Androgen deprivation therapy: past, present and future

© 2 0 1 2 T H E A U T H O R S

B J U I N T E R N A T I O N A L © 2 0 1 2 B J U I N T E R N A T I O N A L | 1 0 9 , S U P P L E M E N T 6 , 1 – 1 2 1

Since Huggins and Hodges demonstrated the responsiveness of prostate cancer to androgen deprivation therapy (ADT), androgen-suppressing strategies have formed the cornerstone of management of advanced prostate cancer. Approaches to ADT have included orchidectomy, oestrogens, luteinizing hormone-releasing hormone (LHRH) agonists, anti-androgens and more recently the gonadotrophin-releasing hormone antagonists. The most extensively studied antagonist, degarelix, avoids the testosterone surge and clinical fl are associated with LHRH agonists,

offering more rapid PSA and testosterone suppression, improved testosterone control and improved PSA progression-free survival compared with agonists. The clinical profi le of degarelix appears to make it a particularly suitable therapeutic option for certain subgroups of patients, including those with metastatic disease, high baseline PSA ( > 20 ng/mL) and highly symptomatic disease. As well as forming the mainstay of treatment for advanced prostate cancer, ADT is increasingly used in earlier disease stages. While data from clinical trials support the use of ADT

neoadjuvant/adjuvant to radiotherapy for locally advanced or high-risk localized prostate cancer, it remains to be established whether specifi c ADT classes/agents provide particular benefi ts in this clinical setting.

KEYWORDS

androgen deprivation therapy , prostate cancer , neoadjuvant hormonal therapy , adjuvant hormonal therapy , GnRH antagonists

Androgen deprivation therapy: past, present and future F. Schr ö der * , E.D. Crawford † , K. Axcrona ‡ , H. Payne § and T.E. Keane ¶ * Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands , † University of Colorado Cancer Center, Aurora, CO, USA , ‡ Department of Urology, Norwegian Radium Hospital, Oslo, Norway , § Department of Clinical Oncology, University College Hospital, London, UK , and ¶ Department of Urology, Medical University of South Carolina, Charleston, SC, USA

THE EVOLUTION OF ADT

In 1941, Huggins et al . demonstrated the favourable impact of androgen deprivation therapy (ADT) via orchidectomy or oestrogens on metastatic prostate cancer (PCa) [ 1,2 ] . Following that discovery, orchidectomy became the gold standard for ADT in advanced PCa [ 3 ] ( Table 1 ). Oestrogens (most commonly diethylstilboestrol) were used as a medical alternative to surgical castration until the late 1960s and 1970s [ 17 ] . However, while oestrogens provided effective testosterone suppression, their use has been limited due to an increased risk of cardiovascular adverse events. Indeed, studies by the Veterans Administration Cooperative Urological Research Group showed an increased risk of cardiovascular mortality with diethylstilboestrol 5 mg [ 4,18 ] .

In the late 1960s and early 1970s, researchers also investigated anti-androgenic compounds. Anti-androgens compete with androgens for binding sites on androgen receptors in the prostate cell

nucleus, promoting apoptosis and inhibiting the growth of PCa [ 8 ] . Over the years, investigators have examined the possible use of these agents as an alternative to castration in advanced PCa. Evidence from a meta-analysis using data from eight trials involving 2717 patients suggested that non-steroidal anti-androgen monotherapy was associated with lower overall survival (OS) than orchidectomy [ 6 ] . Bicalutamide is the most extensively studied non-steroidal anti-androgen. Survival analyses of two large prospective randomized trials including a total of 1435 patients showed that anti-androgen monotherapy with bicalutamide was less effective than castration in patients with M1 disease [ 19 ] but in locally advanced M0 patients ( n = 480) no signifi cant difference in OS was noted [ 5 ] . Thus, European Association of Urology (EAU) guidelines consider non-steroidal anti-androgen monotherapy (eg bicalutamide) as an alternative to castration in patients with locally advanced disease [ 3 ] . Common side effects with non-steroidal agents include gynaecomastia and breast pain. Steroidal anti-androgens are associated

with loss of libido and erectile dysfunction, as well as cardiovascular toxicity and hepatotoxicity [ 8 ] . Questions persist on the benefi t of using anti-androgens in combination with other forms of ADT. In a meta-analysis of 27 randomized trials including 8275 patients with metastatic or locally advanced PCa, adding an anti-androgen to androgen suppression improved 5-year OS by only 2% [ 20 ] .

LHRH agonists offer another reversible alternative to surgical castration and in the 1980s began to supersede oestrogens and orchidectomy [ 21 ] to become the mainstay of ADT for advanced PCa [ 3 ] . In a meta-analysis of data from 10 trials ( n = 1908), OS with LHRH agonists was found to be equivalent to orchidectomy or diethylstilboestrol in advanced disease [ 6 ] . Moreover, ADT with LHRH agonists is now also having an increasingly important role in earlier stages of PCa. In patients with high metastatic risk, immediate androgen suppression with an LHRH agonist given during and for 3 years after external radiotherapy (RT) has been shown to

S C H R Ö D E R E T A L .

© 2 0 1 2 T H E A U T H O R S

2 B J U I N T E R N A T I O N A L © 2 0 1 2 B J U I N T E R N A T I O N A L

improve 10-year disease-free survival (DFS) and OS [ 22 ] . Thus, in patients with locally advanced or high-risk localized disease, the addition of neoadjuvant and adjuvant ADT is now considered the standard of care for men treated with radical RT [ 16 ] . However, LHRH agonist therapy is associated with several drawbacks. The initial stimulation of LHRH receptors causes a testosterone surge, delaying the achievement of castrate testosterone levels for around 2 – 4 weeks. The surge may also be associated with clinical fl are effects in advanced disease (eg bone pain, spinal cord compression, ureteral obstruction and possibly death) [ 23,24 ] . Furthermore, some patients fail to achieve castration levels of testosterone. Tombal and Berges [ 12 ] reported that up to 12% of patients do not reach a testosterone level < 50 ng/dL and up to 37% fail to achieve

levels < 20 ng/dL. Also, breakthrough testosterone increases of > 50 ng/dL have been reported to occur in around 2 – 25% of patients after long-term hormone therapy [ 25,26 ] . Breakthrough increases of 20 – 50 ng/dL were reported in 32% of patients receiving an LHRH agonist (with or without an anti-androgen) [ 27 ] . Importantly, time to progression to androgen-independent disease was signifi cantly shorter in those with testosterone breakthrough increases > 32 ng/dL compared with those without breakthrough [ 26 ] .

RECENT THERAPEUTIC ADVANCES: GNRH ANTAGONISTS

The fl are phenomenon associated with LHRH agonists helped to drive the search for alternative agents. Consequently, the new

millennium saw the development of GnRH antagonists. These agents bind directly to and block GnRH receptors, without causing the initial testosterone surge and fl are associated with agonists [ 13 ] .

ABARELIX

Phase III data showed that abarelix, the fi rst GnRH antagonist approved for use in PCa, was as effective in achieving castration as GnRH agonists with or without anti-androgens and was not associated with a testosterone surge [ 28 – 30 ] . For example, in a European phase III trial, 99% of patients receiving abarelix and 100% of those receiving goserelin/bicalutamide had achieved castration levels of testosterone by day 84 [ 30 ] . However, with regard to long-term effi cacy, data from the abarelix

TABLE 1 Summary of the relative advantages and disadvantages of ADT classes [ 3 – 16 ]

Treatment Advantages DisadvantagesOrchidectomy • Still considered the gold standard for ADT • Negative psychological effect

• Fast and pronounced testosterone control • Irreversible • Simple surgical procedure • Can be performed using local anaesthetic

• Broad spectrum of side effects (vasomotor, sexual, metabolic, physical, cognitive, bone loss)

• No problems with compliance • Surgical complications possible

Oestrogens • Effective testosterone suppression • Overall survival comparable with orchidectomy

• Increased risk of cardiovascular effects and mortality with oral use (particularly with diethylstilboestrol 5 mg)

• Oral or parenteral application • Not recommended by European Association of Urology as fi rst-line treatment

Anti-androgens • Non-steroidal anti-androgen monotherapy can be used in locally advanced prostate cancer as an alternative to castration

