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Prostate Cancer Management: What Does the Future Hold?
EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) 706–714
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Prostate Cancer Management: What Does the Future Hold? Bertrand Tombal * Cliniques Universitaires Saint-Luc, Universite´ Catholique de Louvain, Brussels, Belgium
Article info
Abstract
Keywords: Abiraterone Androgen deprivation Histrelin Osteoporosis Reversibility Sarcopenic obesity Testosterone Vantas
Originally achieved through surgical castration or the administration of oestrogen analogues, androgen-deprivation therapy (ADT) has been the mainstay treatment of advanced prostate cancer (PCa) for >40 yr. In the years following Andrew Schally’s characterisation of the structure of luteinising hormone-releasing hormone (LHRH) in the early 1980s, LHRH agonists have provided PCa patients with an alternative to surgery-based ADT without the notable adverse events (AEs) that may be associated with oestrogen analogues. Furthermore, the development of LHRH analogues has had the added benefit of allowing therapeutic reversibility, which is an important aspect of modern-day ADT. Further benefits that have arisen from the development of LHRH analogues have been an increased understanding of optimal serum testosterone suppression, the development of longer-duration depot formulations that are less likely to induce reinjection testosterone ‘‘flares’’, and the management of the initial treatment flare with LHRH antagonists. Despite these recent advances, the treatment of PCa with LHRH agonists remains suboptimal when compared with surgical castration, and there is still room for therapeutic improvement. Potential mechanisms by which to deliver such therapeutic improvements will require further investigation into intracellular steroidogenesis and androgen pharmacology, pharmacology of LHRH agonists and antagonists, and improving the management of the AEs that are associated with ADT. This article reviews the advances that have been made in improving the recoverability of the hypothalamic–pituitary–testicular axis after cessation of LHRH agonist treatment, the improvements in drug-based intracellular castration in terms of the inhibition of intraprostatic steriodogenesis, the targeting of aberrant testosterone receptor function/levels, and strategies to manage the AEs that are associated with ADT. # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Tel. +32 2 764 5540; Fax: +32 2 764 8919 E-mail address: [email protected]
1.
Introduction
The fact that prostate cancer (PCa) cells die in the absence of androgens was first recognised in the studies of Charles Huggins almost 60 yr ago [1]. This recognition led to androgen-deprivation therapy (ADT) becoming the standard of care for the treatment of advanced PCa for >40 yr. Initially,
ADT was achieved by surgical castration (orchidectomy) or by the use of oestrogen analogues. A significant advance in the pharmacologic management of PCa was made by Andrew Schally and colleagues, who characterised the structure of luteinising hormone-releasing hormone (LHRH) in the early 1980s [2]. They demonstrated that LHRH agonist analogues held promise as potential
1569-9056/$ – see front matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eursup.2010.08.002
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Fig. 1 – Percentage of patients with prostate carcinoma receiving one or more doses of a gonadotropin-releasing hormone (GnRH) agonist or undergoing orchiectomy within the first 6 mo of diagnosis over the time period 1991–1999. Reproduced with permission from Shahinian VB, et al. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 2005;103:1615–24.
therapies for the treatment of patients with androgensensitive PCa as an alternative to surgical castration [3]. In the years following the pivotal observation of Schally et al, the use of surgical castration has decreased and the use of LHRH agonists has increased (Fig. 1) [4]. One explanation is that patients seem to prefer receiving an injection to undergoing a surgical procedure. In 1992, Cassileth et al investigated patient preference regarding surgical castration versus treatment with an LHRH agonist in 147 men with stage D PCa. After receiving extensive information, 115 patients selected treatment with an LHRH agonist and 32 chose orchidectomy. Another explanation for the increase in the use of LHRH agonists is that they have showed reversibility, an important feature of modern ADT. Reversibility allows for the intermittent prescribing of ADT to reduce side-effects and has enabled an increase in short- and long-term adjuvant use, especially in conjunc-
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tion with external-beam radiation therapy (EBRT; Fig. 2) as an important life-extending strategy [4]. Through the years, continued research on LHRH agonists has led to significant improvements in their pharmacology. These improvements include an increased understanding of optimal control of serum testosterone levels [5], the development of longer duration (6–12 mo) depot formulations that are less likely to induce reinjection testosterone flares (ie, miniflares), and, more recently, suppression of the initial testosterone flare with LHRH antagonists. Despite these advances, the treatment of PCa with androgenic agonists remains suboptimal when compared with surgical castration, and there is still room for therapeutic improvement. The many different indications for ADT [6] (Table 1) may require modulating the pharmacology of the LHRH agonist to better fit individual needs. Further investigation into the intracellular biosynthesis,
Fig. 2 – Percentage of patients with prostate carcinoma receiving one or more doses of a gonadotropin-releasing hormone (GnRH) agonist within the first 6 mo of diagnosis without other therapy given (primary use) or receiving one or more doses of a GnRH agonist within 2 mo of radical prostatectomy or radiotherapy performed within 6 mo of diagnosis (adjuvant use) over the period 1991–1999. Reproduced with permission from Shahinian VB, et al. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 2005;103:1615–24.
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Table 1 – Evidence-based indications for androgen-deprivation therapy Adjuvant after radical prostatectomy in cases of positive lymph node status Biochemical failure after therapy with curative intent in patients with a high Gleason score or low PSA DT Concomitant and adjuvant use (6 mo–3 yr) with radiation therapy Locally advanced prostate cancer unfit for radical treatment in cases of high PSA or low PSA DT Metastatic prostate cancer PSA = prostate-specific antigen; PSA DT = prostate-specific antigen doubling time.
biochemistry, and pharmacology of androgens and LHRH agonists and antagonists is needed, along with improvement of the management of the adverse events (AEs) associated with ADT. 2. Improving testosterone recovery for intermittent and adjuvant use of androgen-deprivation therapy A key hurdle in the development of LHRH agonists that better fit the requirements of the emerging indications for hormone therapy is the issue of therapeutic reversibility, in terms of the normalisation of the hypothalamic–pituitary–testicular axis after cessation of LHRH agonist treatment. When a defined period of androgen suppression is required, for adjuvant use in conjunction with EBRT [7] or for intermittent ADT [8,9], the subsequent normalisation of serum testosterone is important. Furthermore, because serum prostatespecific antigen (PSA) expression is highly androgen dependent, the prognostic value of PSA after treatment cessation but before the normalisation of the hypothalamic– pituitary–testicular axis is questionable [10]. With currently available LHRH agonists, the time taken for serum testosterone levels to recover above castrate levels following ADT is highly variable and may extend well beyond the end of treatment. This effect was demonstrated in a study by D’Amico et al [11], who showed that in 102 men who received EBRT and 6 mo of subsequent treatment with an LHRH agonist, the median time to testosterone recovery (TTR) was [(Fig._3)TD$IG]
2.1 yr (interquartile range: 1.6–2.5 yr). Oefelein also demonstrated that after a single 3-mo LHRH agonist injection, the median duration of testosterone suppression to castrate levels (0.2 ng/ml) was 6 mo. He concluded that these observations have important implications for the dosing schedule of LHRH agonists for neoadjuvant use [12]. The TTR mostly depends on the age of the patient and on the duration of ADT [13,14]. Testosterone recovery may be achieved in 73–100% of patients within 6 mo of stopping ADT that lasts for 1 yr, whereas it may be as low as 0–18% at 6 mo in patients who have received ADT for 3 yr [9,10,14,15]. The period of attenuated serum testosterone concentrations in most patients who have received ADT for 3 yr is approximately 18 mo [10,15,16]. For example, in 32 consecutively treated patients with PCa who had received long-term LHRH agonist-based ADT (median duration: 30 mo; range: 24–87 mo), a return to baseline serum testosterone from castrate levels may take up to 2 yr (Fig. 3) [10]. Together with ADT duration, age is an important factor for testosterone recovery, as demonstrated by Bong et al in a series of 15 patients treated with continuous ADT for at least 18 mo (mean duration: 73 mo; range: 48–110 mo). After a mean follow-up period of 31 mo, 78% of patients >70 yr of age remained castrated, compared with 17% of patients 70 yr of age [17]. Taken collectively, these data clearly indicate that the effective duration of ADT far exceeds the duration of LHRH agonist treatment, and this factor must be considered every time a fixed duration of ADT is required. The recent development of a removable implant formulation of histrelin (Vantas) may prove to be a significant advance in the pharmacology and formulation of LHRH agonists. Histrelin’s affinity for the receptor is higher than leuprolide or goserelin, which enables full receptor occupancy at a relatively low dose level, and its release by diffusion from the Vantas implant is steady and controlled [18]. Because of this low dose level and the unique removable implant, Vantas may offer a much more rapid normalisation of the hypothalamic–pituitary–testicular axis. In a study by Fridmans et al [19], it was demonstrated that in patients who had been treated with the histrelin implant (methacrylate
Fig. 3 – Response of testosterone (T) after cessation of luteinising hormone-releasing hormone (LHRH) agonist therapy: (a) box plot analysis; (b) individual responses. Reproduced with permission from Kaku H, et al. Time course of serum testosterone and luteinizing hormone levels after cessation of longterm luteinizing hormone-releasing hormone agonist treatment in patients with prostate cancer. The Prostate 2006;66:439–44. M = month.
