials currently under way are investigating whether the addition of chemotherapy with known efficacy in the hormone-refractory setting can provide a survival advantage when used adjuvantly.     

CYP17 inhibitors for prostate cancer therapy

Prostate cancer (PC) is now the second most prevalent cause of death in men in the USA and Europe. At present, the major treatment options include surgical or medical castration. These strategies cause ablation of the production of testosterone (T), dihydrotestosterone (DHT) and related androgens by the testes. However, because these procedures do not affect adrenal, prostate and other tissues' androgen production, they are often combined with androgen receptor antagonists to block their action. Indeed, recent studies have unequivocally established that in castration-resistant prostate cancer (CRPC) many androgen-regulated genes become re-expressed and tissue androgen levels increase despite low serum levels. Clearly, inhibition of the key enzyme which catalyzes the biosynthesis of androgens from pregnane precursors, 17α-hydroxy/17,20-lyase (hereafter referred to as CYP17) could prevent androgen production from all sources. Thus, total ablation of androgen production by potent CYP17 inhibitors may provide effective treatment of prostate cancer patients. This review highlights the role of androgen biosynthesis in the progression of prostate cancer and the impact of CYP17 inhibitors, such as ketoconazole, abiraterone acetate, VN/124-1 (TOK-001) and TAK-700 in the clinic and in clinical development. Article from the special issue on Targeted Inhibitors.     

New paradigms for advanced prostate cancer

In men with metastatic hormone-refractory prostate cancer, androgen blockade produces dramatic and rapid declines in prostate-specific antigen (PSA), bone pain, and urinary tract obstruction. Nevertheless, there have been limited options with at best palliative results for patients who progress despite a castrate testosterone level. This paradigm changed in 2004 with the publication of 2 randomized clinical trials that demonstrated a 20% to 24% survival benefit for docetaxel-based therapy when compared to mitoxantrone and prednisone, data that supported US Food and Drug Administration approval of docetaxel-based therapy for the treatment of metastatic hormone-refractory prostate cancer. This article reviews the preliminary data and the timing and sequencing implications of ongoing clinical trials. Studies are evaluating the combination of docetaxel with agents that target bone, tumor vasculature, and the vitamin D receptor as well as second-line agents, such as satraplatin. The role of immune therapy is also evolving, and further studies will define the optimal timing of chemotherapy with immune therapy.     

Immunization against luteinizing hormone-releasing hormone fusion proteins does not decrease prostate cancer in the transgenic adenocarcinoma mouse prostate model

This study was undertaken to test the effect of immunization against luteinizing hormone-releasing hormone (LHRH) fusion proteins on the development and progression of prostate cancer in the transgenic adenocarcinoma mouse prostate (TRAMP) model. Two LHRH fusion proteins, ovalbumin with seven LHRH peptides (OV-LHRH-7), and thioredoxin with seven LHRH peptides (TH-LHRH-7) were used in a cocktail vaccine. Two groups of male TRAMP mice were immunized with the cocktail. Primary immunizations were at either 4 or 8 weeks of age. LHRH immunized mice (n=19) were compared with castrated (n=19) and intact mice (n=18) for testosterone concentration, tumor weight, and lifespan. Immunization against LHRH in the TRAMP mice resulted in significant production of antibodies to LHRH compared with surgically castrated and intact control mice. Testicular weight was significantly reduced in the LHRH immunized groups compared with intact control mice. Serum testosterone was reduced (P<0.05) in the immunized mice compared with intact control mice and was not different from that of castrated mice (P>0.05). Tumor weight was variable and inconsistent throughout all treatment groups. Lifespan was not increased by immunization against LHRH or castration. Intact control mice (lived the longest (227+/-11 days), whereas immunized mice lived 206+/-11 days and castrated mice lived 213+/-13 days. Tumors from immunized TRAMP mice appeared more aggressive than tumors of castrated and intact mice, as demonstrated by 35% expression of gross lung tumors in the immunized mice whereas none were observed in the castrated or intact TRAMP mice. Prostate cancer is initially dependent upon androgens for growth and development, but cells have the ability to escape androgen dependence and progress to an androgen independent state, which was evident in this study. The TRAMP mouse model immunized against LHRH may have utility in future studies and treatments of the androgen independent prostate cancer.     