• Overall survival with non-steroidal anti-androgens may be lower than with orchidectomy

• May preserve libido, physical performance and bone mineral density (leading to improved quality of life/compliance)

• May be less effective in high tumour burden (metastatic disease)

• Used with other ADTs for complete androgen blockade (reduces risk of LHRH agonist ‘ fl are ’ )

• Steroidal anti-androgens associated with hepatotoxicity, cardiovascular toxicity, loss of libido, impotence

• Reversible • Non-steroidal anti-androgens associated with hepatotoxicity, gynaecomastia, breast pain, hot fl ushes • Oral application

LHRH agonists • Overall survival appears to be similar as for orchidectomy • Side effects comparable with surgical castration • Standard of care for advanced prostate cancer/high-risk

localized disease ( + radiotherapy): associated with improved survival in combination with radiotherapy

• Initial testosterone surge delays therapeutic benefi t and may lead to clinical symptoms (clinical fl are)

• Potential tumour-promoting effects of increased testosterone • Reversible

GnRH antagonists

• Reversible • Hormonal side-effect profi le comparable with LHRH agonists • Direct and logical mechanism of action • Higher incidence of injection-site reactions than leuprolide a • Fast, profound and sustained testosterone and PSA suppression • No 3-month formulation • Prolong PSA progression-free survival a • The antagonist abarelix has been associated with the risk of

systemic allergic reactions; no systemic anaphylactic reactions were observed during the clinical development of degarelix in patients with prostate cancer

• Effi cacy and safety maintained in long-term ( > 3 years) a • No initial testosterone surge or subsequent microsurges • Benefi cial effects on bone markers (serum alkaline phosphatase) a

a Reported for degarelix only.

A N D R O G E N D E P R I V A T I O N T H E R A P Y : P A S T , P R E S E N T A N D F U T U R E

© 2 0 1 2 T H E A U T H O R S

B J U I N T E R N A T I O N A L © 2 0 1 2 B J U I N T E R N A T I O N A L 3

package insert, based on two randomized trials, warned that in some patients effectiveness of testosterone suppression diminishes with continued dosing and that effectiveness beyond 12 months had not been established [ 31 ] . Moreover, after 24 weeks, waning of castration rates appeared to occur more frequently with abarelix than with active controls [ 32 ] . Furthermore, escape from castration was found to occur more frequently with abarelix (22%) than with the comparator agonist/anti-androgen (8%) in the phase III European trial, and also time to escape was signifi cantly shorter with abarelix [ 33 ] .The clinical use of abarelix was also limited by a risk of immediate-onset histamine-mediated hypersensitivity reactions and in 2005 abarelix was voluntarily withdrawn from the US market [ 34 ] .

DEGARELIX

The third-generation GnRH antagonist degarelix is currently the most extensively studied and widely available antagonist approved for the treatment of advanced PCa. Degarelix has been the subject of a comprehensive and on-going clinical development programme, including comparative studies with the GnRH agonist leuprolide.

Effi cacy

In a large pivotal, 1-year, randomized, open-label study involving 610 patients with PCa (CS21), degarelix was as effective as leuprolide in suppressing testosterone to

castrate levels [ 11 ] . However, unlike leuprolide, there was no initial testosterone surge or subsequent microsurges with degarelix. Moreover, the reduction in testosterone and PSA levels was signifi cantly faster with degarelix. Some studies have shown that faster PSA reduction may be associated with longer time to progression to hormone-refractory disease and improved OS [ 14,35 ] . In addition, PSA progression-free survival (PFS), which is indicative of time to castration-resistant disease [ 15 ] , was signifi cantly longer for degarelix vs leuprolide ( P = 0.05) ( Figure 1 ) [ 36 ] . Delaying progression to castrate-resistant disease is clearly desirable as it also delays the initiation of second-line therapies. As well as PSA, degarelix has also shown benefi cial effects on bone markers. Thus, in patients with metastatic PCa or with baseline PSA levels ≥ 50 ng/mL, reductions in serum alkaline phosphatase (S-ALP; a marker of bone formation) were shown to be signifi cantly greater for degarelix than leuprolide [ 37 ] .

Long-term effi cacy

Long-term treatment with degarelix is being evaluated in a 5-year extension trial (CS21A). Patients who completed the pivotal 1-year trial (CS21), either continued on degarelix at the same monthly dose or crossed over from leuprolide to degarelix. An interim analysis, with a median follow-up of 27.5 months, showed that the effi cacy of degarelix was maintained in the long term [ 15 ] . Thus, PSA PFS hazard rates for those

continuing to receive degarelix 240/80 mg in CS21A were similar (0.14 events/year) to those in the fi rst year in the pivotal trial (0.11 events/year; P = 0.464). For patients who crossed from leuprolide to degarelix, PSA PFS hazard rates improved signifi cantly, from 0.20 to 0.08 events/year ( P = 0.003). The extension trial also showed that effective suppression of testosterone and PSA was maintained for > 3 years in patients continuing to receive degarelix 240/80 mg and in those who crossed over from leuprolide to degarelix. During the fi rst year in CS21, luteinizing hormone (LH) was suppressed at low levels in degarelix and leuprolide groups and this level of suppression was maintained in both groups during the fi rst 3 months of CS21A. Follicle-stimulating hormone (FSH) suppression was greater with degarelix vs leuprolide in the fi rst year during CS21. However, in the fi rst 3 months of CS21A, while FSH suppression was maintained with continuing degarelix, further suppression was noted in the group crossing over from leuprolide to degarelix [ 15 ] .

Safety

The overall incidence of adverse events was similar for degarelix and leuprolide in the pivotal CS21 comparative study [ 11 ] . Although patients receiving degarelix experienced a higher incidence of injection-site reactions and chills compared with leuprolide, they experienced a lower incidence of urinary tract infection and musculoskeletal and connective tissue events. No immediate-onset systemic allergic reactions were reported with degarelix. In the long-term extension trial, the overall incidence of adverse events was similar in those who received continuous degarelix and those crossing over from leuprolide after 1 year, and decreased throughout the 4 years of follow-up in both treatment groups [ 15 ] . At year 4, the incidence of individual adverse events was low, with no major between-group differences. Crossing over from leuprolide to degarelix was associated with more injection-site reactions in year 2. However, in patients who crossed from leuprolide to degarelix, the incidence of these effects decreased in years 3 and 4 to reach levels similar to those of patients who had received continuous degarelix. Patients who crossed from leuprolide to degarelix experienced an improved musculoskeletal

FIG. 1. PSA progression-free survival probability – ie probability of freedom from PSA recurrence or death. Reprinted from Tombal B, Miller K, Boccon-Gibod L et al . Additional analysis of the secondary end point of biochemical recurrence rate in a Phase 3 trial (CS21) comparing degarelix 80 mg vs leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol 2010;57:836 – 842 [ 36 ] with permission from Elsevier.

100

90

80

70

60

50

40

Degarelix 240/80 mgP = 0.05

(log-rank)

Leuprolide 7.5 mg

Prob

abili

ty, %

30

20

10

00

Number at riskDegarelix 207 206 201 197 193 189 187 185 181 175 169 165 161 156Leuprolide 201 197 194 192 190 188 182 179 174 172 167 162 156 150

28 56 84 112 140 168 196

Time, days

224 252 280 308 336 364


© 2 0 1 2 T H E A U T H O R S


adverse event rate after crossover, becoming similar to that in patients continuing on degarelix.

Degarelix received European regulatory approval in 2009 for advanced hormone-dependent PCa, based on robust effi cacy and tolerability data from clinical studies where it displayed fast, profound and sustained testosterone suppression without the systemic allergic reactions associated with abarelix [ 38 ] . GnRH antagonists now offer an established alternative to LHRH agonists for ADT in PCa.

PATIENTS LIKELY TO BENEFIT FROM THE PHARMACOLOGICAL PROFILE OF GNRH ANTAGONISTS

In certain subgroups of patients (eg those with later-stage disease), treatment differences between GnRH antagonists and agonists are more evident as event rates are likely to be higher over shorter time periods. Thus, data in CS21 and CS21A trials were analysed for possible treatment differences in patient subgroups with more advanced disease [ 15,36,37 ] .