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copolymer hydrogel implant; treatment duration range: 29–37 mo), luteinising hormone (LH) levels increased in >50% of patients within 2 wk and in all patients by 6 wk after implant removal. Serum testosterone increased in all these patients within 10 wk of treatment cessation. In the same study, serum hormone level recovery following cessation of treatment with a standard LHRH agonist depot injection (treatment duration range: 17–38 mo) was also investigated. Serum LH and testosterone levels remained fully suppressed for 9 mo in seven of eight patients [19]. 3.
Improving intracellular castration
Unfortunately, improving the optimal control of testosterone is not enough because PCa cells invariably become ‘‘resistant to castration’’ with time [20]. Several mechanisms are involved in the development of castration-resistant PCa (CRPC), including intracrine androgen production, androgen receptor (AR) and AR coactivator upregulation and/or overexpression, mutations in the AR that confer ligand promiscuity, and agonist-independent AR activation [21–28]. With this improved understanding, it has become clear that several unexploited processes within the androgen cascade can be targeted for the treatment of CRPC. 4.
Inhibiting intraprostatic steroidogenesis
Despite optimal suppression of serum testosterone, intratumoural androgen levels may remain elevated, primarily as a result of the overexpression of key enzymes in de novo androgen biosynthesis [26]. These androgens may work as an intratumoural ‘‘reservoir’’ that is sufficient to maintain the androgen dependence of PCa during ADT [29]. A key enzyme in the de novo androgen biosynthesis is 17a-hydroxylase (CYP17; Fig. 4) [30]. Inhibition of CYP17 therefore leads to downstream suppression of testosterone biosynthesis. Abiraterone is a potent inhibitor of CYP17 that has been recently brought into clinical development [30,31]. In an open-label, dose-escalation study [30] in castrated patients (n = 21) with PCa who were chemotherapy naive, escalating doses of abiraterone (200–2000 mg) were administered once daily in 28-d treatment cycles. Abiraterone administration increased adrenocorticotrophic hormone levels upstream of CYP17 and decreased biosynthesis of androgens, including testosterone, downstream of CYP17 in all patients (Fig. 4b). PSA reductions 50% that lasted between 69 and 578 d were observed in >50% of the patients. Radiologic regression, normalisation of lactate dehydrogenase, and improved symptoms, with a reduction in analgesic use, were also documented. Additionally, this study demonstrated that abiraterone is well tolerated, despite the side-effects (eg, hypertension, hypokalaemia, and lower-limb oedema) resulting from an increased production of mineralocorticoids that can be successfully managed with eplerenone. When the study just cited was expanded (54 patients were included) into a phase 2 investigation of abiraterone 1000 mg daily [31], pharmacodynamic effects were maintained. Radiologic evaluation confirmed a partial response in 9 of 24 phase 2 patients
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(37.5%) with measurable disease. PSA declines of 50% and 90% were observed in 28 patients (67%) and 8 patients (19%), respectively. 5.
Targeting the androgen receptor
In addition to de novo nongonadal androgen biosynthesis, aberrant AR levels and function have been cited as a mechanism of treatment resistance in PCa [21–28]. Antiandrogens are therefore frequently used in conjunction with orchidectomy or pharmaceutical ADT to further suppress AR signalling [32]. Antiandrogens have been used broadly to protect the patient against the detrimental effect of the clinical flare resulting from the testosterone surge induced at the first dose of an LHRH agonist or in permanent combination with an LHRH agonist (ie, maximal androgen blockade) to improve the efficacy of medical castration. Despite the sound hypothesis for the use of AR antagonists such as bicalutamide or partial AR agonists such as flutamide, the long-term clinical efficacy of maximal androgen blockade is modest and highly variable [33]. Possible explanations for this include low receptor affinity and partial agonist properties [34]. Taken collectively, these observations highlight the need for significant improvement of these agents in terms of better receptor affinity and AR antagonists. Two agents with such properties that were recently identified and optimised through iterative structure-activity investigations in human PCa cell lines overexpressing AR are the diarylthiohydantoins, RD162 and MDV3100 [34]. In binding competition assays with 16b-[18F]fluoro5a-DHT (FDHT) in CRPC cell lines that overexpress AR, RD162 and MDV3100 had a five- to eight-fold greater affinity for the AR ligand binding domain than bicalutamide and only two- to three-fold less affinity than FDHT [34]. In the battery of studies presented by Tran et al [34], both RD162 and MDV3100 were shown to be full AR antagonists that prevent AR nuclear translocation and DNA binding. To assess the maximum tolerated dose, the clinical efficacy and safety of MDV3100 (60–600 mg/d orally) in humans, a phase 1–2 dose-escalation cohort study was conducted in 140 patients with progressive metastatic CRPC [35]. MDV3100 exhibited antitumour activity at all doses investigated, including decreases in PSA 50% in 78 patients (56%) (Fig. 5), soft tissue response in 13 of 59 patients (22%), stabilised bone disease in 61 of 109 patients (56%), and conversion from unfavourable to favourable circulating tumour cell counts in 25 of 51 patients (49%). The median time to radiologic progression was 47 wk (95% confidence interval [CI] 34: not reached). Treatment was discontinued due to an AE in only 1 of 87 patients receiving MDV3100 at a dose 240 mg/d, whereas the discontinuation rate due to AEs increased to 7 of 53 patients at 360 mg/d. Fatigue was the most common grade 3–4 AE occurring in 16 of 140 patients (240 mg/d, 5 of 29 patients; 360 mg/d, 6 of 28 patients; 480 mg/d, 5 of 22 patients). These results for MDV3100, as an example of a next-generation AR antagonist, hold promise for the future development of agents with true antagonist properties. However, despite these encouraging results, some challenges remain. These include
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Fig. 4 – Physiologic consequences of treatment with abiraterone acetate. (A) Steroid biosynthesis pathway. (B) Abiraterone inhibits 17 a-hydroxylase (crossed out in red), which results in a reduction in serum cortisol and a consequent increase in adrenocorticotropic hormone (ACTH) that drives the steroid biosynthesis pathway. Levels of deoxycorticosterone and corticosterone increase by a median of 10- and 40-fold, respectively. Up to a four-fold increase in 11-deoxycortisol is observed, but there is complete inhibition of C17,20-lyase (crossed out in red) and significant suppression of dehydroepiandrosterone (DHEA), androstenedione, and testosterone. (C) Addition of dexamethasone 0.5 mg/d to abiraterone acetate results in suppression of ACTH to three-fold less than baseline levels, a consequent decrease in deoxycorticosterone levels to less than the limit of sensitivity of the assay used (<5 ng/dl), and a consequent decrease in corticosterone levels by two-fold. Similarly, 11-deoxycortisol levels decrease. Downstream steroid levels remain suppressed. Reprinted with permission. # 2008 American Society of Clinical Oncology. All rights reserved. Attard G, et al. J Clin Oncol 2008;26:4563–71.
elucidating how the efficacy of such agents is affected by disparate AR conditions (eg, AR mutations), how best to combine AR ablative strategies with nonhormonal strategies, and how to develop novel treatment strategies that are synergistic to AR antagonists [20].
