The addition of bicalutamide 150 mg to radiotherapy significantly improves overall survival in men with locally advanced prostate cancer

Abstract

Purpose:

Castration therapy adjuvant to radiotherapy can significantly improve overall survival compared with radiotherapy alone in patients with locally advanced prostate cancer. Although many of the adverse effects of castration therapy are manageable, they can have a detrimental effect on quality of life. Here we evaluate the efficacy and tolerability of the non-castration-based therapy bicalutamide (‘Casodex’) 150 mg adjuvant to radiotherapy in patients with T1-4, M0, any n prostate cancer.

Methods:

The subset of patients within the early prostate cancer (EPC) program who received radiotherapy with curative intent (n = 1,370) were included in the analysis. These patients were randomized to receive oral bicalutamide 150 mg once daily (n = 699) or placebo (n = 671).

Results:

The median follow-up for patients included in this analysis was 7.2 years. In patients with locally advanced disease (n = 305), bicalutamide adjuvant to radiotherapy significantly improved: progression-free survival (PFS), reducing the risk of objective progression by 44% compared with radiotherapy alone [hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.40, 0.78; P < 0.001). Prostate-specific antigen (PSA)–PFS, reducing the risk of PSA progression by 59% compared with radiotherapy alone (HR 0.41; 95% CI 0.30, 0.55; P < 0.001). Overall survival, reducing the risk of death by 35% compared with radiotherapy alone (HR 0.65; 95% CI 0.44, 0.95; P = 0.03). This significant overall survival benefit for bicalutamide was driven by a lower risk of prostate cancer-related deaths (16.1 vs 24.3%, respectively). There was no significant difference in PFS or overall survival in patients with localized disease (n = 1,065).

Conclusions:

In patients with locally advanced disease, bicalutamide 150 mg adjuvant to radiotherapy demonstrates significant clinical benefits in terms of overall survival, PFS and PSA–PFS compared with radiotherapy alone. The overall survival benefit in these patients is consistent with prior studies evaluating castration-based therapies adjuvant to radiotherapy (Bolla et al. in Lancet 360:103–108, 2002; Pilepich et al. in Int J Radiat Oncol Biol Phys 61:1285–1290, 2005). In addition, the clinical benefit of bicalutamide 150 mg in locally advanced patients, but not in those with localized disease, is consistent with the overall results from the EPC program (McLeod et al. BJU Int 97:247–254, 2006). Given the quality-of-life advantages of bicalutamide relative to castration, bicalutamide 150 mg adjuvant to radiotherapy is an attractive alternative for men with locally advanced prostate cancer.

Introduction

Clinical studies have shown that 17–64% of patients with locally advanced prostate cancer who receive radiotherapy alone experience clinical progression, and 26–43% die within 5 years of initiating treatment (Roach et al. 2000; Chuba et al. 2001; Vicini et al. 2002). The high-precision technique, conformal radiotherapy, has improved local control through dose escalation without increasing morbidity (Hanks et al. 1999). In addition, hormonal therapy has been combined with radiotherapy in patients with locally advanced disease with the dual objective of potentially eradicating micrometastases, and decreasing the risk of local recurrence as a result of secondary metastases through radiation-induced apoptosis (Aus et al. 2005).

There is considerable evidence demonstrating that castration therapy with a luteinizing hormone-releasing hormone (LHRH) agonist adjuvant to radiotherapy can significantly improve overall survival compared with radiotherapy alone in patients with locally advanced disease (Table 1) (Bolla et al. 2002; Pilepich et al. 2005). The most recently published analysis, the Radiation Therapy Oncology Group (RTOG) 85-31 trial, was performed at a median follow-up of 7.6 years and demonstrated that goserelin (‘Zoladex’) adjuvant to radiotherapy significantly reduced the risk of death by 23% compared with radiotherapy alone (P = 0.001) (Pilepich et al. 2005).

Table 1.

Summary of findings from studies showing an overall survival benefit with goserelin adjuvant to radiotherapy compared with radiotherapy alone

Study	No. evaluated patients (tumor classification)	Median follow-up (years)	Overall survival (goserelin plus radiotherapy vs radiotherapy alone)
RTOG 85-31 (Pilepich et al. 2005)	945 (cT1–2, N+, M0 or cT3, any N, M0)	7.6	49 vs 39%a (P = 0.002)
EORTC 22863 (Bolla et al. 2002)	412 (cT1–2, WHO grade 3, N0–1, M0 or cT3–4, N0–1, M0)	5.5	78 vs 62%b (P = 0.0002)

EORTC European Organisation for the Research and Treatment of Cancer; RTOG Radiation Therapy Oncology Group; WHO World Health Organization

^aEstimated 10-year rate

^bFive-year rate

There is, however, a range of adverse effects associated with castration therapy (Kirby et al. 1998; Iversen et al. 2000; Sieber et al. 2004; Green et al. 2004), including loss of libido, erectile dysfunction (Iversen et al. 2001), and a reduction in muscle mass and bone mineral density (Sieber et al. 2004). While many of these adverse effects are manageable, they can have a detrimental effect on quality of life at a time when issues such as reduced sexual activity and physical ability are of considerable importance to patients.