PATIENTS WITH METASTATIC DISEASE

Analysis of this subgroup revealed differences in PSA profi les for degarelix 240/80 mg and leuprolide. As well as fewer PSA failures with degarelix vs leuprolide in patients with metastatic disease during the CS21 trial, there was also an initial PSA increase in leuprolide patients which did not occur with degarelix 240/80 mg [ 36 ] . In addition, the proportion of patients achieving PSA < 4 ng/mL over the study period was higher with degarelix 240/80 mg than with leuprolide. Patients with metastatic disease also revealed differences in effects on bone markers. Elevated S-ALP and bone-specifi c ALP have been associated with progression of skeletal metastases in PCa [ 39,40 ] and may be signifi cant predictors of early death [ 41 – 44 ] . In CS21, all patients with metastatic disease had high baseline S-ALP levels, refl ecting the presence of skeletal metastases. However, patients receiving degarelix experienced a faster and more profound control of S-ALP than those receiving leuprolide. Furthermore, patients receiving degarelix maintained S-ALP suppression throughout the study, without the late increases in S-ALP (which might suggest therapy failure) noted with

leuprolide. Thus, degarelix appears to offer prolonged control of skeletal metastases compared with GnRH agonists [ 37 ] .

PATIENTS WITH BASELINE PSA > 20 ng/mL

Patients with baseline PSA > 20 ng/mL are at highest risk of PSA failure and in the 1-year degarelix trial (CS21), PSA failure occurred exclusively in this patient subgroup [ 36 ] . Moreover, in this subgroup, those receiving degarelix had a signifi cantly longer time to PSA failure compared with those receiving leuprolide ( P = 0.04; log-rank). In the extension study, a signifi cant improvement in PSA PFS was observed after crossover from leuprolide to degarelix in patients with baseline PSA > 20 ng/mL [ 15 ] . Thus, the PSA PFS hazard rate decreased signifi cantly from 0.38 events annually in year 1 to 0.19 events annually after crossover in patients on leuprolide (chi-square test; P = 0.031). The corresponding hazard rates for degarelix were 0.23 during the fi rst year and 0.23 events annually in subsequent years ( P = 0.988). In addition, the time for 25% of patients to experience PSA failure or death, was signifi cantly longer (514 days) for degarelix vs leuprolide (303 days, P = 0.01; using data for degarelix beyond 1 year from CS21A) [ 38 ] ( Figure 2 ).

PATIENTS WITH HIGHLY SYMPTOMATIC DISEASE

Studies are on-going to evaluate the effect of degarelix in patients requiring fast

symptom relief or prostate volume reduction. For example, the effect of degarelix 240/80 mg on reduction of total prostate volume, relief of lower urinary tract symptoms (LUTS) and improvement of quality of life was compared with goserelin/bicalutamide in a 3-month trial in 182 men with a total prostate volume > 30 mL (CS31 [ 45 ] ). After 3 months of treatment, reduction in total prostate volume for degarelix ( − 37.2%) and goserelin/bicalutamide ( − 39.0%) was comparable and fulfi lled the predefi ned criterion for non-inferiority. The reduction in International Prostate Symptom Score (IPSS) was greater with degarelix than with goserelin/bicalutamide, and differences between treatments reached statistical signifi cance in patients with baseline IPSS ≥ 13 (moderate/severe LUTS) ( − 6.7 vs − 4.0; P = 0.02). When examining an individual patient ’ s benefi t, the proportion of patients achieving clinically meaningful LUTS relief (ie IPSS decrease of ≥ 3 points from baseline) was also signifi cantly higher in patients treated with degarelix at week 12 (61.0 vs 44.3%, P = 0.02). Both treatment groups achieved a statistically signifi cant improvement in quality of life from baseline ( P < 0.001).

This study shows that degarelix is benefi cial for LUTS relief in symptomatic PCa patients and may offer an alternative option to standard LUTS treatment, particularly for men with more advanced/symptomatic disease.

FIG. 2. The probability of freedom from PSA failure or death over time for patients with baseline PSA ≥ 20 ng/mL in the CS21 and CS21A trials. The magnifi ed area of the graph shows the time for 25% of patients with baseline PSA ≥ 20 ng/mL to experience PSA failure or death (TTP 25% ). Reprinted from Boccon-Gibod L, van der Meulen E, Persson B-E. An update on the use of gonadotropin-releasing hormone antagonists in prostate cancer. Ther Adv Urol 2011; 3: 127 – 40 [ 38 ] with permission from Sage Publications. KM, Kaplan – Meier.

TTP25% difference 210 days(Cl: 50–371 days) P = 0.01

90

100

80

1009080 Degarelix 240/80 mg

Weibull estimateKM estimate

Leuprolide 7.5 mgWeibull estimateKM estimate

70

Prob

abili

ty, % 60

50403020100

0 6 12 18 24Time since first dose, months

30 36 42 48


© 2 0 1 2 T H E A U T H O R S


EARLY VS DELAYED ENDOCRINE THERAPY

Timing of the introduction of ADT in advanced PCa remains controversial. The underpowered European Organisation for Research and Treatment of Cancer (EORTC) study 30846, found similar OS or cancer-specifi c survival (CSS) between immediate and delayed endocrine therapy [ 46 ] ; there was a 22% increase in the risk of death with delayed treatment although the difference was not statistically signifi cant (non-inferiority was also not proved). However, the Eastern Cooperative Oncology Group (ECOG) study 3886 showed that immediate ADT was associated with a signifi cant improvement in OS, CSS and PFS [ 47 ] . A review of studies from the pre-PSA era concluded that early ADT provided a relatively small benefi t in OS but did not improve CSS although it signifi cantly reduced disease progression and resulting complication rates [ 48 ] . In the PSA era, EORTC trial 30891 showed similar results, with a small benefi t in OS, but no CSS benefi t [ 49 ] . American Society of Clinical Oncology guidelines on initial hormonal treatment for androgen-sensitive, metastatic, recurrent or progressive PCa concluded that no specifi c recommendations could be made regarding the question of early vs deferred ADT until data from studies using modern medical diagnostic/biochemical tests and standardized follow-up schedules become available [ 50 ] . EAU guidelines consider that in advanced PCa, immediate ADT (at diagnosis) signifi cantly reduces disease progression and the complication rate due to progression, compared with deferred ADT (at symptomatic progression) but that the survival benefi t is at best marginal and not related to CSS [ 3 ] .

ADT IN COMBINATION WITH RT: NEW THERAPEUTIC STRATEGIES

While ADT remains the mainstay of the medical management of advanced/metastatic PCa, for which it is recommended as palliative treatment by current EAU guidelines [ 3,51 ] , it is starting to play an increasing role in earlier stages of the disease as a neoadjuvant/adjuvant to RT.

HIGH-RISK LOCALIZED OR LOCALLY ADVANCED DISEASE

The addition of neoadjuvant/adjuvant ADT is now considered the standard of care for

high-risk localized (T3a or Gleason score 8 – 10 or PSA > 20 ng/mL) or locally advanced disease treated with radical RT [ 16 ] . This multimodal approach is supported by robust data from randomized clinical trials [ 22,52 – 57 ] ( Table 2 ).

Neoadjuvant ADT

Neoadjuvant hormonal therapy (NHT) before defi nitive RT can produce, on average, a reduction of 25 – 30% in prostate size [ 58,59 ] . The fi rst phase III study of NHT was the Radiation Therapy Oncology Group (RTOG 86-10) trial, which included 456 evaluable patients with locally advanced disease (T2 – T4) [ 60 ] . Patients received goserelin/fl utamide for 2 months prior to RT and then for 2 months during RT, or RT alone. NHT signifi cantly decreased 5-year local progression (46% vs 71%, P < 0.001) and increased PFS with normal PSA levels vs RT alone (36% vs 15%, P < 0.001) [ 60 ] . Ten-year OS (43% vs 34%) and median survival (8.7 years vs 7.3 years) favoured NHT over RT alone although these differences did not achieve statistical signifi cance [ 52 ] . However, other effi cacy variables showed signifi cant superiority in the NHT arm: disease-specifi c mortality ( P < 0.01), distant metastasis ( P = 0.006), DFS ( P < 0.0001) and biochemical failure ( P < 0.0001).