6. Coping with the side-effects of androgendeprivation therapy Because testosterone is the principal male hormone, its withdrawal is associated with a series of side-effects
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Fig. 5 – Waterfall plot of percentage change in prostate-specific antigen (PSA) from baseline. (A) Maximum decrease from baseline; (B) decrease at 12 wk from baseline (red lines show patients who discontinued treatment before 12 wk for an adverse event or disease progression); (C) 12-wk decreases by dose. Reprinted from The Lancet, 375(9724), Scher HI, et al, Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study, 1437–46, Copyright (2010), with permission from Elsevier.
[6,36,37]. Until recently, most studies on ADT focused on the ‘‘symptomatic’’ toxicity of testosterone withdrawal, such as hot flushes, loss of libido, emotional instability, or fatigue. Although bothering, these can often be managed with simple recommendations. Recent data, however, suggest that less obvious long-term AEs such as metabolic effects, sarcopenic obesity, and osteoporosis can also arise from LHRH-induced hypogonadism. Epidemiologic data indicate that ADT increases the risk of cardiovascular disease and cardiovascular mortality [38]. Whereas male sex is an acknowledged risk factor for coronary artery disease, there is also evidence to suggest that testosterone has cardioprotective properties in men with and
without PCa [39]. This finding may explain why chronic hypogonadism increases the risk of cardiovascular mortality in patients receiving ADT. This relationship was demonstrated in a retrospective analysis of Medicare claims of >22 000 patients with PCa who did or did not receive ADT (Fig. 6) [39]. When analysed by a univariate model, patients receiving ADT compared with those not receiving ADT had a higher rate of cardiovascular events in the 12 mo before PCa diagnosis (19% vs 15%; p < 0.001) and 12–60 mo after diagnosis (24% vs 18%; p < 0.001). The incidence rate of cardiovascular risk factors (hypertension and diabetes) was higher in patients receiving ADT compared with those not receiving ADT: hypertension, 20% versus 17% ( p < 0.001);
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Fig. 6 – Kaplan-Meier estimate of probability of cardiovascular events over time. Reproduced with permission from Saigal CS, et al. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer 2007;110:1493–500. ADT = androgen-deprivation therapy; NA = not applicable; CL = confidence limits.
diabetes, 7% versus 5% ( p < 0.002) [39]. These data correlate with the findings of other studies showing that ADT-based treatment for PCa compared with non-ADT-based strategies significantly increases ( p 0.03) the rate of the individual components of metabolic syndrome (increased waist circumference, plasma glucose, and triglycerides* [*p = 0.06]) and metabolic syndrome as a whole [40]. These findings may go some way to explaining the observed increase in cardiovascular events in patients receiving ADT for PCa. Another serious complication arising from hypogonadism is a decrease in bone mineral density that leads to a significant increase in the risk of fractures [41]. A primary mechanism for this effect may be that LHRH agonists increase parathyroid hormone–mediated osteoclast activation [42]. This perturbation of bone turnover is associated with high rates of bone loss (2–3% per year of therapy) despite the concomitant administration of supplemental calcium and vitamin D, and the careful exclusion of secondary causes of osteoporosis [43]. The effects of ADT-induced bone mineral density loss have been highlighted in several studies, including three large claims-based studies [44–46]. These studies showed that LHRH agonists increase the relative risk of fracture by 21–45% (lower 95% CI limit range: 1.09–1.36; upper 95% CI limit range: 1.34–1.70). Furthermore, these studies showed that LHRH treatment and LHRH treatment duration were independent risk factors of fractures in men with PCa. Existing strategies for the management of the long-term AEs of ADT have mainly been pharmacologically based [47]. However, these strategies may not always translate into improved physical and functional capacities. Resistance exercise training is a nonpharmacologically based management strategy that improves muscle mass and reduces sarcopenia in elderly adults [48,49]. These observations have been expanded into training programmes for men who are receiving ADT for the treatment of PCa, in the hope of
seeing similar musculoskeletal benefits. In a recent randomised study, patients with PCa receiving ADT were randomised to either a programme of combined resistance and aerobic exercise or standard care for 12 wk [50]. Patients who exercised showed significant benefits in terms of lean mass measures compared with standard-care patients (total body: p = 0.047; upper limb: p < 0.001; lower limb: p = 0.019). Similar benefits were observed with respect to muscle strength ( p < 0.01) and measures of balance (6-metre walk time: p = 0.024; 6-metre backward walk time: p = 0.039). Significant improvements in qualityof-life measures including general health ( p = 0.022) and reduced fatigue ( p = 0.021) were observed in patients randomised to the exercise programme. These results, in conjunction with the findings of other studies [47,51,52], support the use of resistance training as a management strategy for such ADT-related AEs as sarcopenic obesity [47]. 7.
Conclusions
Improvements are still greatly needed in the management of PCa. They may arise from increasing the efficiency of currently available treatment regimens to suit the requirements of new indications for ADT, improving our knowledge of the intracellular effects of ADT, and developing more effective management programmes for the AEs associated with ADT. Conflicts of interest Bertrand Tombal received an honorarium for speaking at the Orion Pharma European Association of Urology symposium. Funding support Orion Pharma supported medical writing services for the preparation and review of this supplement. Medical writing services provided by David Candlish and Andrew Stead (inScience Communications, a Wolters Kluwer business). References [1] Tombal B, Berges R. How good do current LHRH agonists control testosterone? Can this be improved with Eligard1? Eur Urol Suppl 2005;4(8):30–6, Corrigendum. Eur Urol 2006;49:937. [2] Schally AV, Kastin AJ, Arimura A. Hypothalamic follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-regulating hormone: structure, physiology, and clinical studies. Fertil Steril 1971;22: 703–21. [3] Tolis G, Ackman D, Stellos A, et al. Tumor growth inhibition in patients with prostatic carcinoma treated with luteinizing hormone-releasing hormone agonists. Proc Natl Acad Sci U S A 1982;79:1658–62. [4] Shahinian VB, Kuo YF, Freeman JL, Orihuela E, Goodwin JS. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 2005;103:1615–24. [5] Zlotta A, Debruyne FMJ. Expert opinon on optimal testosterone control in prostate cancer. Eur Urol Suppl 2005;4(8):37–41. [6] Isbarn H, Boccon-Gibod L, Carroll PR, et al. Androgen deprivation therapy for the treatment of prostate cancer: consider both benefits and risks. Eur Urol 2009;55:62–75.
EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) 706–714
713
[7] Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients
[26] Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of
with locally advanced prostate cancer treated with radiotherapy
genes converting adrenal androgens to testosterone in androgen-
and goserelin. N Engl J Med 1997;337:295–300. [8] Crook JM, Szumacher E, Malone S, Huan S, Segal R. Intermittent androgen suppression in the management of prostate cancer. Urology 1999;53:530–4. [9] Goldenberg SL, Bruchovsky N, Gleave ME, Sullivan LD, Akakura K. Intermittent androgen suppression in the treatment of prostate cancer: a preliminary report. Urology 1995;45:839–44, discussion 844–5.
independent prostate cancer. Cancer Res 2006;66:2815–25. [27] Yuan X, Balk SP. Mechanisms mediating androgen receptor reactivation after castration. Urol Oncol 2009;27:36–41. [28] Zhu ML, Kyprianou N. Androgen receptor and growth factor signaling cross-talk in prostate cancer cells. Endocr Relat Cancer 2008;15: 841–9. [29] Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004;10:33–9.
[10] Kaku H, Saika T, Tsushima T, et al. Time course of serum testoster-
[30] Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective
one and luteinizing hormone levels after cessation of long-term
inhibitor of CYP17, abiraterone acetate, confirms that castration-
luteinizing hormone-releasing hormone agonist treatment in
resistant prostate cancer commonly remains hormone driven. J Clin
patients with prostate cancer. Prostate 2006;66:439–44.
Oncol 2008;26:4563–71.
[11] D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Interval
[31] Attard G, Reid AH, A’Hern R, et al. Selective inhibition of CYP17 with
to testosterone recovery after hormonal therapy for prostate cancer
abiraterone acetate is highly active in the treatment of castration-
and risk of death. Int J Radiat Oncol Biol Phys 2009;75:10–5. [12] Oefelein MG. Time to normalization of serum testosterone after 3-month luteinizing hormone-releasing hormone agonist administered in the neoadjuvant setting: implications for dosing schedule and neoadjuvant study consideration. J Urol 1998;160:1685–8. [13] Yoon FH, Gardner SL, Danjoux C, Morton G, Cheung P, Choo R.
resistant prostate cancer. J Clin Oncol 2009;27:3742–8. [32] Chen Y, Sawyers CL, Scher HI. Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharmacol 2008;8:440–8. [33] Beekman KW, Hussain M. Hormonal approaches in prostate cancer: application in the contemporary prostate cancer patient. Urol Oncol 2008;26:415–9.
Testosterone recovery after prolonged androgen suppression in
[34] Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation
patients with prostate cancer. J Urol 2008;180:1438–43, discussion
antiandrogen for treatment of advanced prostate cancer. Science
1443–4.
2009;324:787–90.
[14] Nejat RJ, Rashid HH, Bagiella E, Katz AE, Benson MC. A prospective
[35] Scher HI, Beer TM, Higano CS, et al. Antitumour activity of
analysis of time to normalization of serum testosterone after
MDV3100 in castration-resistant prostate cancer: a phase 1-2
withdrawal of androgen deprivation therapy. J Urol 2000;164: 1891–4. [15] Hall MC, Fritzsch RJ, Sagalowsky AI, Ahrens A, Petty B, Roehrborn CG. Prospective determination of the hormonal response after
study. Lancet 2010;375:1437–46. [36] Tombal B. A holistic approach to androgen deprivation therapy: treating the cancer without hurting the patient. Urol Int 2009;83: 373–8.
cessation of luteinizing hormone-releasing hormone agonist treat-
[37] Wong YN, Freedland SJ, Egleston B, Vapiwala N, Uzzo R, Armstrong K.
ment in patients with prostate cancer. Urology 1999;53:898–902,
The role of primary androgen deprivation therapy in localized
discussion 903.
prostate cancer. Eur Urol 2009;56:609–16.
[16] Bolla M, Collette L, Blank L, et al. Long-term results with immediate
[38] Satariano WA, Ragland KE, Van Den Eeden SK. Cause of death
androgen suppression and external irradiation in patients with
in men diagnosed with prostate carcinoma. Cancer 1998;83:
locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002;360:103–6. [17] Bong GW, Clarke Jr HS, Hancock WC, Keane TE. Serum testosterone recovery after cessation of long-term luteinizing hormone-releasing hormone agonist in patients with prostate cancer. Urology 2008;71: 1177–80. [18] Dineen MK, Tierney DS, Kuzma P, Pentikis HS. An evaluation of the pharmacokinetics and pharmacodynamics of the histrelin implant for the palliative treatment of prostate cancer. J Clin Pharmacol 2005;45:1245–9. [19] Fridmans A, Chertin B, Koulikov D, et al. Reversibility of androgen deprivation therapy in patients with prostate cancer. J Urol 2005; 173:784–9. [20] Knudsen KE, Scher HI. Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer. Clin Cancer Res 2009;15:4792–8. [21] Culig Z, Bartsch G. Androgen axis in prostate cancer. J Cell Biochem 2006;99:373–81. [22] Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer 2001;1:34–45. [23] Guo Z, Dai B, Jiang T, et al. Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell 2006;10:309–19.
1180–8. [39] Saigal CS, Gore JL, Krupski TL, Hanley J, Schonlau M, Litwin MS. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer 2007;110:1493–500. [40] Braga-Basaria M, Dobs AS, Muller DC, et al. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol 2006;24:3979–83. [41] Dandona P, Rosenberg MT. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract 2010;64:682–96. [42] Leder BZ, Smith MR, Fallon MA, Lee ML, Finkelstein JS. Effects of gonadal steroid suppression on skeletal sensitivity to parathyroid hormone in men. J Clin Endocrinol Metab 2001;86:511–6. [43] Smith MR, McGovern FJ, Zietman AL, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001;345:948–55. [44] Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005;352: 154–64. [45] Smith MR, Boyce SP, Moyneur E, Duh MS, Raut MK, Brandman J. Risk of clinical fractures after gonadotropin-releasing hormone agonist therapy for prostate cancer. J Urol 2006;175:136–9, discussion 139. [46] Smith MR, Lee WC, Brandman J, Wang Q, Botteman M, Pashos CL.
[24] Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by
Gonadotropin-releasing hormone agonists and fracture risk: a
intratumoral de novo steroidogenesis during progression of cas-
claims-based cohort study of men with nonmetastatic prostate
tration-resistant prostate cancer. Cancer Res 2008;68:6407–15.
cancer. J Clin Oncol 2005;23:7897–903.
[25] Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of
[47] Galvao DA, Nosaka K, Taaffe DR, et al. Resistance training and
intratumoral androgens in metastatic prostate cancer: a mechanism
reduction of treatment side effects in prostate cancer patients.
for castration-resistant tumor growth. Cancer Res 2008;68:4447–54.
Med Sci Sports Exerc 2006;38:2045–52.
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[48] Frontera WR, Meredith CN, O’Reilly KP, Knuttgen HG, Evans WJ. Strength conditioning in older men: skeletal muscle hypertrophy and improved function. J Appl Physiol 1988;64:1038–44. [49] Taaffe DR. Sarcopenia—exercise as a treatment strategy. Aust Fam Physician 2006;35:130–4.
without bone metastases: a randomized controlled trial. J Clin Oncol 2010;28:340–7. [51] Galvao DA, Nosaka K, Taaffe DR, et al. Endocrine and immune responses to resistance training in prostate cancer patients. Prostate Cancer Prostatic Dis 2008;11:160–5.