The antiandrogen bicalutamide provides an alternative to castration therapy, as it has similar survival benefits to castration in M0 patients (Iversen et al. 2000), with additional quality-of-life benefits, in terms of maintenance of sexual and physical activity (Iversen et al. 2000, 2002). In addition, several studies have indicated that treatment with bicalutamide (‘Casodex’) for up to 2 years does not adversely affect bone mineral density (Sieber et al. 2004; Smith et al. 2004).

The ongoing bicalutamide early prostate cancer (EPC) program, the world’s largest prostate cancer treatment program to date, is evaluating the efficacy and tolerability of adding bicalutamide 150 mg once daily to standard care (radical prostatectomy, radiotherapy, or watchful waiting) in patients with localized and locally advanced prostate cancer (McLeod et al. 2006). This article reports the findings for the radiotherapy subgroup of patients at a median follow-up of 7.2 years, which is a similar median follow-up to that of the RTOG 85-31 trial (7.6 years).

Methods

Eligibility and study design

Methods for the EPC program have been described in detail elsewhere (See et al. 2002; Wirth et al. 2004; McLeod et al. 2006) and are presented here in brief.

The three ongoing, randomized, double-blind, placebo-controlled trials within the EPC program (trial 23, n = 3,292 from 96 centers; trial 24, n = 3,603 from 191 centers; and trial 25, n = 1,218 from 62 centers) were prospectively designed and powered for a stratified combined analysis.

Eligible patients were men aged ≥ 18 years (upper age limit in trial 25 of 75 years) with clinically or pathologically confirmed localized (T1-2, N0/Nx) or locally advanced (T3-4, any N; or any T, N+) prostate cancer with no evidence of distant metastases. Patients were randomized in a 1:1 ratio to receive oral bicalutamide 150 mg or placebo once daily following standard care (radical prostatectomy, radiotherapy, or watchful waiting), which was initiated by the centers as per local practice. Patients were excluded from the EPC trials if they had received prior systemic therapy for prostate cancer, although neoadjuvant therapy (of the investigator’s choice) was permitted in trials 23 and 24 (but not trial 25).

The EPC program was designed to reflect current standard care worldwide; therefore, surgical procedures, radiotherapy techniques and dose-fractionation schedules, as well as type and duration of neoadjuvant hormonal therapy, were not specified in the protocol. It should be noted that any differences between the trials or between individual centers apply equally to both treatment arms and do not bias the results.

The three trials are being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and the Ethics Committee or Institutional Review Board at each contributing center. All patients have provided written, informed consent.

Endpoints

Primary endpoints in the EPC program are time to objective progression-free survival (PFS) and overall survival. Prostate-specific antigen (PSA)–PFS and tolerability were secondary endpoints.

Statistical analysis

Time-to-event data were analyzed on an intent-to-treat basis using a Cox proportional hazards regression model with covariates for trial, randomized treatment, initial PSA level, tumor grade and stage. The results are presented as hazard ratios (HRs), with the associated 95% confidence intervals (CIs) and P-values. The adverse-effect data are descriptive only.

Results

Patients

Of the 1,370 patients who received radiotherapy as standard care in the EPC program, 699 were randomized to receive bicalutamide 150 mg and 671 were randomized to receive radiotherapy alone (Fig. 1). The treatment groups were well balanced with respect to baseline demographics and disease characteristics (Table 2).

Fig. 1.

Flow diagram of study patients

Table 2.