The Trans-Tasman Radiation Oncology Group (TROG) 96.01 trial compared NHT with goserelin/fl utamide for 3 or 6 months (starting 2 and 5 months prior to RT, respectively) with RT alone in men with locally advanced PCa [ 53 ] . The study included 802 evaluable patients ( ∼ 84% high-risk). Analysis of 10-year data showed that NHT for 6 months signifi cantly reduced all-cause mortality (hazard ratio [ HR ] 0.63, P < 0.0008), PCa-specifi c mortality (HR 0.49, P = 0.0008) and distant progression (HR 0.49, P = 0.001) vs RT alone; NHT for 3 months did not signifi cantly improve these endpoints compared with RT alone. Also, both 3 and 6 months of NHT signifi cantly reduced PSA progression and local progression and signifi cantly improved event-free survival compared with RT alone [ 53 ] .

Adjuvant ADT

The benefi t of adding ADT to RT is now well established in terms of improvement in local

disease control, development of metastasis, DFS and OS. Available evidence supports 2 – 3 years of adjuvant ADT following RT [ 22,55 ] , and recent data suggest the bulk of the benefi t occurs in the fi rst year [ 61 ] . Two trials have shown superior 10-year survival rates with adjuvant ADT. The EORTC 22863 trial evaluated 3 years of goserelin adjuvant to RT vs RT alone in patients with locally advanced, non-metastatic PCa [ 62 ] . After a median follow-up of 9.1 years, the 10-year OS rates were 39.8% in patients receiving RT alone and 58.1% in those allocated combined treatment (HR 0.60, P = 0.0004) [ 22 ] . Ten-year clinical DFS was also higher (47.7%) in the adjuvant group vs the RT alone group (22.7%; HR 0.42, P < 0.0001). Another trial (RTOG 85-31) in patients who had undergone defi nitive RT, examined long-term adjuvant goserelin (indefi nite or until disease progression) in patients with locally advanced PCa and a high metastatic risk [ 54 ] . Adjuvant ADT produced a signifi cantly greater OS rate at 10 years (49%) vs RT alone (39%; P = 0.002) and the survival advantage was greatest in men with Gleason score 8 – 10 (adjuvant arm, 39%; RT alone, 25%; P = 0.0046). The risk of local failure or distant metastasis was also reduced with adjuvant therapy in this trial.

A third trial (RTOG 92-02) in men with locally advanced PCa compared 4 months of ADT with goserelin/fl utamide before and during RT, followed by either no additional therapy or 2 years of adjuvant goserelin [ 63 ] . At 10 years, there was no signifi cant improvement in OS with long-term adjuvant ADT, except for the subgroup with Gleason scores of 8 – 10 (OS in the long-term ADT group was 45.1% vs 31.9%; P = 0.0061) [ 55 ] . At 10 years, long-term adjuvant ADT also achieved signifi cantly improved DFS, local progression, distant metastasis and biochemical failure, vs short-term ADT.

ADT adjuvant to RT has also demonstrated superiority to ADT monotherapy for men with locally advanced or high-risk localized PCa. Thus, in the Scandinavian Prostate Cancer Group/Swedish Association for Urological Oncology study, men with locally advanced PCa received ADT (leuprolide/fl utamide) for 3 months, followed by RT or no additional treatment while continuing ADT with fl utamide. At 10 years, RT plus ADT was associated with signifi cantly reduced overall mortality (relative risk: 0.68; P = 0.004) and PCa-specifi c mortality (relative


© 2 0 1 2 T H E A U T H O R S


TABL

E 2

Stud

ies o

f ADT

neo

adju

vant

and

adj

uvan

t to

radi

othe

rapy

: 10-

year

effi

cacy

out

com

es

Stud

yPa

tient

sTr

eatm

ent

Med

ian

follo

w-u

p (y

)

10-y

ear

effi c

acy

outc

omes

Mor

talit

ySu

rviv

alLo

cal f

ailu

re/

prog

ress

ion

(%)

DM

(%)

Over

all/a

ll-ca

use

(%)

DSM

(%)

DFS

(%)

OS (%

) N

HT/

conco

mit

ant

RTOG

86-

10

(Roa

ch e

t al

. [ 5

2 ] )

Loca

lly a

dvan

ced

PCa

(T2-

4,

N0-

1) ( n

= 4

56)

Gos

erel

in/fl

utam

ide

2 m

bef

ore

and

2 m

dur

ing

RT11

.9 – 1

3.2

23 * *

11

.2 * *

* 43

35 * *

RT a

lone

(con

trol

)36

3.4

3447

TROG

96.

01

(Den

ham

et

al .

[ 53 ]

)

Loca

lly a

dvan

ced

PCa

(T2b

, T2

c, T

3 an

d T4

, N0

M0)

( n

= 8

02)

Gos

erel

in/fl

utam

ide

(6 m

) + R

T10

.629

.2 * *

* 11

.4 * *

* 13

.3 * *

* G

oser

elin

/fl ut

amid

e (3

m) +

RT

36.7

18.9

15.7

* * *

RT a

lone

(con

trol

)42

.522

.028

.2 A

HT

EORT

C 22

863

(Bol

la e

t al

. [ 2

2 ] )

Loca

lly a

dvan

ced

(T1 –

2 po

orly

di

ffer

entia

ted

and

M0,

T3

-4, N

0-1

M0)

( n =

415

)

Gos

erel

in (3

y) +

RT

9.1

47.7

* * *

58.1

* * *

RT a

lone

(con

trol

)22

.739

.8

RTOG

85-

31

(Pile

pich

et

al .

[ 54 ]

)

T3 o

r N

1 M

0 ( n

= 9

77)

Gos

erel

in (i

ndefi

nite

/unt

il pr

ogre

ssio

n) +

RT

7.6

16 * *

49

* *

23 * *

* 24

* * *

RT a

lone

(con

trol

)22

3938

39RT

OG 9

2-02

(H

orw

itz

et a

l . [ 5

5 ] )

T2c-

4 or

N0-

2 PS

A < 1

50 n

g/m

L) ( n

= 1

521)

Gos

erel

in/fl

utam

ide

4 m

bef

ore/

durin

g RT

+ g

oser

elin

for

2 y

11.3

22.5

* * *

53.9

12.3

* * *

14.8

* * *

Gos

erel

in/fl

utam

ide

4 m

bef

ore/

durin

g RT

(con

trol

)13

.251

.622

.222

.8

SPG

C-7/

SF

UO-

3 (W

idm

ark

et a

l . [ 5

6 ] )

Loca

lly a

dvan

ced

PCa

(T1b

-2

grad

e 2 –

3; T

3 N

0 M

0; P

SA

< 70

ng/m

L) ( n

= 8

75)

Leup

rolid

e/fl u

tam

ide

(3 m

) + R

T +

cont

inuo

us fl

utam

ide

7.6

29.6

* *

11.9

* * *

Leup

rolid

e/fl u

tam

ide

(3 m

) +

cont

inuo

us fl

utam

ide

(con

trol

)39

.423

.9

PR3/

PR07

(W

arde

et

al .

[ 57 ]

)

Loca

lly a

dvan

ced

(T3/

T4 o

r T2

, PS

A > 4

0 ng

/mL

or T

2, P

SA

> 20

ng/m

L an

d G

leas

on

≥ 8 a

nd N

0 /N

X, M

0)

( N =

120

5)

LHRH

ago

nist

or

orch

idec

tom

y +

RT6.

0AD

T +

RT

sign

ifi ca

ntly

re

duce

d

pros

tate

ca

ncer

dea

th

risk

vs A

DT

alon

e: H

R 0.

54 * *

*

ADT

+ RT

si

gnifi

cant

ly

impr

oved

ov

eral

l su

rviv

al a

t 7

year

s vs

AD

T al

one:

H

R 0.

77 *

LHRH

ago

nist

or

orch

idec

tom

y al

one

(con

trol

)

* P ≤

0.0

5, * *

P ≤

0.01

, * * *

P ≤

0.0

01 v

s con

trol

gro

up.

