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Introduction

Men with localised or locally advanced prostate cancer typically receive radiotherapy, radical prostatectomy or watchful waiting as standard care [1]. There is scope for improvement on each of these standard care options, however, as disease progression and survival outcomes can be unsatisfactory [2-6].

Patients undergoing radiotherapy for locally advanced disease are often given adjuvant luteinising hormone-releasing hormone agonist therapy based on the proven survival benefit of goserelin (ZOLADEXTM) in these settings [2,7]. Likewise, adjuvant hormone ablation has been associated with a marked survival benefit in patients found to be node positive during radical prostatectomy for clinically localised disease [5]. However, castration- based therapies, which exert their therapeutic effect by suppressing testosterone levels, are associated with a number of pharmacologically predictable side effects. These include impotence, loss of libido and decreased vitality [8], as well as reductions in bone mineral density and lean muscle mass, which may lead to an increased risk of osteoporotic bone fractures [9,10] Although many of these side effects are manageable to an extent [1,11,12], they may limit the use of castration in patients for whom quality-of-life issues such as maintenance of sexual function and physical ability are a high priority.

Non-steroidal antiandrogens such as bicalutamide (CASODEXTM) do not suppress testosterone levels and offer potential quality- of-life advantages over castration. Pooled data from two randomised trials have shown that there is no significant difference between bicalutamide 150 mg and castration in terms of prolonging overall survival in patients with non-metastatic disease [8] (Figure 1). In this same analysis, bicalutamide 150 mg was associated with significant advantages over castration with regard to maintaining sexual interest and physical capacity. There is also evidence from other studies that bicalutamide 150 mg preserves bone mineral density and lean muscle mass compared with castration [10,13]. Bicalutamide 150 mg may, therefore, be an attractive alternative hormonal therapy for patients with non- -metastatic disease who wish to maintain an active lifestyle.

The role of adding bicalutamide 150 mg to standard care (radiotherapy, radical prostatectomy or watchful waiting) for localised or locally advanced, non-metastatic prostate cancer is being evaluated in the world's largest prostate cancer treatment programme to date – the Early Prostate Cancer (EPC) programme. This article provides an overview of the data from the recently published third analysis of the entire EPC programme [14] and the separate analysis of the Scandinavian Prostate Cancer Group Study No. 6 trial (SPCG-6, also known as Trial 25) [15]. Using these data, the underlying question of which patients are likely to benefit from bicalutamide 150 mg therapy is explored.

The EPC programme

The ongoing EPC programme comprises three complementary, double-blind, randomised, placebo-controlled trials [16] (Figure 2). A total of 8113 patients with localised or locally advanced, non-metastatic prostate cancer were enrolled and randomised in a 1: 1 ratio to receive standard care plus either bicalutamide 150 mg (n=4052) or placebo (n=4061). The primary end points of the EPC programme were overall survival and objective progression- free survival (PFS); tolerability was a secondary end point.

The EPC programme was designed to have 90% power to detect a 15% reduction in the rate of objective progression and overall survival for bicalutamide 150 mg compared with standard care alone [17]. To achieve this, overall recruitment of at least 7500 patients was required [16]. The three trials were set up in various geographical locations so that the required number of patients could be enrolled and also to reflect variation in clinical practice worldwide. Trial 23 was conducted in North America (n=3292 from 96 centres), Trial 24 in Europe, South Africa, Australia, Israel and Mexico (n=3603 from 196 centres), and SPCG-6 in Scandinavia (n=1218 from 61 centres). The effect of bicalutamide 150 mg was to be determined through a combined analysis of all three trials, as stated in each individual trial protocol. To identify where the effects of bicalutamide 150 mg were the greatest, examination of outcomes in the individual trials, as well as in prospectively defined subgroups (for example, disease stage at study entry and standard care received), were intended from the outset.

The third analysis of the EPC programme was pre-planned and took place at 7.4 years' median follow-up [14].