Patient demographics and baseline disease characteristics

	Bicalutamide 150 mg plus radiotherapy (n = 699)	Placebo plus radiotherapy (n = 671)
Mean age, years (range)	69.6 (48–85)	69.3 (47–82)
Race (%)
Caucasian	87.0	88.8
Black	6.3	5.7
Other	6.7	5.5
Stage of disease (%)
T1/T2	77.5	79.1
T3	21.7	20.1
T4	0.7	0.8
Nodal status (%)
N0	30.8	33.1
Nx	68.2	65.9
N+	1.0	1.0
Tumor grade (Gleason score) a (%)
Well differentiated (2–4)	23.8	22.1
Moderately differentiated (5–6)	49.6	52.2
Poorly differentiated (7–10)	23.7	25.6
Not known	1.4	0.1
Median PSA level, ng/ml (range)
Prior to radiotherapy	11.3 (0.3–681.0)	11.2 (0.4–204.0)
At randomization	3.4 (NQ–119.3)	3.5 (NQ–147.2)
Localized disease	3.3 (NQ–69.0)	3.4 (NQ–101.3)
Locally advanced disease	3.8 (NQ–119.3)	4.0 (NQ–147.2)
Use of neoadjuvant therapy (%)	30.0	32.5
Trial (%)
23	46.5	47.7
24	47.9	48.4
25	5.6	3.9

NQ non-quantifiable (0.2 ng/ml in trial 23; 1.0 ng/ml in trials 24 and 25); PSA prostate-specific antigen

^aIn some cases, Gleason score was derived by conversion of World Health Organization grades

A total of 538 patients (77%) randomized to receive bicalutamide 150 mg adjuvant to radiotherapy had localized disease and 161 patients (23%) had locally advanced disease. In comparison, 527 patients (79%) randomized to radiotherapy alone had localized disease and 144 patients (21%) had locally advanced disease (Fig. 1).

Treatment duration

This analysis was undertaken at a median follow-up of 7.2 years. The median duration of randomized treatment was 1.8 years (range 1 day to 7.8 years) for the 694 patients who received bicalutamide 150 mg adjuvant to radiotherapy and 1.9 years (range 4 days to 8.2 years) for the 664 patients receiving radiotherapy alone. Second-line systemic therapy as a result of disease progression has been initiated in 153 (21.9%) patients in the bicalutamide group (LHRH agonist 9.4%; antiandrogen 7.2%; orchiectomy 1.1%; combined androgen blockade 2.5%; other 1.6%) and 243 (36.2%) patients in the radiotherapy alone group (LHRH agonist 11.3%; antiandrogen 10.6% (open-label bicalutamide 5.1%); orchiectomy 1.9%; combined androgen blockade 5.1%; other 2.2%).

Radiotherapy

Information on the characteristics of the radiotherapy used was not collected at the onset of the trial program. However, we have attempted to collect this information this retrospectively in trials 24 and 25 (but not trial 23); it should be noted that some records were no longer available or incomplete. Of the 725 patients receiving radiotherapy in trials 24 and 25, information was collected for 681 (93.9%) patients on the type of radiotherapy given, 643 (88.9%) patients on the dose of radiotherapy, 619 (85.4%) patients on the number of fractions, and 621 (85.7%) patients on the duration of therapy. Of the data collected, the vast majority of patients received external-beam radiotherapy alone (93.4%), while 6.5% of patients received external-beam radiotherapy and brachytherapy. In those patients undergoing external-beam radiotherapy alone, the median dose was 64 Gy, with a median of 32 fractions and a median duration of therapy of 6.6 weeks.

Efficacy

Objective progression-free survival

In the overall radiotherapy population, the objective disease progression endpoint was met by 231 patients (33.0%) receiving bicalutamide 150 mg and 261 patients (38.9%) receiving radiotherapy alone (Table 3). Bicalutamide 150 mg adjuvant to radiotherapy significantly improved objective PFS, reducing the risk of objective progression by 25% compared with radiotherapy alone (HR 0.75; 95% CI 0.63, 0.90; P = 0.002) (Fig. 2a and Table 3). In patients with localized disease, there was no significant difference in objective PFS between the two treatment groups (Fig. 2b and Table 3). In patients with locally advanced disease, bicalutamide 150 mg adjuvant to radiotherapy significantly improved objective PFS, reducing the risk of objective progression by 44% compared with radiotherapy alone (HR 0.56; 95% CI 0.40, 0.78; P < 0.001) (Fig. 2c and Table 3).

Table 3.