AR, apoE, and cognitive function

Reduced androgen levels in aged men and women might be risk factors for age-related cognitive decline and Alzheimer's disease (AD). Ongoing clinical trials are designed to evaluate the potential benefit of estrogen in women and of testosterone in men. In this review, we discuss the potential beneficial effects of androgens and androgen receptors (ARs) in males and females. In addition, we discuss the hypothesis that AR interacts with apolipoprotein (apoE)4, encoded by epsilon4 and a risk factor for age-related cognitive decline and AD, and the potential consequences of this interaction.     

Surgical Stress Delays Prostate Involution in Mice

Androgens control growth of prostate epithelial cells and androgen deprivation induces apoptosis, leading to prostate involution. We investigated the effects of surgical stress on prostate involution induced by androgen ablation and determined the underlying mechanisms. Androgen ablation in mice was induced by surgical castration and administration of the anti-androgenic drugs bicalutamide and MDV3100. Surgical stress was induced by sham castration under isoflurane anesthesia. Surgical stress delayed apoptosis and prostate involution induced by anti-androgenic drugs. These effects of stress were prevented by administering the selective beta2-adrenoreceptor antagonist ICI118,551 and were also blocked in BAD^3SA/WT mice expressing phosphorylation-deficient mutant BAD3SA. These results indicate that apoptosis and prostate involution in response to androgen ablation therapy could be delayed by surgical stress via the beta2-adrenoreceptor/BAD signaling pathway. Thus, surgery could interfere with androgen ablation therapy, whereas administration of beta2-adrenoreceptor antagonists may enhance its efficacy.     

Androgen supplementation and prostate cancer risk: strategies for pretherapy assessment and monitoring

Since in men androgen levels decrease with age and result in symptoms of hypogonadism, the use of testosterone supplementation to treat symptoms resulting from hypogonadism is increasing. One potential complication of this treatment is the possibility of an increased risk of prostate cancer. Although most authorities agree that androgen is involved in the exacerbation of existing carcinoma of the prostate, the action of androgens on the carcinogenic process is not well understood. Attempts to demonstrate a correlation between hormone levels and prostate cancer have yielded inconsistent results. No clear evidence exists that androgen supplementation to restore physiologic levels produces any deleterious effects on the prostate. It is highly doubtful that when testosterone therapy is administered to middle-aged or older men, any potential prostate cancer promotion effect will be clinically manifested in the absence of already established cancer. It is, however, imperative that existing or developing prostate cancer be ruled out before initiation and during androgen replacement therapy. As with any therapeutic regimen, careful monitoring of the patient receiving treatment is recommended and constitutes good medical care.     

Androgen deficiency in the aging male: benefits and risks of androgen supplementation

There is now convincing evidence that in a subset of aging men, increasing with age, plasma testosterone levels fall below a critical level resulting in hypogonadism. This state of testosterone deficiency has an impact on bone, muscle and brain function and is maybe a factor in the accumulation of visceral fat which again has a significant impact on the cardiovascular risk profile. From the above it follows that androgen replacement to selected men with proven androgen deficiency will have beneficial effects. There is, however a concern that androgen administration to aging men may be harmful in view of effects on prostate disease. Benign prostate hyperplasia (BPH) and prostate cancer are typically diseases of the aging male, steeply increasing with age. But epidemiological studies provide no clues that the levels of circulating androgen are correlated with or predict prostate disease. Similarly, androgen replacement studies in men do not suggest that these men suffer in a higher degree from prostate disease than control subjects. It seems a defensible practice to treat aging men with androgens if and when they are testosterone-deficient, but long-term studies including sufficient numbers of men are needed.     