ADT,

andr

ogen

dep

rivat

ion

ther

apy;

AHT

, adj

uvan

t hor

mon

al th

erap

y; D

M, d

istan

t met

asta

ses;

DFS,

dise

ase-

free

surv

ival

; DSM

, dise

ase-

spec

ifi c

mor

talit

y; E

ORTC

, Eur

opea

n Or

gani

satio

n fo

r Res

earc

h an

d Tr

eatm

ent o

f Can

cer;

HR, h

azar

d ra

tio; N

HT, n

eoad

juva

nt h

orm

onal

ther

apy;

m, m

onth

s; OS

, ove

rall

surv

ival

; RT,

radi

othe

rapy

; RTO

G, R

adia

tion

Ther

apy

Onco

logy

Gro

up; S

PGC-

7/SF

UO-3

, Sca

ndin

avia

n Pr

osta

te

Canc

er G

roup

/Sw

edish

Ass

ocia

tion

for U

rolo

gica

l Onc

olog

y; T

ROG,

Tran

s-Ta

sman

Rad

iatio

n On

colo

gy G

roup

; y, y

ears

.


© 2 0 1 2 T H E A U T H O R S


risk: 0.44; P < 0.0001) and PSA recurrence (relative risk: 0.16; P < 0.0001; [ 56 ] ). A separate Intergroup PR3/PR07 study compared lifelong ADT (bilateral orchidectomy or LHRH agonist) with or without RT in 1205 men with locally advanced disease [ 57 ] . At a median follow-up of 6.0 years, the addition of RT to ADT signifi cantly improved survival (HR 0.77; P = 0.03) and reduced the disease-specifi c mortality risk (HR 0.54; P = 0.001) vs ADT alone.

INTERMEDIATE-RISK DISEASE

The benefi t of adding NHT or ADT adjuvant to RT in patients with intermediate-risk localized PCa (eg stage T2b-T2c, or PSA 10 – 20 ng/mL, or Gleason score 7) is equivocal [ 64 ] . These patients are heterogeneous and often grouped with high-risk patients in clinical studies, making

results diffi cult to interpret. However, NHT to RT has been shown to signifi cantly improve biochemical control [ 65 ] and OS [ 66 ] in trials enrolling mostly intermediate-risk patients (comprising ∼ 70 − 79% of the study population). In addition, in the RTOG 94-08 trial involving 1979 patients with stage T1b, T1c, T2a, or T2b PCa and a PSA ≤ 20 ng/mL, short-term ADT for 4 months before and during RT was associated with signifi cantly decreased disease-specifi c mortality and increased OS vs RT alone; the benefi t was mainly seen in intermediate-risk, but not low-risk, men ( Figure 3 ) [ 67 ] .

TIMING AND DURATION OF NEOADJUVANT/ADJUVANT ADT

The optimal timing and duration of neoadjuvant/adjuvant ADT is still to be established. Current EAU guidelines consider that in locally advanced disease (T3-4 N0

M0), OS is improved by concomitant and adjuvant hormonal therapy for a total duration of 3 years [ 3 ] . In a prospective randomized trial (EORTC 22961) in > 900 men with locally advanced disease, 6 months of ADT adjuvant to RT was found to be inferior to 3 years of ADT adjuvant to RT; 5-year overall mortality was numerically higher with short-term ADT than with long-term ADT [ 68 ] . However, a recent analysis of data from 3666 PCa patients treated with either combined ADT and RT or RT alone concluded that the bulk of the benefi t of adjuvant ADT occurs in the fi rst year (approximately 85% of that obtainable from a full 3 years, on average), thus questioning recommendations for 3 years of ADT vs 2 years [ 61 ] .

The optimal duration of neoadjuvant ADT (with RT) remains to be defi ned. RTOG 86-10 showed that therapy for 4 months (neoadjuvant for 2 months plus concomitant for 2 months) was benefi cial [ 52 ] , whereas in TROG 96.01, 6-month NHT decreased distant progression, PCa-specifi c mortality and all-cause mortality, whereas 3-month NHT had no effect on these variables, vs RT alone [ 53 ] . Another trial comparing 3 vs 8 months of neoadjuvant ADT in localized disease did not show a signifi cant difference in biochemical DFS or OS between treatment arms (except for the high-risk group) [ 69 ] . It has been suggested that biochemical response to NHT, rather than its duration, may be more important in determining the benefi t of combined hormonal and RT treatment in the neoadjuvant setting [ 70 ] . Further analysis of data from the trial comparing 8- vs 3-month NHT showed signifi cantly higher biochemical DFS in patients who achieved an excellent biochemical response, indicated by pre-RT post-hormone therapy PSA ≤ 0.1 ng/mL. Consequently, it is possible that achievement of a rapid decrease in PSA in response to NHT may allow minimization of ADT duration and thus of any related adverse events.

In the absence of comparative studies of different forms of ADT given as NHT or adjuvant hormonal therapy (AHT), it is not clear if any particular class/agent provides particular benefi ts when used in this manner. Nevertheless, it seems likely that agents with fast symptom and volume control and rapid PSA control may be benefi cial in this regard.

FIG. 3. Kaplan – Meier estimates of

overall survival in patients with (a) low- and (b) intermediate-risk disease treated with ADT + RT vs

RT alone. Reprinted from Jones CU, Hunt D, McGowan DG et al .

Radiotherapy and short-term androgen deprivation for

localized prostate cancer. New Engl J Med 2011; 365: 107 – 18

[ 67 ] with permission from The Publishing Division of the

Massachusetts Medical Society. ADT, androgen deprivation

therapy; RT, radiotherapy.

100a

ADT plus RTRT alone

P = 0.60ADT plus RT:RT alone:

113114

351334

317297

261253

Time following randomization, years

140145

2929

351334

Low risk

No. at riskADT plus RTRT alone

No. ofdeaths

Totalno.

75

50

Ove

rall

surv

ival

, %25

00 3 6 9 12

100b

ADT plus RTRT alone

P = 0.03ADT plus RT:RT alone:

198236

524544

471489

380369

Time following randomization, years

220202

4647

524544

Intermediate risk

No. at riskADT plus RTRT alone

No. ofdeaths

Totalno.

75

50

Ove

rall

surv

ival

, %

25

00 3 6 9 12


© 2 0 1 2 T H E A U T H O R S


ADT NEOADJUVANT/ADJUVANT TO RADICAL PROSTATECTOMY (RP)

Surgical treatment of clinical stage T3 PCa has traditionally been discouraged; however, EAU guidelines now acknowledge that, while still controversial, it is increasingly apparent that surgery has a place in the treatment of locally advanced disease [ 3 ] . While 56 – 78% of patients primarily treated by surgery eventually require adjuvant or salvage RT or ADT [ 71,72 ] , excellent 5-, 10- and 15-year OS and CSS rates have been reported (eg references 71 – 73 ] . However, RP for clinical T3 PCa requires suffi cient surgical expertise to achieve acceptable levels of morbidity.

The rationale for using ADT neoadjuvant to RP is to decrease tumour size prior to surgery to improve surgical curability [ 74 ] . Evidence for the use of neoadjuvant/adjuvant ADT with RP is less compelling than that for RT. Current EAU guidelines consider that further studies are needed to investigate the application of ADT neo-adjuvant to RP and that while NHT does not provide a signifi cant advantage in OS or DFS over RP alone it substantially improves local pathological variables [ 3 ] . A systematic review of clinical trials in localized or locally advanced PCa showed that NHT prior to RP signifi cantly reduced positive margin rates ( P < 0.00001), organ confi nement ( P < 0.0001) and lymph-node invasion ( P < 0.02) vs RP alone, but had no effect on OS or DFS [ 74 ] . A review of AHT following RP found no effect on OS but improved disease-specifi c survival ( P = 0.0004) in one study; DFS was also better with AHT ( P < 0.00001) [ 75 ] . These fi ndings are also refl ected in EAU guidelines.

ECOG study 3886 in men with node-positive PCa who have undergone RP and pelvic lymphadenectomy showed that immediate ADT signifi cantly improved overall, disease-specifi c, and PFS compared with the withholding of ADT until disease progression occurs [ 47 ] . ADT after RP and pelvic lymphadenectomy also signifi cantly reduced progression and overall and disease-specifi c mortality.