Analysis of objective PFS, overall survival and PSA–PFS in the overall radiotherapy subgroup by disease stage

Endpoint	No. patients	No. events/total no. patients (%)		HR (95% CI)	P-value
		Bicalutamide 150 mg plus radiotherapy	Placebo plus radiotherapy
Objective PFS a
Overall	1,370	231/699 (33.0)	261/671 (38.9)	0.75 (0.63, 0.90)	0.002
Localized	1,065	165/538 (30.7)	175/527 (33.2)	0.86 (0.69, 1.06)	0.17
Locally advanced	305	66/161 (41.0)	86/144 (59.7)	0.56 (0.40, 0.78)	<0.001
Overall survival b
Overall	1,370	192/699 (27.5)	207/671 (30.8)	0.86 (0.70, 1.04)	0.12
Localized	1,065	143/538 (26.6)	146/527 (27.7)	0.94 (0.75, 1.19)	0.63
Locally advanced	305	49/161 (30.4)	61/144 (42.4)	0.65 (0.44, 0.95)	0.03
PSA–PFS c
Overall	1,370	303/699 (43.3)	358/671 (53.4)	0.61 (0.52, 0.71)	<0.001
Localized	1,065	221/538 (41.1)	249/527 (47.2)	0.73 (0.61, 0.87)	<0.001
Locally advanced	305	82/161 (50.9)	109/144 (75.7)	0.41 (0.30, 0.55)	<0.001

CI confidence interval; HR hazard ratio; PFS progression-free survival; PSA prostate-specific antigen

^aTime from date of randomization to date of objectively confirmed progression, or death in the absence of objectively confirmed progression

^bTime from date of randomization to date of death from any cause

^cTime from randomization to the first of increase of serum PSA to twice that recorded at randomization, objectively confirmed progression, or death from any cause

Fig. 2.

Kaplan–Meier plots of objective progression-free survival for bicalutamide 150 mg plus radiotherapy versus radiotherapy alone for a the overall population (n = 1,370); b patients with localized disease (n = 1,065); and c patients with locally advanced disease (n = 305) at a median follow-up of 7.2 years

Overall survival

In the overall radiotherapy population and in patients with localized disease, there was no significant difference in overall survival between patients receiving bicalutamide 150 mg adjuvant to radiotherapy and radiotherapy alone (Fig 3a, b and Table 3). However, in patients with locally advanced disease, bicalutamide 150 mg adjuvant to radiotherapy significantly improved overall survival, reducing the risk of death by 35% relative to radiotherapy alone (HR 0.65; 95% CI 0.44, 0.95; P = 0.03) (Fig. 3c). In this subgroup of patients, 30% of patients receiving bicalutamide 150 mg had died and 42% in the radiotherapy alone population had died (Table 3); this was an important new finding. The significant overall survival benefit with bicalutamide 150 mg adjuvant to radiotherapy was driven by a lower risk of prostate cancer-related deaths compared with radiotherapy alone (16.1 vs 24.3%, respectively) (Fig. 4).

Fig. 3.

Kaplan–Meier plots of overall survival for bicalutamide 150 mg plus radiotherapy versus radiotherapy alone for a the overall population (n = 1,370); b patients with localized disease (n = 1,065); and c patients with locally advanced disease (n = 305) at a median follow-up of 7.2 years

Fig. 4.

Total and prostate cancer-specific deaths for bicalutamide 150 mg plus radiotherapy versus radiotherapy alone for the overall population (n = 1,370), patients with localized disease (n = 1,065), and patients with locally advanced disease (n = 305) at a median follow-up of 7.2 years

Prostate-specific antigen progression-free survival

In the overall radiotherapy population, the PSA progression endpoint was met by 303 patients (43.3%) receiving bicalutamide 150 mg and 358 patients (53.4%) receiving radiotherapy alone (Table 3). The greatest benefit in terms of reducing PSA progression was again in those patients with locally advanced disease. In these patients, bicalutamide 150 mg adjuvant to radiotherapy significantly improved PSA–PFS, reducing the risk of PSA progression by 59% compared with radiotherapy alone (HR 0.41; 95% CI 0.30, 0.55; P < 0.001) (Table 3).

Safety and tolerability

Adverse events

As expected with a non-steroidal antiandrogen, the most commonly reported adverse events in patients who received bicalutamide 150 mg adjuvant to radiotherapy were breast pain (75.1%) and gynecomastia (67.3%) (Table 4). These events, however, were mild to moderate in > 90% of cases. The incidences of other adverse events, such as impotence (12.7% for bicalutamide vs 9.9% for placebo), decreased libido (4.0 vs 1.4%, respectively), hot flashes (9.8 vs 5.4%, respectively), and abnormal liver function (2.2 vs 1.8%, respectively), were similar in both treatment groups.

Table 4.