[50] Galvao DA, Taaffe DR, Spry N, Joseph D, Newton RU. Combined
[52] Segal RJ, Reid RD, Courneya KS, et al. Randomized controlled trial of
resistance and aerobic exercise program reverses muscle loss in
resistance or aerobic exercise in men receiving radiation therapy
men undergoing androgen suppression therapy for prostate cancer
for prostate cancer. J Clin Oncol 2009;27:344–51.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Prostate Cancer Management: What Does the Future Hold? Bertrand Tombal * Cliniques Universitaires Saint-Luc, Universite´ Catholique de Louvain, Brussels, Belgium
Article info
Abstract
Keywords: Abiraterone Androgen deprivation Histrelin Osteoporosis Reversibility Sarcopenic obesity Testosterone Vantas
Originally achieved through surgical castration or the administration of oestrogen analogues, androgen-deprivation therapy (ADT) has been the mainstay treatment of advanced prostate cancer (PCa) for >40 yr. In the years following Andrew Schally’s characterisation of the structure of luteinising hormone-releasing hormone (LHRH) in the early 1980s, LHRH agonists have provided PCa patients with an alternative to surgery-based ADT without the notable adverse events (AEs) that may be associated with oestrogen analogues. Furthermore, the development of LHRH analogues has had the added benefit of allowing therapeutic reversibility, which is an important aspect of modern-day ADT. Further benefits that have arisen from the development of LHRH analogues have been an increased understanding of optimal serum testosterone suppression, the development of longer-duration depot formulations that are less likely to induce reinjection testosterone ‘‘flares’’, and the management of the initial treatment flare with LHRH antagonists. Despite these recent advances, the treatment of PCa with LHRH agonists remains suboptimal when compared with surgical castration, and there is still room for therapeutic improvement. Potential mechanisms by which to deliver such therapeutic improvements will require further investigation into intracellular steroidogenesis and androgen pharmacology, pharmacology of LHRH agonists and antagonists, and improving the management of the AEs that are associated with ADT. This article reviews the advances that have been made in improving the recoverability of the hypothalamic–pituitary–testicular axis after cessation of LHRH agonist treatment, the improvements in drug-based intracellular castration in terms of the inhibition of intraprostatic steriodogenesis, the targeting of aberrant testosterone receptor function/levels, and strategies to manage the AEs that are associated with ADT. # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Tel. +32 2 764 5540; Fax: +32 2 764 8919 E-mail address: [email protected]
1.
Introduction
The fact that prostate cancer (PCa) cells die in the absence of androgens was first recognised in the studies of Charles Huggins almost 60 yr ago [1]. This recognition led to androgen-deprivation therapy (ADT) becoming the standard of care for the treatment of advanced PCa for >40 yr. Initially,
ADT was achieved by surgical castration (orchidectomy) or by the use of oestrogen analogues. A significant advance in the pharmacologic management of PCa was made by Andrew Schally and colleagues, who characterised the structure of luteinising hormone-releasing hormone (LHRH) in the early 1980s [2]. They demonstrated that LHRH agonist analogues held promise as potential
1569-9056/$ – see front matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eursup.2010.08.002
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[(Fig._1)TD$IG]
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Fig. 1 – Percentage of patients with prostate carcinoma receiving one or more doses of a gonadotropin-releasing hormone (GnRH) agonist or undergoing orchiectomy within the first 6 mo of diagnosis over the time period 1991–1999. Reproduced with permission from Shahinian VB, et al. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 2005;103:1615–24.
therapies for the treatment of patients with androgensensitive PCa as an alternative to surgical castration [3]. In the years following the pivotal observation of Schally et al, the use of surgical castration has decreased and the use of LHRH agonists has increased (Fig. 1) [4]. One explanation is that patients seem to prefer receiving an injection to undergoing a surgical procedure. In 1992, Cassileth et al investigated patient preference regarding surgical castration versus treatment with an LHRH agonist in 147 men with stage D PCa. After receiving extensive information, 115 patients selected treatment with an LHRH agonist and 32 chose orchidectomy. Another explanation for the increase in the use of LHRH agonists is that they have showed reversibility, an important feature of modern ADT. Reversibility allows for the intermittent prescribing of ADT to reduce side-effects and has enabled an increase in short- and long-term adjuvant use, especially in conjunc-
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tion with external-beam radiation therapy (EBRT; Fig. 2) as an important life-extending strategy [4]. Through the years, continued research on LHRH agonists has led to significant improvements in their pharmacology. These improvements include an increased understanding of optimal control of serum testosterone levels [5], the development of longer duration (6–12 mo) depot formulations that are less likely to induce reinjection testosterone flares (ie, miniflares), and, more recently, suppression of the initial testosterone flare with LHRH antagonists. Despite these advances, the treatment of PCa with androgenic agonists remains suboptimal when compared with surgical castration, and there is still room for therapeutic improvement. The many different indications for ADT [6] (Table 1) may require modulating the pharmacology of the LHRH agonist to better fit individual needs. Further investigation into the intracellular biosynthesis,
Fig. 2 – Percentage of patients with prostate carcinoma receiving one or more doses of a gonadotropin-releasing hormone (GnRH) agonist within the first 6 mo of diagnosis without other therapy given (primary use) or receiving one or more doses of a GnRH agonist within 2 mo of radical prostatectomy or radiotherapy performed within 6 mo of diagnosis (adjuvant use) over the period 1991–1999. Reproduced with permission from Shahinian VB, et al. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 2005;103:1615–24.
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Table 1 – Evidence-based indications for androgen-deprivation therapy Adjuvant after radical prostatectomy in cases of positive lymph node status Biochemical failure after therapy with curative intent in patients with a high Gleason score or low PSA DT Concomitant and adjuvant use (6 mo–3 yr) with radiation therapy Locally advanced prostate cancer unfit for radical treatment in cases of high PSA or low PSA DT Metastatic prostate cancer PSA = prostate-specific antigen; PSA DT = prostate-specific antigen doubling time.
biochemistry, and pharmacology of androgens and LHRH agonists and antagonists is needed, along with improvement of the management of the adverse events (AEs) associated with ADT. 2. Improving testosterone recovery for intermittent and adjuvant use of androgen-deprivation therapy A key hurdle in the development of LHRH agonists that better fit the requirements of the emerging indications for hormone therapy is the issue of therapeutic reversibility, in terms of the normalisation of the hypothalamic–pituitary–testicular axis after cessation of LHRH agonist treatment. When a defined period of androgen suppression is required, for adjuvant use in conjunction with EBRT [7] or for intermittent ADT [8,9], the subsequent normalisation of serum testosterone is important. Furthermore, because serum prostatespecific antigen (PSA) expression is highly androgen dependent, the prognostic value of PSA after treatment cessation but before the normalisation of the hypothalamic– pituitary–testicular axis is questionable [10]. With currently available LHRH agonists, the time taken for serum testosterone levels to recover above castrate levels following ADT is highly variable and may extend well beyond the end of treatment. This effect was demonstrated in a study by D’Amico et al [11], who showed that in 102 men who received EBRT and 6 mo of subsequent treatment with an LHRH agonist, the median time to testosterone recovery (TTR) was [(Fig._3)TD$IG]
2.1 yr (interquartile range: 1.6–2.5 yr). Oefelein also demonstrated that after a single 3-mo LHRH agonist injection, the median duration of testosterone suppression to castrate levels (0.2 ng/ml) was 6 mo. He concluded that these observations have important implications for the dosing schedule of LHRH agonists for neoadjuvant use [12]. The TTR mostly depends on the age of the patient and on the duration of ADT [13,14]. Testosterone recovery may be achieved in 73–100% of patients within 6 mo of stopping ADT that lasts for 1 yr, whereas it may be as low as 0–18% at 6 mo in patients who have received ADT for 3 yr [9,10,14,15]. The period of attenuated serum testosterone concentrations in most patients who have received ADT for 3 yr is approximately 18 mo [10,15,16]. For example, in 32 consecutively treated patients with PCa who had received long-term LHRH agonist-based ADT (median duration: 30 mo; range: 24–87 mo), a return to baseline serum testosterone from castrate levels may take up to 2 yr (Fig. 3) [10]. Together with ADT duration, age is an important factor for testosterone recovery, as demonstrated by Bong et al in a series of 15 patients treated with continuous ADT for at least 18 mo (mean duration: 73 mo; range: 48–110 mo). After a mean follow-up period of 31 mo, 78% of patients >70 yr of age remained castrated, compared with 17% of patients 70 yr of age [17]. Taken collectively, these data clearly indicate that the effective duration of ADT far exceeds the duration of LHRH agonist treatment, and this factor must be considered every time a fixed duration of ADT is required. The recent development of a removable implant formulation of histrelin (Vantas) may prove to be a significant advance in the pharmacology and formulation of LHRH agonists. Histrelin’s affinity for the receptor is higher than leuprolide or goserelin, which enables full receptor occupancy at a relatively low dose level, and its release by diffusion from the Vantas implant is steady and controlled [18]. Because of this low dose level and the unique removable implant, Vantas may offer a much more rapid normalisation of the hypothalamic–pituitary–testicular axis. In a study by Fridmans et al [19], it was demonstrated that in patients who had been treated with the histrelin implant (methacrylate
Fig. 3 – Response of testosterone (T) after cessation of luteinising hormone-releasing hormone (LHRH) agonist therapy: (a) box plot analysis; (b) individual responses. Reproduced with permission from Kaku H, et al. Time course of serum testosterone and luteinizing hormone levels after cessation of longterm luteinizing hormone-releasing hormone agonist treatment in patients with prostate cancer. The Prostate 2006;66:439–44. M = month.