Findings from the EPC third analysis

Patient demographics
The two treatment arms were well balanced in terms of patient demographics and disease characteristics at baseline [18] (Table 1). Differences in disease prognosis and management were evident across individual trial populations, with prognosis worsening from Trial 23 to 24 to SPCG-6; this reflects the different clinical practices across the continents. Consistent with North American practice, most patients in Trial 23 were treated with radical prostatectomy and, unlike in Trials 24 and SPCG-6, those with lymph-node involvement or who were candidates for watchful waiting were excluded. Conversely, in accordance with Scandinavian practice, most patients in SPCG-6 were managed with watchful waiting [15]. As the differences between the trials apply equally to both treatment arms, they do not bias the size of treatment effects.

Overall efficacy results
Across the entire EPC programme, bicalutamide 150 mg significantly reduced the risk of objective progression by 21% compared with standard care alone (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.73, 0.85; p<0.001) [14]. There was no significant difference in overall survival between the treatment groups, with 23% of patients having died in both arms (HR 0.99; 95% CI 0.91, 1.09; p=0.89).

These findings suggest that at least some patients benefit from bicalutamide 150 mg therapy. Further investigation of outcomes in individual trials and prospectively defined subgroups were, therefore, warranted to identify where the benefits of bicalutamide therapy were greatest.

Identifying which patients benefit most from bicalutamide 150 mg therapy
In the subgroup of patients with localised disease, the addition of bicalutamide 150 mg to standard care provided no significant benefit in terms of overall survival or objective PFS, irrespective of the standard care received [14]. Moreover, there was a statistically insignificant trend towards decreased overall survival in bicalutamide-treated patients who would otherwise have undergone watchful waiting (HR 1.16; 95% CI 0.99, 1.37; p=0.07). The accumulation of several small imbalances in various causes of death, rather than one specific cause, appears to account for the increased number of deaths with bicalutamide in this patient subgroup. Nevertheless, these data suggest that, in patients with localised disease treated with bicalutamide, there is a level of tumour burden below which hormonal therapy may be harmful. Bicalutamide 150 mg should not, therefore, be used as immediate hormonal therapy for patients with localised disease.

In contrast with the results in patients with localised disease, the benefits of bicalutamide 150 mg were clearly demonstrated in those with locally advanced disease. When patients with locally advanced disease in the adjuvant and watchful waiting populations were considered, bicalutamide 150 mg significantly improved objective PFS, irrespective of the standard care received (HR 0.65; 95% CI: 0.57, 0.74; p<0.001), although there was no significant overall survival benefit. The objective PFS benefit extended into the radiotherapy (HR 0.56; 95% CI 0.40, 0.78; p<0.001), radical prostatectomy (HR 0.75; 95% CI 0.61, 0.91; p=0.004) and watchful waiting (HR 0.60; 95% CI 0.49, 0.73; p<0.001) subgroups (14) (Figure 4). Differences between the three standard care subgroups were found, however, in terms of overall survival.

For patients who received radiotherapy for locally advanced disease, adjuvant bicalutamide 150 mg significantly improved overall survival (HR 0.65; 95% CI 0.44, 0.95; p=0.03; Figure 3) compared with radiotherapy alone [14]. The difference in mortality was driven by a lower risk of prostate-cancer-related deaths with adjuvant bicalutamide 150 mg relative to radiotherapy alone (16.1% versus 24.3%, respectively). This is the first time that an overall survival benefit has been observed for any non-castrationbased hormonal therapy given as adjuvant treatment to patients with prostate cancer. Although this finding arises from a subgroup analysis and the risk of a false-positive result must be acknowledged, the results are unlikely to be due to chance given that they were driven by reduced prostate cancer mortality and because a highly significant objective PFS benefit was observed. Moreover, the magnitude of the overall survival benefit seen with bicalutamide 150 mg in this patient group (35% reduction in the risk of death) compares favourably with that reported with goserelin in the Radiation Therapy Oncology Group (RTOG) 85-31 trial, which comprises a near contemporary series of patients [2]. At 7.6 years' median follow-up, which is similar to the current length of follow-up in the EPC programme (median 7.4 years), goserelin adjuvant to radiotherapy significantly reduced the risk of death by 23% in patients with locally advanced disease compared with radiotherapy alone (HR 0.77; p=0.001).