The role of AHT with RT after RP is also being evaluated. In RTOG 9601, patients with rising PSA post-RP received RT alone or RT plus bicalutamide (for 24 months). Interim results showed signifi cant improvements in freedom from PSA

progression and development of metastatic disease in the bicalutamide group (there were too few deaths to allow evaluation of OS, the primary endpoint, at this stage in the study and longer-term follow-up is awaited) [ 76 ] .

The RADICALS (Radiotherapy and Androgen Deprivation In Combination After Local Surgery; NCT00541047) trial, which is currently underway in the UK, Canada, Denmark and the Republic of Ireland, will evaluate optimal timing of RT and duration of hormone therapy after RP [ 77,78 ] . Thus, after RP, patients will be randomized to adjuvant or early salvage RT. Within each of these arms patients will receive either RT alone or RT plus 6 months or 2 years of adjuvant ADT.

POTENTIAL MECHANISMS UNDERLYING THE BENEFITS OF NEOADJUVANT/ ADJUVANT ADT

How can we explain the success of combining a potentially curative local treatment of the primary tumour with endocrine therapy? In trials combining RT with ADT, the improved outcome may be explained in part by the radiosensitizing effect of ADT but may also result from a systemic effect of ADT [ 79 ] . In the EORTC 22863 trial of adjuvant ADT in locally advanced PCa [ 62 ] , there would appear to be a very high risk of subclinical metastatic disease, while other trials included patients with overt lymph node metastatic disease [ 47,54 ] . Indeed, the ECOG 3886 study, with RP as local treatment, showed a survival benefi t for immediate ADT of similar magnitude to the benefi t observed in the concomitant and adjuvant RT studies [ 47 ] . It is expected that this metastatic subset contributes most to the early deaths in these studies and it seems unlikely that an improved local control alone is able to infl uence this early mortality risk. The success of ADT plus local therapy in such patients may refl ect that treatment of the primary tumour in the presence of metastatic disease may prevent further metastases coming from clonal populations in the primary, as suggested by Messing et al . [ 80 ] . This would appear to be supported by a recent study which confi rmed that most, if not all, metastatic PCas have monoclonal origins [ 81 ] . The signifi cance of the role of aggressive

treatment of the primary combined with endocrine treatment in lymph-node positive disease was confi rmed in a multicentre matched analysis which showed that adjuvant combination treatment with long-term hormonal therapy and RT after RP is associated with signifi cantly better long-term survival compared with AHT alone in node-positive PCa [ 82 ] . Moreover, the survival benefi t was achieved regardless of the extent of nodal invasion.

Finally, a recent systematic review of randomized studies of ADT in PCa which examined a possible interaction between local treatment and ADT concluded that the role of local treatment in locally advanced and lymph node metastatic disease is important and supports an interaction between local treatment and systemic ADT [ 79 ] . Indeed, if the primary tumour continues to produce metastases then the key treatment factor in this setting may be effective local treatment of the primary to prevent this, rather than the type of local therapy (RT or RP) utilized.

ADJUVANT ADT PLUS CHEMOTHERAPY

The phase III Southwest Oncology Group (SWOG) S9921 trial is investigating the potential role of AHT plus chemotherapy following RP [ 83 ] . Following RP, men with high-risk features at RP ( n = 983) were assigned to goserelin and bicalutamide for 2 years, either alone or combined with mitoxantrone. Interim data for the AHT-alone control arm showed a 5-year biochemical-failure free survival rate of 92.5%, and a 5-year OS rate of 95.9%. The fi nal primary treatment comparison results are awaited.

CONCLUSIONS

In the 70 years since Huggins and Hodges fi rst demonstrated the favourable impact of ADT in PCa, it has continued to evolve as a therapeutic strategy. For many years, LHRH agonists were the standard of care for ADT in PCa. However, their use has been associated with suboptimal testosterone control which, together with unwanted surge and fl are effects, may infl uence disease control. The more recent introduction of GnRH antagonists, now offers an alternative fi rst-line approach to


© 2 0 1 2 T H E A U T H O R S


ADT in PCa. Thus, agents such as degarelix, the most extensively studied and widely available member of this therapeutic class, offer faster and more effective control of testosterone, rapid PSA control and improved PSA PFS (potentially prolonging the time to castrate-resistant disease) compared with agonists. Moreover, recent clinical data confi rm the long-term effi cacy and tolerability of this agent, with maintenance of testosterone and PSA suppression and control for > 3 years. Moreover, degarelix data indicate that the pharmacological properties of GnRH antagonists translate into clinical advantages, which may be more pronounced in patients with metastatic disease, high baseline PSA ( > 20 ng/mL) and highly symptomatic patients.

In recent years, the role of ADT has expanded beyond advanced disease and it is now starting to play an increasing role in earlier disease stages. There is increased OS and PFS when ADT is used adjuvant to RT for locally advanced and high-risk localized PCa and this combined modality therapy is superior to RT or ADT alone. Indeed, neoadjuvant/adjuvant ADT is now considered as the standard of care for locally advanced or high-risk localized disease treated with radical RT. While it remains to be seen which ADT provides most benefi t in this therapeutic approach, it is likely that agents that offer rapid control of symptoms, prostate volume and PSA control may be of particular benefi t in this context. The rapid testosterone and PSA suppression achieved with GnRH antagonists may therefore suggest potential advantages for these agents in clinical settings that utilize neoadjuvant/adjuvant therapy; studies of these agents in this therapeutic context are on-going.

ACKNOWLEDGEMENTS

Medical writing assistance (funded by Ferring Pharmaceuticals) was provided by Thomas Lavelle of Bioscript Stirling Ltd.

DISCLOSURES/CONFLICT OF INTEREST

F. Schr ö der: Consultant/Advisor: Ferring, Genprobe, GlaxoSmithKline.

E. D. Crawford: Grant/Research: Ferring, Genprobe. Consultant/Advisor/Speakers ’

Bureau: Ferring, GlaxoSmithKline, Indevus, Poinard, sanofi aventis, Soar Biodynamics.

K. Axcrona: Consultant/Advisor/Speaker: Astellas Pharma. Research grant: Ferring.

H. Payne: has attended and received honorarium for advisory boards and served as a consultant for AstraZeneca, Janssen, Johnson and Johnson, sanofi aventis, Takeda, Amgen, Ferring and Novartis.

T. E. Keane: Ferring Pharmaceuticals – Advisor/Speaker; Amgen – Advisor/Speaker; Endo Pharmaceuticals – Advisor/Speaker.

REFERENCES

1 Huggins C , Hodges CV . Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate . Cancer Res 1941 ; 1 : 293 – 7

2 Huggins C , Stevens RE , Hodges CV . Studies on prostatic cancer. II. The effects of castration on advanced carcinoma of the prostate cancer . Archives of Surgery 1941 ; 43 : 209 – 23

3 Heidenreich A , Bolla M , Joniau S et al . European Association of Urology. Guidelines on prostate cancer . January 2011. Available from http://www.uroweb.org/gls/pdf/08_Prostate_Cancer.pdf [ Accessed: December 2011 ]

4 Byar DP , Corle DK . Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group studies . NCI Monogr 1988 ; 7 : 165 – 70

5 Iversen P , Tyrrell CJ , Kaisary AV et al . Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup . J Urol 2000 ; 164 : 1579 – 82

6 Seidenfeld J , Samson DJ , Hasselblad V et al . Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis . Ann Intern Med 2000 ; 132 : 566 – 77

7 Bubley GJ . Is the fl are phenomenon clinically signifi cant? Urology 2001 ; 58 ( Suppl 2A ): 5 – 9

8 Anderson J . The role of antiandrogen monotherapy in the treatment of

prostate cancer . BJU Int 2003 ; 91 : 455 – 461

9 Wirth MP , Hakenberg OW , Froehner M . Antiandrogens in the treatment of prostate cancer . Eur Urol 2007 ; 51 : 306 – 13

10 Kabir S , Mancuso P , Rashid P et al . Androgen deprivation therapy. Managing side effects . Aust Fam Physician 2008 ; 37 : 641 – 5

11 Klotz L , Boccon-Gibod L , Shore ND et al . The effi cacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer . BJU Int 2008 ; 102 : 1531 – 8