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copolymer hydrogel implant; treatment duration range: 29–37 mo), luteinising hormone (LH) levels increased in >50% of patients within 2 wk and in all patients by 6 wk after implant removal. Serum testosterone increased in all these patients within 10 wk of treatment cessation. In the same study, serum hormone level recovery following cessation of treatment with a standard LHRH agonist depot injection (treatment duration range: 17–38 mo) was also investigated. Serum LH and testosterone levels remained fully suppressed for 9 mo in seven of eight patients [19]. 3.
Improving intracellular castration
Unfortunately, improving the optimal control of testosterone is not enough because PCa cells invariably become ‘‘resistant to castration’’ with time [20]. Several mechanisms are involved in the development of castration-resistant PCa (CRPC), including intracrine androgen production, androgen receptor (AR) and AR coactivator upregulation and/or overexpression, mutations in the AR that confer ligand promiscuity, and agonist-independent AR activation [21–28]. With this improved understanding, it has become clear that several unexploited processes within the androgen cascade can be targeted for the treatment of CRPC. 4.
Inhibiting intraprostatic steroidogenesis
Despite optimal suppression of serum testosterone, intratumoural androgen levels may remain elevated, primarily as a result of the overexpression of key enzymes in de novo androgen biosynthesis [26]. These androgens may work as an intratumoural ‘‘reservoir’’ that is sufficient to maintain the androgen dependence of PCa during ADT [29]. A key enzyme in the de novo androgen biosynthesis is 17a-hydroxylase (CYP17; Fig. 4) [30]. Inhibition of CYP17 therefore leads to downstream suppression of testosterone biosynthesis. Abiraterone is a potent inhibitor of CYP17 that has been recently brought into clinical development [30,31]. In an open-label, dose-escalation study [30] in castrated patients (n = 21) with PCa who were chemotherapy naive, escalating doses of abiraterone (200–2000 mg) were administered once daily in 28-d treatment cycles. Abiraterone administration increased adrenocorticotrophic hormone levels upstream of CYP17 and decreased biosynthesis of androgens, including testosterone, downstream of CYP17 in all patients (Fig. 4b). PSA reductions 50% that lasted between 69 and 578 d were observed in >50% of the patients. Radiologic regression, normalisation of lactate dehydrogenase, and improved symptoms, with a reduction in analgesic use, were also documented. Additionally, this study demonstrated that abiraterone is well tolerated, despite the side-effects (eg, hypertension, hypokalaemia, and lower-limb oedema) resulting from an increased production of mineralocorticoids that can be successfully managed with eplerenone. When the study just cited was expanded (54 patients were included) into a phase 2 investigation of abiraterone 1000 mg daily [31], pharmacodynamic effects were maintained. Radiologic evaluation confirmed a partial response in 9 of 24 phase 2 patients
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(37.5%) with measurable disease. PSA declines of 50% and 90% were observed in 28 patients (67%) and 8 patients (19%), respectively. 5.
Targeting the androgen receptor
In addition to de novo nongonadal androgen biosynthesis, aberrant AR levels and function have been cited as a mechanism of treatment resistance in PCa [21–28]. Antiandrogens are therefore frequently used in conjunction with orchidectomy or pharmaceutical ADT to further suppress AR signalling [32]. Antiandrogens have been used broadly to protect the patient against the detrimental effect of the clinical flare resulting from the testosterone surge induced at the first dose of an LHRH agonist or in permanent combination with an LHRH agonist (ie, maximal androgen blockade) to improve the efficacy of medical castration. Despite the sound hypothesis for the use of AR antagonists such as bicalutamide or partial AR agonists such as flutamide, the long-term clinical efficacy of maximal androgen blockade is modest and highly variable [33]. Possible explanations for this include low receptor affinity and partial agonist properties [34]. Taken collectively, these observations highlight the need for significant improvement of these agents in terms of better receptor affinity and AR antagonists. Two agents with such properties that were recently identified and optimised through iterative structure-activity investigations in human PCa cell lines overexpressing AR are the diarylthiohydantoins, RD162 and MDV3100 [34]. In binding competition assays with 16b-[18F]fluoro5a-DHT (FDHT) in CRPC cell lines that overexpress AR, RD162 and MDV3100 had a five- to eight-fold greater affinity for the AR ligand binding domain than bicalutamide and only two- to three-fold less affinity than FDHT [34]. In the battery of studies presented by Tran et al [34], both RD162 and MDV3100 were shown to be full AR antagonists that prevent AR nuclear translocation and DNA binding. To assess the maximum tolerated dose, the clinical efficacy and safety of MDV3100 (60–600 mg/d orally) in humans, a phase 1–2 dose-escalation cohort study was conducted in 140 patients with progressive metastatic CRPC [35]. MDV3100 exhibited antitumour activity at all doses investigated, including decreases in PSA 50% in 78 patients (56%) (Fig. 5), soft tissue response in 13 of 59 patients (22%), stabilised bone disease in 61 of 109 patients (56%), and conversion from unfavourable to favourable circulating tumour cell counts in 25 of 51 patients (49%). The median time to radiologic progression was 47 wk (95% confidence interval [CI] 34: not reached). Treatment was discontinued due to an AE in only 1 of 87 patients receiving MDV3100 at a dose 240 mg/d, whereas the discontinuation rate due to AEs increased to 7 of 53 patients at 360 mg/d. Fatigue was the most common grade 3–4 AE occurring in 16 of 140 patients (240 mg/d, 5 of 29 patients; 360 mg/d, 6 of 28 patients; 480 mg/d, 5 of 22 patients). These results for MDV3100, as an example of a next-generation AR antagonist, hold promise for the future development of agents with true antagonist properties. However, despite these encouraging results, some challenges remain. These include
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Fig. 4 – Physiologic consequences of treatment with abiraterone acetate. (A) Steroid biosynthesis pathway. (B) Abiraterone inhibits 17 a-hydroxylase (crossed out in red), which results in a reduction in serum cortisol and a consequent increase in adrenocorticotropic hormone (ACTH) that drives the steroid biosynthesis pathway. Levels of deoxycorticosterone and corticosterone increase by a median of 10- and 40-fold, respectively. Up to a four-fold increase in 11-deoxycortisol is observed, but there is complete inhibition of C17,20-lyase (crossed out in red) and significant suppression of dehydroepiandrosterone (DHEA), androstenedione, and testosterone. (C) Addition of dexamethasone 0.5 mg/d to abiraterone acetate results in suppression of ACTH to three-fold less than baseline levels, a consequent decrease in deoxycorticosterone levels to less than the limit of sensitivity of the assay used (<5 ng/dl), and a consequent decrease in corticosterone levels by two-fold. Similarly, 11-deoxycortisol levels decrease. Downstream steroid levels remain suppressed. Reprinted with permission. # 2008 American Society of Clinical Oncology. All rights reserved. Attard G, et al. J Clin Oncol 2008;26:4563–71.
elucidating how the efficacy of such agents is affected by disparate AR conditions (eg, AR mutations), how best to combine AR ablative strategies with nonhormonal strategies, and how to develop novel treatment strategies that are synergistic to AR antagonists [20].