Major impact of hormonal therapy in localized prostate cancer--death can already be an exception

For about 50 years, androgen blockade in prostate cancer has been limited to monotherapy (surgical castration) or high doses of estrogens in patients with advanced disease and bone metastases. The discovery of medical castration with LHRH agonists has led to fundamental changes in the endocrine therapy of prostate cancer. In 1979, the first prostate cancer patient treated with an LHRH agonist received such treatment at the Laval University Medical Center. A long series of studies have clearly demonstrated that medical castration with an LHRH agonist has inhibitory effects on prostate cancer equivalent to those of surgical castration. The much higher acceptability of LHRH agonists has been essential to permit a series of studies in localized disease. Based upon the finding that the testicles and adrenals contribute approximately equal amounts of androgens in the human prostate, the combination of medical (LHRH agonist) or surgical castration associated with a pure antiandrogen (flutamide, nilutamide or bicalutamide) has led to the first demonstration of a prolongation of life in prostate cancer, namely a 10–20% decreased risk of death according to the various metaanalyses of all the studies performed in advanced disease. In analogy with the other types of advanced cancers, the success of combined androgen blockade in metastatic disease is limited by the development of resistance to treatment. To avoid the problem of resistance to treatment while taking advantage of the relative ease of diagnosis of prostate cancer at an “early” stage, the much higher acceptability of LHRH agonists has permitted a series of studies which have demonstrated a major reduction in deaths from prostate cancer ranging from 31% to 87% at 5 years of follow-up in patients with localized or locally advanced prostate cancer. Most importantly, recent data show that the addition of a pure antiandrogen to an LHRH agonist in order to block the androgens made locally in the prostate leads to a 90% long-term control or probable cure of prostate cancer.     

1,2,4-Oxadiazoles: a new class of anti-prostate cancer agents

Sulfide and sulfonyl derivatives of 1,2,4-oxadiazoles were synthesized and screened by MTT assay on the prostate cancer cells, DU-145. Six compounds were identified as potential anti-prostate cancer agents with IC(50) values ranging from 0.5 to 5.1μM. These compounds exhibited good activity on the androgen independent cells PC-3, while the results were moderate on androgen dependent LNCaP cells, suggesting the possibility of a mechanism of action different from that of the bioisosteric bicalutamide. Also a very low cytotoxicity was observed on non-cancerous cells MCF-10A.     

Le cancer de la prostate: Acquis et challenges pour l'an 2000

Principles of the diagnosis and treatment of prostate cancer at any stage are still improving. Early diagnosis is accessible throughout the use of the PSA test associated with digital rectal examination which lead to indicate transrectal biopsies. This allowed to treat patients at an earlier stage and significantly improved prognosis in the case of organ confined disease. Progress made in the radical prostatectomy technique have contributed to decrease the postoperative morbidity and is the treatment of reference in clinically localized disease. Radiation therapy still remains a valuable alternative, however, results are more difficult to evaluate. Hormonal treatment using androgen deprivation is indicated at the stage of metastasis. LHRH agonist associated with anti antiandrogens are as much efficacious as surgical castration. Unfortunately, the prognosis of advanced disease remains unpredictable. Objectives for the future will be to improve the diagnostic and staging of prostate cancer et to better define therapeutic indications; better understand the effects of androgen deprivation; and to propose new therapies for hormone refractory cancers.     

A new extra long acting depot preparation of the LHRH analogue Zoladex®. First endocrinological and pharmacokinetic data in patients with advanced prostate cancer

A new depot formulation of the LHRH analogue Zoladex® (goserelin acetate) has been developed which releases the drug over a period of at least 3 months as judged by measurement of drug content in depots at intervals after insertion in male rats and by the suppression of oestrogen secretion and oestrus in female rats. This formulation is based on the lactide/glycolide polymer system used for the standard 1-month Zoladex® depot, but the dose has been increased to 10.8 mg and the characteristics have been modified to enable a longer release of drug to be achieved.

Thirty-eight patients with histologically proven, locally advanced (stage T3 or T4) and/or metastatic prostate cancer were treated with this new longer acting LHRH analogue depot formulation containing 10.8 mg Zoladex®. After initial increase of serum testosterone in the first week of therapy, castration levels were reached in all patients after 4 weeks and this was maintained for more than 14 weeks. At the time of depot exhaustion, when escape from castration levels of androgen occurred, all patients received a single injection of a standard 1-month depot containing 3.6 mg Zoladex® which restored castration levels of androgen thus showing that the pituitary gland was again suppressed. The tolerance and acceptability of the longer-acting depot is high and comparable to the 1-month depot. Taking into account social and psychological factors, patients with advanced prostate carcinoma will soon be able to be treated with a longer acting LHRH depot formulation every 3 months an alternative of the 1-month depot now widely used clinically.