12 Tombal B , Berges R . Optimal control of testosterone: a clinical case-based approach of modern androgen-deprivation therapy . Eur Urol Suppl 2008 ; 7 : 15 – 21

13 Van Poppel H , Nilsson S Testosterone surge: rationale for gonadotropin-releasing hormone blockers? Urology 2008 ; 71 : 1001 – 6

14 Lin GW , Yao XD , Zhang SL et al . Prostate-specifi c antigen half-life: a new predictor of progression-free survival and overall survival in Chinese prostate cancer patients . Asian J Androl 2009 ; 11 : 443 – 50

15 Crawford ED , Tombal B , Miller K et al . A phase III extension trial with a one-arm crossover from leuprolide to degarelix: comparison of gonadotropin-releasing hormone agonist and antagonist effect on prostate cancer . J Urol 2011 ; 186 : 889 – 97

16 Payne H , Mason M . Androgen deprivation therapy as adjuvant/neoadjuvant to radiotherapy for high-risk localised and locally advanced prostate cancer: recent developments . Br J Cancer 2011 ; 105 : 1628 – 34

17 Crawford ED . Hormonal therapy in prostate cancer: historical approaches . Rev Urol 2004 ; 6 ( suppl 7 ): S3 – S11

18 Veterans Administration Co-operative Urological Research Group . Treatment and survival of patients with cancer of the prostate . Surg Gynecol Obstet 1967 ; 124 : 1011 – 7

19 Tyrrell CJ , Kaisary AV , Iversen P et al . A randomised comparison of ‘ Casodex ’ (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer . Eur Urol 1998 ; 33 : 447 – 56

20 Prostate Cancer Trialists ’ Collaborative


© 2 0 1 2 T H E A U T H O R S

1 0 B J U I N T E R N A T I O N A L © 2 0 1 2 B J U I N T E R N A T I O N A L

Group . Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials . Lancet 2000 ; 355 : 1491 – 8

21 Hussain S , Gunnell D , Donovan J et al . Secular trends in prostate cancer mortality, incidence and treatment: England and Wales, 1975 – 2004 . BJU Int 2008 ; 101 : 547 – 55 .

22 Bolla M , Van Tienhoven G , Warde P et al . External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study . Lancet Oncol. 2010 ; 11 : 1066 – 73

23 Waxman J , Man A , Hendry WF et al . Importance of early tumour exacerbation in patients treated with long acting analogues of gonadotrophin releasing hormone for advanced prostatic cancer . Br Med J (Clin Res Ed) 1985 ; 291 : 1387 – 8

24 Thompson IM . Flare associated with LHRH-agonist therapy . Rev Urol 2001 ; 3 Suppl 3 : S10 – 4

25 Tombal B . The importance of testosterone control in prostate cancer . Eur Urol Suppl 2007 ; 6 : 834 – 9

26 Morote J , Orsola A , Planas J et al . Redefi ning clinically signifi cant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy . J Urol 2007 ; 178 : 1290 – 5

27 Morote J , Planas J , Salvador C , Ravent ó s CX , Catal á n R , Revent ó s J . Individual variations of serum testosterone in patients with prostate cancer receiving androgen deprivation therapy . BJU Int 2009 ; 103 : 332 – 5

28 Trachtenberg J , Gittleman M , Steidle C et al . A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer . J Urol 2002 ; 167 : 1670 – 4

29 McLeod D , Zinner N , Tomera K et al . A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer . Urology 2001 ; 58 : 756 – 61

30 Selvaggi F , Khoe GSS , Van Cangh P et al . Comparison of abarelix depot (A-D) and goserelin (G) plus bicalutamide (B) in advanced prostate cancer: results of a multicentre, open-label, randomised, phase III study . Eur Urol 2001 ; 39 ( Suppl 5 ): 78

31 Druglib.com . Plenaxis (abarelix) summary, March 2012 . Available at http://www.druglib.com/druginfo/plenaxis ) [ accessed March 2012 ]

32 Mongiat-Artus P , Teillac P . Abarelix: the fi rst gonadotrophin-releasing hormone antagonist for the treatment of prostate cancer . Expert Opin Pharmacother 2004 ; 5 : 2171 – 9

33 Debruyne F , Bhat G , Garnick MB . Abarelix for injectable suspension: fi rst-in-class gonadotropin-releasing hormone antagonist for prostate cancer . Future Oncol 2006 ; 2 : 677 – 96

34 Huhtaniemi I , White R , McArdle CA , Persson BE . Will GnRH antagonists improve prostate cancer treatment? Trends Endocrinol Metab 2009 ; 20 : 43 – 50

35 Hanninen M , Venner P , North S . A rapid PSA half-life following docetaxel chemotherapy is associated with improved survival in hormone refractory prostate cancer . Can Urol Assoc J 2009 ; 3 : 369 – 74

36 Tombal B , Miller K , Boccon-Gibod L et al . Additional analysis of the secondary end point of biochemical recurrence rate in a Phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics . Eur Urol 2010 ; 57 : 836 – 42

37 Schr ö der FH , Tombal B , Miller K et al . Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: results from a 12-month, comparative, phase III study . BJU Int 2010 ; 106 : 182 – 7

38 Boccon-Gibod L , van der Meulen E , Persson B-E . An update on the use of gonadotropin-releasing hormone antagonists in prostate cancer . Ther Adv Urol 2011 ; 3 : 127 – 40

39 Lein M , Wirth M , Miller K et al . Serial markers of bone turnover in men with metastatic prostate cancer treated with zoledronic acid for detection of bone metastases progression . Eur Urol 2007 ; 52 : 1381 – 7

40 Lorente JA , Morote J , Raventos C et al . Clinical effi cacy of bone alkaline phosphatase and prostate specifi c antigen in the diagnosis of bone metastasis in prostate cancer . J Urol 1996 ; 155 : 1348 – 51

41 Robinson D , Sandblom G , Johansson R et al . Prediction of survival of metastatic

prostate cancer based on early serial measurements of prostate specifi c antigen and alkaline phosphatase . J Urol 2008 ; 179 : 117 – 22

42 Johansen JS , Brasso K , Iversen P et al . Changes of biochemical markers of bone turnover and YKL-40 following hormonal treatment for metastatic prostate cancer are related to survival . Clin Cancer Res 2007 ; 13 : 3244 – 9

43 Ramankulov A , Lein M , Kristiansen G et al . Plasma osteopontin in comparison with bone markers as indicator of bone metastasis and survival outcome in patients with prostate cancer . Prostate 2007 ; 67 : 330 – 40

44 Jung K , Lein M , Von Stephan CHK et al . Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: diagnostic and prognostic implications . Int J Cancer 2004 ; 111 : 783 – 91

45 Axcrona K , Aaltomaa S , da Silva CM et al . ADT for volume reduction, symptom relief and quality of life improvement in men with prostate cancer: Degarelix versus goserelin plus bicalutamide . BJU Int 2012 ; Apr 13. doi: 10.1111/j.1464-410X.2012.11107.x. [ Epub ahead of print ]

46 Schr ö der FH , Kurth K-H , Fossa SD et al . Early versus delayed endocrine treatment of T2-T3 pN1-3 M0 prostate cancer without local treatment of the primary tumour: fi nal results of European Organization for the Research and Treatment of Cancer protocol 30846 after 13 years of follow-up (a randomised controlled trial) . Eur Urol 2009 ; 55 : 14 – 22

47 Messing EM , Manola J , Yao J et al . Eastern Cooperative Oncology Group study EST 3886. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy . Lancet Oncol 2006 ; 7 : 472 – 9

48 Nair B , Wilt T , MacDonald R , Rutks I . Early versus deferred androgen suppression in the treatment of advanced prostatic cancer . Cochrane Database Syst Rev 2002 ; 1 : CD003506

49 Studer UE , Whelan P , Albrecht W et al . Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment


© 2 0 1 2 T H E A U T H O R S


of Cancer (EORTC) Trial 30891 . J Clin Oncol 2006 ; 24 : 1868 – 76

50 Loblaw DA , Virgo KS , Nam R et al . Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline . J Clin Oncol 2007 ; 25 : 1596 – 605