6. Coping with the side-effects of androgendeprivation therapy Because testosterone is the principal male hormone, its withdrawal is associated with a series of side-effects
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Fig. 5 – Waterfall plot of percentage change in prostate-specific antigen (PSA) from baseline. (A) Maximum decrease from baseline; (B) decrease at 12 wk from baseline (red lines show patients who discontinued treatment before 12 wk for an adverse event or disease progression); (C) 12-wk decreases by dose. Reprinted from The Lancet, 375(9724), Scher HI, et al, Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study, 1437–46, Copyright (2010), with permission from Elsevier.
[6,36,37]. Until recently, most studies on ADT focused on the ‘‘symptomatic’’ toxicity of testosterone withdrawal, such as hot flushes, loss of libido, emotional instability, or fatigue. Although bothering, these can often be managed with simple recommendations. Recent data, however, suggest that less obvious long-term AEs such as metabolic effects, sarcopenic obesity, and osteoporosis can also arise from LHRH-induced hypogonadism. Epidemiologic data indicate that ADT increases the risk of cardiovascular disease and cardiovascular mortality [38]. Whereas male sex is an acknowledged risk factor for coronary artery disease, there is also evidence to suggest that testosterone has cardioprotective properties in men with and
without PCa [39]. This finding may explain why chronic hypogonadism increases the risk of cardiovascular mortality in patients receiving ADT. This relationship was demonstrated in a retrospective analysis of Medicare claims of >22 000 patients with PCa who did or did not receive ADT (Fig. 6) [39]. When analysed by a univariate model, patients receiving ADT compared with those not receiving ADT had a higher rate of cardiovascular events in the 12 mo before PCa diagnosis (19% vs 15%; p < 0.001) and 12–60 mo after diagnosis (24% vs 18%; p < 0.001). The incidence rate of cardiovascular risk factors (hypertension and diabetes) was higher in patients receiving ADT compared with those not receiving ADT: hypertension, 20% versus 17% ( p < 0.001);
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Fig. 6 – Kaplan-Meier estimate of probability of cardiovascular events over time. Reproduced with permission from Saigal CS, et al. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer 2007;110:1493–500. ADT = androgen-deprivation therapy; NA = not applicable; CL = confidence limits.
diabetes, 7% versus 5% ( p < 0.002) [39]. These data correlate with the findings of other studies showing that ADT-based treatment for PCa compared with non-ADT-based strategies significantly increases ( p 0.03) the rate of the individual components of metabolic syndrome (increased waist circumference, plasma glucose, and triglycerides* [*p = 0.06]) and metabolic syndrome as a whole [40]. These findings may go some way to explaining the observed increase in cardiovascular events in patients receiving ADT for PCa. Another serious complication arising from hypogonadism is a decrease in bone mineral density that leads to a significant increase in the risk of fractures [41]. A primary mechanism for this effect may be that LHRH agonists increase parathyroid hormone–mediated osteoclast activation [42]. This perturbation of bone turnover is associated with high rates of bone loss (2–3% per year of therapy) despite the concomitant administration of supplemental calcium and vitamin D, and the careful exclusion of secondary causes of osteoporosis [43]. The effects of ADT-induced bone mineral density loss have been highlighted in several studies, including three large claims-based studies [44–46]. These studies showed that LHRH agonists increase the relative risk of fracture by 21–45% (lower 95% CI limit range: 1.09–1.36; upper 95% CI limit range: 1.34–1.70). Furthermore, these studies showed that LHRH treatment and LHRH treatment duration were independent risk factors of fractures in men with PCa. Existing strategies for the management of the long-term AEs of ADT have mainly been pharmacologically based [47]. However, these strategies may not always translate into improved physical and functional capacities. Resistance exercise training is a nonpharmacologically based management strategy that improves muscle mass and reduces sarcopenia in elderly adults [48,49]. These observations have been expanded into training programmes for men who are receiving ADT for the treatment of PCa, in the hope of
seeing similar musculoskeletal benefits. In a recent randomised study, patients with PCa receiving ADT were randomised to either a programme of combined resistance and aerobic exercise or standard care for 12 wk [50]. Patients who exercised showed significant benefits in terms of lean mass measures compared with standard-care patients (total body: p = 0.047; upper limb: p < 0.001; lower limb: p = 0.019). Similar benefits were observed with respect to muscle strength ( p < 0.01) and measures of balance (6-metre walk time: p = 0.024; 6-metre backward walk time: p = 0.039). Significant improvements in qualityof-life measures including general health ( p = 0.022) and reduced fatigue ( p = 0.021) were observed in patients randomised to the exercise programme. These results, in conjunction with the findings of other studies [47,51,52], support the use of resistance training as a management strategy for such ADT-related AEs as sarcopenic obesity [47]. 7.
Conclusions
Improvements are still greatly needed in the management of PCa. They may arise from increasing the efficiency of currently available treatment regimens to suit the requirements of new indications for ADT, improving our knowledge of the intracellular effects of ADT, and developing more effective management programmes for the AEs associated with ADT. Conflicts of interest Bertrand Tombal received an honorarium for speaking at the Orion Pharma European Association of Urology symposium. Funding support Orion Pharma supported medical writing services for the preparation and review of this supplement. Medical writing services provided by David Candlish and Andrew Stead (inScience Communications, a Wolters Kluwer business). References [1] Tombal B, Berges R. How good do current LHRH agonists control testosterone? Can this be improved with Eligard1? Eur Urol Suppl 2005;4(8):30–6, Corrigendum. Eur Urol 2006;49:937. [2] Schally AV, Kastin AJ, Arimura A. Hypothalamic follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-regulating hormone: structure, physiology, and clinical studies. Fertil Steril 1971;22: 703–21. [3] Tolis G, Ackman D, Stellos A, et al. Tumor growth inhibition in patients with prostatic carcinoma treated with luteinizing hormone-releasing hormone agonists. Proc Natl Acad Sci U S A 1982;79:1658–62. [4] Shahinian VB, Kuo YF, Freeman JL, Orihuela E, Goodwin JS. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 2005;103:1615–24. [5] Zlotta A, Debruyne FMJ. Expert opinon on optimal testosterone control in prostate cancer. Eur Urol Suppl 2005;4(8):37–41. [6] Isbarn H, Boccon-Gibod L, Carroll PR, et al. Androgen deprivation therapy for the treatment of prostate cancer: consider both benefits and risks. Eur Urol 2009;55:62–75.
EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) 706–714
713
[7] Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients
[26] Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of
with locally advanced prostate cancer treated with radiotherapy
genes converting adrenal androgens to testosterone in androgen-
and goserelin. N Engl J Med 1997;337:295–300. [8] Crook JM, Szumacher E, Malone S, Huan S, Segal R. Intermittent androgen suppression in the management of prostate cancer. Urology 1999;53:530–4. [9] Goldenberg SL, Bruchovsky N, Gleave ME, Sullivan LD, Akakura K. Intermittent androgen suppression in the treatment of prostate cancer: a preliminary report. Urology 1995;45:839–44, discussion 844–5.
independent prostate cancer. Cancer Res 2006;66:2815–25. [27] Yuan X, Balk SP. Mechanisms mediating androgen receptor reactivation after castration. Urol Oncol 2009;27:36–41. [28] Zhu ML, Kyprianou N. Androgen receptor and growth factor signaling cross-talk in prostate cancer cells. Endocr Relat Cancer 2008;15: 841–9. [29] Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004;10:33–9.
[10] Kaku H, Saika T, Tsushima T, et al. Time course of serum testoster-
[30] Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective
one and luteinizing hormone levels after cessation of long-term
inhibitor of CYP17, abiraterone acetate, confirms that castration-
luteinizing hormone-releasing hormone agonist treatment in
resistant prostate cancer commonly remains hormone driven. J Clin
patients with prostate cancer. Prostate 2006;66:439–44.
Oncol 2008;26:4563–71.
[11] D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Interval
[31] Attard G, Reid AH, A’Hern R, et al. Selective inhibition of CYP17 with
to testosterone recovery after hormonal therapy for prostate cancer
abiraterone acetate is highly active in the treatment of castration-
and risk of death. Int J Radiat Oncol Biol Phys 2009;75:10–5. [12] Oefelein MG. Time to normalization of serum testosterone after 3-month luteinizing hormone-releasing hormone agonist administered in the neoadjuvant setting: implications for dosing schedule and neoadjuvant study consideration. J Urol 1998;160:1685–8. [13] Yoon FH, Gardner SL, Danjoux C, Morton G, Cheung P, Choo R.
resistant prostate cancer. J Clin Oncol 2009;27:3742–8. [32] Chen Y, Sawyers CL, Scher HI. Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharmacol 2008;8:440–8. [33] Beekman KW, Hussain M. Hormonal approaches in prostate cancer: application in the contemporary prostate cancer patient. Urol Oncol 2008;26:415–9.
Testosterone recovery after prolonged androgen suppression in
[34] Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation
patients with prostate cancer. J Urol 2008;180:1438–43, discussion
antiandrogen for treatment of advanced prostate cancer. Science
1443–4.
2009;324:787–90.
[14] Nejat RJ, Rashid HH, Bagiella E, Katz AE, Benson MC. A prospective
[35] Scher HI, Beer TM, Higano CS, et al. Antitumour activity of
analysis of time to normalization of serum testosterone after
MDV3100 in castration-resistant prostate cancer: a phase 1-2
withdrawal of androgen deprivation therapy. J Urol 2000;164: 1891–4. [15] Hall MC, Fritzsch RJ, Sagalowsky AI, Ahrens A, Petty B, Roehrborn CG. Prospective determination of the hormonal response after
study. Lancet 2010;375:1437–46. [36] Tombal B. A holistic approach to androgen deprivation therapy: treating the cancer without hurting the patient. Urol Int 2009;83: 373–8.
cessation of luteinizing hormone-releasing hormone agonist treat-
[37] Wong YN, Freedland SJ, Egleston B, Vapiwala N, Uzzo R, Armstrong K.
ment in patients with prostate cancer. Urology 1999;53:898–902,
The role of primary androgen deprivation therapy in localized
discussion 903.
prostate cancer. Eur Urol 2009;56:609–16.
[16] Bolla M, Collette L, Blank L, et al. Long-term results with immediate
[38] Satariano WA, Ragland KE, Van Den Eeden SK. Cause of death
androgen suppression and external irradiation in patients with
in men diagnosed with prostate carcinoma. Cancer 1998;83:
locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002;360:103–6. [17] Bong GW, Clarke Jr HS, Hancock WC, Keane TE. Serum testosterone recovery after cessation of long-term luteinizing hormone-releasing hormone agonist in patients with prostate cancer. Urology 2008;71: 1177–80. [18] Dineen MK, Tierney DS, Kuzma P, Pentikis HS. An evaluation of the pharmacokinetics and pharmacodynamics of the histrelin implant for the palliative treatment of prostate cancer. J Clin Pharmacol 2005;45:1245–9. [19] Fridmans A, Chertin B, Koulikov D, et al. Reversibility of androgen deprivation therapy in patients with prostate cancer. J Urol 2005; 173:784–9. [20] Knudsen KE, Scher HI. Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer. Clin Cancer Res 2009;15:4792–8. [21] Culig Z, Bartsch G. Androgen axis in prostate cancer. J Cell Biochem 2006;99:373–81. [22] Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer 2001;1:34–45. [23] Guo Z, Dai B, Jiang T, et al. Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell 2006;10:309–19.
1180–8. [39] Saigal CS, Gore JL, Krupski TL, Hanley J, Schonlau M, Litwin MS. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer 2007;110:1493–500. [40] Braga-Basaria M, Dobs AS, Muller DC, et al. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol 2006;24:3979–83. [41] Dandona P, Rosenberg MT. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract 2010;64:682–96. [42] Leder BZ, Smith MR, Fallon MA, Lee ML, Finkelstein JS. Effects of gonadal steroid suppression on skeletal sensitivity to parathyroid hormone in men. J Clin Endocrinol Metab 2001;86:511–6. [43] Smith MR, McGovern FJ, Zietman AL, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001;345:948–55. [44] Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005;352: 154–64. [45] Smith MR, Boyce SP, Moyneur E, Duh MS, Raut MK, Brandman J. Risk of clinical fractures after gonadotropin-releasing hormone agonist therapy for prostate cancer. J Urol 2006;175:136–9, discussion 139. [46] Smith MR, Lee WC, Brandman J, Wang Q, Botteman M, Pashos CL.
[24] Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by
Gonadotropin-releasing hormone agonists and fracture risk: a
intratumoral de novo steroidogenesis during progression of cas-
claims-based cohort study of men with nonmetastatic prostate
tration-resistant prostate cancer. Cancer Res 2008;68:6407–15.
cancer. J Clin Oncol 2005;23:7897–903.
[25] Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of
[47] Galvao DA, Nosaka K, Taaffe DR, et al. Resistance training and
intratumoral androgens in metastatic prostate cancer: a mechanism
reduction of treatment side effects in prostate cancer patients.
for castration-resistant tumor growth. Cancer Res 2008;68:4447–54.
Med Sci Sports Exerc 2006;38:2045–52.
714
EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) 706–714
[48] Frontera WR, Meredith CN, O’Reilly KP, Knuttgen HG, Evans WJ. Strength conditioning in older men: skeletal muscle hypertrophy and improved function. J Appl Physiol 1988;64:1038–44. [49] Taaffe DR. Sarcopenia—exercise as a treatment strategy. Aust Fam Physician 2006;35:130–4.
without bone metastases: a randomized controlled trial. J Clin Oncol 2010;28:340–7. [51] Galvao DA, Nosaka K, Taaffe DR, et al. Endocrine and immune responses to resistance training in prostate cancer patients. Prostate Cancer Prostatic Dis 2008;11:160–5.
[50] Galvao DA, Taaffe DR, Spry N, Joseph D, Newton RU. Combined
[52] Segal RJ, Reid RD, Courneya KS, et al. Randomized controlled trial of
resistance and aerobic exercise program reverses muscle loss in
resistance or aerobic exercise in men receiving radiation therapy
men undergoing androgen suppression therapy for prostate cancer
for prostate cancer. J Clin Oncol 2009;27:344–51.