In patients with locally advanced disease undergoing radical prostatectomy, there was no significant difference in overall survival between the adjuvant bicalutamide and standard care alone groups (HR 1.09; 95% CI 0.85, 1.39; p=0.51). However, in patients with locally advanced disease who would otherwise have undergone watchful waiting, a trend towards improved overall survival with bicalutamide 150 mg was observed (HR 0.81; 95% CI 0.66, 1.01; p=0.06). This survival trend was largely accounted for by findings in Trial 25, which included 359 of the 657 patients in the locally advanced, watchful waiting subgroup of the overall population; the watchful waiting patients in Trial 25 had a worse prostate cancer prognosis than the corresponding patients in Trial 24 as shown by higher PSA levels at trial entry. In Trial 25, there was statistical evidence that bicalutamide 150 mg improved overall survival (p=0.007) in this subset of patients [15].

Safety and tolerability of bicalutamide 150 mg
The latest data from the EPC programme confirm the good tolerability of bicalutamide 150 mg, consistent with findings from earlier analyses [17,18]. As expected with a non-steroidal antiandrogen, the most common adverse events with bicalutamide 150 mg were gynaecomastia (68.8%) and breast pain (73.6%) [14], which reflect the pharmacological action in blocking androgen receptors. These events were, however, of mild to moderate intensity in most cases (>90%) and were associated with a relatively low withdrawal rate (16.8%). Other adverse events were reported at low incidences, including impotence (9.3% with bicalutamide 150 mg versus 6.5% with standard care alone), decreased libido (3.6% versus 1.2%, respectively), hot flushes (9.2% versus 5.4%, respectively) and abnormal liver function tests (3.1% versus 1.7%, respectively).

Although not offered to patients in the EPC programme, effective options for the management of bicalutamide-induced gynaecomastia and breast pain are available. Data from randomised studies have demonstrated that radiotherapy is successful in suppressing these adverse events when used prophylactically (19) and in reducing their intensity when used therapeutically [20]. Tamoxifen has also shown efficacy in preventing and treating gynaecomastia and breast pain in randomised trials with no apparent detrimental effects on PSA control [21,22], but before it can be recommended in routine clinical practice, the impact of antioestrogen therapy on cancer control remains to be determined.

When compared with the tolerability profile of castration, bicalutamide 150 mg offers clear advantages, including maintenance of sexual and physical activity and preservation of bone mineral density and lean muscle mass [8,10,23]. The good tolerability profile of bicalutamide 150 mg means that this agent represents an attractive alternative to castration, particularly for patients who wish to maintain an active lifestyle.

Conclusions

The third analysis of the EPC programme, conducted at a median follow-up of 7.4 years, suggests that bicalutamide 150 mg is a valuable hormonal treatment option for patients with locally advanced disease, but not for those with localised disease. These data represent the first evidence of a significant overall survival benefit for a non-castration-based hormonal therapy as adjuvant to radiotherapy in patients with locally advanced disease, with findings comparable to those reported with goserelin as adjuvant to radiotherapy in the RTOG 85-31 trial. As bicalutamide 150 mg offers tolerability advantages over castration, particularly regarding maintenance of sexual and physical activity, it represents an attractive alternative hormonal therapy for men wishing to maintain an active lifestyle. In studying the effects of bicalutamide 150 mg in such a large number of patients, the EPC programme has improved our understanding of not only the role of bicalutamide 150 mg but also hormonal therapy as a concept in the management of non-metastatic prostate cancer.

Acknowledgements
We thank Dr Sharon Gladwin from Complete Medical Communications, who provided medical writing support funded by AstraZeneca.

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Peter Iversen MD
Department of Urology D-2112
University of Copenhagen, Rigshospitalet
Blegdamsvej 9, 2100
Copenhagen, Denmark
tel. +45 3545 2314, fax +45 3545 2158
piv@rh.hosp.dk