51 Mottet N , Bellmunt J , Bolla M et al . EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer . Eur Urol 2011 ; 59 : 572 – 83

52 Roach M III, Bae K , Speight J et al . Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610 . J Clin Oncol 2008 ; 26 : 585 – 91

53 Denham JW , Steigler A , Lamb DS et al . Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial . Lancet Oncol 2011 ; 12 : 451 – 9

54 Pilepich MV , Winter K , Lawton CA et al . Androgen suppression adjuvant to defi nitive radiotherapy in prostate carcinoma-long-term results of phase III RTOG 85-31 . Int J Radiat Oncol Biol Phys 2005 ; 61 : 1285 – 90

55 Horwitz EM , Bae K , Hanks GE et al . Ten-year follow-up of radiation therapy oncology group protocol 92-02: A phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer . J Clin Oncol 2008 ; 26 : 2497 – 504

56 Widmark A , Klepp O , Solberg A et al .; Scandinavian Prostate Cancer Group Study 7, Swedish Association for Urology Oncology 3 . Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial . Lancet 2009 ; 373 : 301 – 8

57 Warde P , Mason M , Ding K et al ; NCIC CTG PR.3/MRC UK PR07 investigators . Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial . Lancet 2011 ; 378 : 2104 – 11

58 Zelefsky MJ , Leibel SA , Burman CM et al . Neoadjuvant hormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional

conformal radiation therapy . Int J Radiat Oncol Biol Phys 1994 ; 29 : 755 – 61

59 Henderson A , Langley SE , Laing RW . Is bicalutamide equivalent to goserelin for prostate volume reduction before radiation therapy? A prospective, observational study . Clin Oncol (R Coll Radiol) 2003 ; 15 : 318 – 21

60 Pilepich MV , Krall JM , al-Sarraf M et al . Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group . Urology 1995 ; 45 : 616 – 23

61 Williams S , Buyyounouski M , Kestin L , Duchesne G , Pickles T . Predictors of androgen deprivation therapy effi cacy combined with prostatic irradiation: the central role of tumor stage and radiation dose . Int J Radiation Oncol Biol Phys 2011 ; 79 : 724 – 31

62 Bolla M , Collette L , Blank L et al . Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial . Lancet 2002 ; 360 : 103 – 8

63 Hanks GE , Pajak TF , Porter A et al .; Radiation Therapy Oncology Group . Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02 . J Clin Oncol 2003 ; 21 : 3972 – 8

64 Dal Pra A , Cury FL , Souhami L . Combining radiation therapy and androgen deprivation for localized prostate cancer-a critical review . Curr Oncol 2010 ; 17 : 28 – 38

65 Laverdi è re J , Nabid A , De Bedoya LD et al . The effi cacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2-T3 prostate cancer . J Urol 2004 ; 171 : 1137 – 40

66 D ’ Amico AV , Chen MH , Renshaw AA , Loffredo M , Kantoff PW . Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial . JAMA 2008 ; 299 : 289 – 95

67 Jones CU , Hunt D , McGowan DG et al . Radiotherapy and short-term androgen

deprivation for localized prostate cancer . New Engl J Med 2011 ; 365 : 107 – 18

68 Bolla M , De Reijke TM , van Tienhoven G et al . Duration of androgen suppression in the treatment of prostate cancer . N Engl J Med 2009 360 : 2516 – 27

69 Crook J , Ludgate C , Malone S et al . Report of a multicenter Canadian phase III randomized trial of 3 months vs. 8 months neoadjuvant androgen deprivation before standard-dose radiotherapy for clinically localized prostate cancer . Int J Radiat Oncol Biol Phys 2004 ; 60 : 15 – 23

70 Alexander A , Crook J , Jones S et al . Is biochemical response more important than duration of neoadjuvant hormone therapy before radiotherapy for clinically localized prostate cancer? An analysis of the 3- versus 8-month randomized trial . Int J Radiat Oncol Biol Phys 2010 ; 76 : 23 – 30

71 Ward JF , Slezak JM , Blute ML et al . Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent of prostate-specifi c antigen testing: 15-year outcome . BJU Int 2005 ; 95 : 751 – 6

72 Hsu CY , Joniau S , Oyen R et al . Outcome of surgery for clinical unilateral T3a prostate cancer: a single-institution experience . Eur Urol 2007 ; 51 : 121 – 8

73 Van den Ouden D , Hop WC , Schroder FH . Progression in and survival of patients with locally advanced prostate cancer (T3) treated with radical prostatectomy as monotherapy . J Urol 1998 ; 160 : 1392 – 7

74 Shelley MD , Kumar S , Wilt T , Staffurth J , Coles B , Mason MD . A systematic review and meta-analysis of randomised trials of neo-adjuvant hormone therapy for localised and locally advanced prostate carcinoma . Cancer Treat Rev 2009 ; 35 : 9 – 17

75 Shelley MD , Kumar S , Coles B , Wilt T , Staffurth J , Mason MD . Adjuvant hormone therapy for localised and locally advanced prostate carcinoma: a systematic review and meta-analysis of randomised trials . Cancer Treat Rev 2009 ; 35 : 540 – 6

76 Shipley WU , Hunt D , Lukka HR et al . Initial report of RTOG 9601, a phase III trial in prostate cancer: Effect of anti-androgen therapy (AAT) with bicalutamide during and after radiation


© 2 0 1 2 T H E A U T H O R S

1 2 B J U I N T E R N A T I O N A L © 2 0 1 2 B J U I N T E R N A T I O N A L

therapy (RT) on freedom from progression and incidence of metastatic disease in patients following radical prostatectomy (RP) with pT2-3, N0 disease and elevated PSA levels . J Clin Oncol 2011 ; 29 ( Suppl 7 ): 1

77 Medical Research Council Clinical Trials Unit . RADICALS – Radiotherapy and androgen deprivation in combination after local surgery: a randomised controlled trial in prostate cancer . Available at: http://www.radicals-trial.org/default.aspx [ accessed 23 March 2012 ]

78 Parker C , Sydes MR , Catton C et al .; RADICALS Trial Management Group . Radiotherapy and androgen deprivation in combination after local surgery (RADICALS): a new Medical Research Council/National Cancer Institute of Canada phase III trial of adjuvant treatment after radical prostatectomy . BJU Int 2007 ; 99 : 1376 – 9

79 Verhagen PCMS , Schroder FH , Collette L et al . Does local treatment of the prostate in advanced and/or lymph node

metastatic disease improve effi cacy of androgen-deprivation therapy? a systematic review . Eur Urol 2010 ; 58 : 261 – 9

80 Messing EM , Manola J , Sarosdy M , Wilding G , Crawford ED , Trump D . Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer . N Engl J Med 1999 ; 341 : 1781 – 8

81 Liu W , Laitinen S , Khan S et al . Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer . Nat Med 2009 ; 15 : 559 – 65

82 Briganti A , Karnes RJ , Da Pozzo LF et al . Combination of adjuvant hormonal and radiation therapy signifi cantly prolongs survival of patients with pT2 – 4 pN + prostate cancer: results of a matched analysis . Eur Urol 2011 ; 59 : 832 – 40

83 Dorff TB , Flaig TW , Tangen CM et al . Adjuvant androgen deprivation for

high-risk prostate cancer after radical prostatectomy: SWOG S9921 study . J Clin Oncol 2011 ; 29 : 2040 – 5

Correspondence: Professor F Schr ö der, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. e-mail: [email protected]

Abbreviations : ADT , androgen deprivation therapy ; AHT , adjuvant hormonal therapy ; CSS , cancer-specifi c survival ; DFS , disease-free survival ; EAU , European Association of Urology ; ECOG , Eastern Cooperative Oncology Group ; EORTC , European Organisation for Research and Treatment of Cancer ; HR , hazard ratio ; LH , luteinizing hormone ; NHT , neoadjuvant hormonal therapy ; OS , overall survival ; PCa , prostate cancer ; PFS , progression-free survival ; RP , radical prostatectomy ; RT , radiotherapy ; RTOG , Radiation Therapy Oncology Group ; S-ALP , serum alkaline phosphatase ; TROG , Trans-Tasman Radiation Oncology Group .

Documents

Androgen deprivation therapy: past, present and future