Adverse effects occurring in ≥ 10% of the radiotherapy subgroup of patients in either treatment group

	No. patients (%)
	Bicalutamide 150 mg plus radiotherapy (n = 694)	Placebo plus radiotherapy (n = 664)
Breast pain	521 (75.1)	63 (9.5)
Gynecomastia	467 (67.3)	72 (10.8)
Diarrhea	108 (15.6)	93 (14.0)
Asthenia	94 (13.5)	65 (9.8)
Impotence	88 (12.7)	66 (9.9)
Back pain	83 (12.0)	92 (13.9)
Pharyngitis	79 (11.4)	74 (11.1)
Rectal hemorrhage	79 (11.4)	75 (11.3)
Constipation	77 (11.1)	61 (9.2)
Rash	75 (10.8)	59 (8.9)
Hematuria	66 (9.5)	84 (12.7)
Arthralgia	60 (8.6)	74 (11.1)

Withdrawal rates due to adverse events were 218 (31.4%) and 73 (11.0%), respectively. A total of 114 patients (16.4%) receiving bicalutamide and 7 patients (1.1%) receiving radiotherapy alone withdrew due to gynecomastia and/or breast pain.

Deaths

Fewer patients receiving bicalutamide adjuvant to radiotherapy died of prostate cancer compared with those who received radiotherapy alone (7.1 vs 9.2%, respectively) (Table 5). Non-prostate cancer-related deaths occurred in 20.5% of patients receiving bicalutamide 150 mg and in 22.0% of patients receiving radiotherapy alone.

Table 5.

Most common causes of death (≥ 0.7% in either treatment group) in the radiotherapy subgroup of patients

	No. patients (%)
	Bicalutamide 150 mg plus radiotherapy (n = 694)	Placebo plus radiotherapy (n = 664)
Prostate cancer	49 (7.1)	61 (9.2)
Myocardial infarction	18 (2.6)	23 (3.5)
Cause unknown	14 (2.0)	14 (2.1)
Gastrointestinal carcinoma	12 (1.7)	10 (1.5)
Cerebrovascular accident	11(1.6)	9 (1.4)
Carcinoma	10 (1.4)	2 (0.3)
Pneumonia	8 (1.2)	10 (1.5)
Lung carcinoma	6 (0.9)	10 (1.5)
Heart arrest	6 (0.9)	5 (0.8)
Lung disorder	5 (0.7)	2 (0.3)
Heart failure	4 (0.6)	5 (0.8)
Pulmonary embolus	3 (0.4)	6 (0.9)

Discussion

For the first time, an overall survival benefit for any non-castration-based hormonal therapy given as adjuvant treatment to patients with prostate cancer is reported. In patients with locally advanced disease, the addition of bicalutamide 150 mg to radiotherapy of curative intent significantly reduced the risk of death by 35% compared with radiotherapy alone. Importantly, this observation at a median follow-up of 7.2 years was driven by a reduction in the risk of prostate cancer-related deaths and thus reflects a real benefit for patients with prostate cancer. In addition, the significant overall survival benefit with adjuvant bicalutamide 150 mg in patients with locally advanced disease was accompanied by significant improvements in objective PFS and reduced time to PSA progression.

The results from this analysis have arisen from a subgroup analysis of the entire EPC program (McLeod et al. 2006). Consequently, it is important to assess the credibility of the results. The fact that PFS and PSA progression were significant in the entire EPC program means that the results seen for PFS and PSA progression from this locally advanced radiotherapy subset are highly unlikely to be due to chance. In terms of overall survival, there was no significant difference across the entire EPC program. While this does increase the possibility of a false positive finding in a subgroup analysis, the survival benefit seen in locally advanced radiotherapy patients was driven by a reduction in prostate cancer mortality, and was coupled with a highly significant PFS benefit, and both of these observations add to the validity of this finding.

In addition to the overall results of the EPC program, the results presented here are consistent with prior studies evaluating castration-based therapies adjuvant to radiotherapy (Bolla et al. 2002). For example, the 35% significant reduction in the risk of death observed with bicalutamide 150 mg adjuvant to radiotherapy compares favorably with that observed with goserelin adjuvant to radiotherapy in the RTOG 85-31 trial (n = 945) (Pilepich et al. 2005). In the RTOG 85-31 trial, goserelin significantly reduced the risk of death by 23% in patients with locally advanced disease compared with radiotherapy alone (HR 0.77; P = 0.001). As with the present analysis, this was driven by a lower risk of prostate cancer-related deaths (16 vs 22%, respectively in RTOG 85-31) (Pilepich et al. 2005). Furthermore, the overall survival benefit in RTOG 85-31 became apparent at 7.6 years’ median follow-up, which is similar to the median follow-up at this analysis performed at 7.2 years. These similarities are of particular importance given that goserelin is the only other hormonal therapy with a proven overall survival benefit in this setting (Pilepich et al. 2005). The data presented here, therefore, indicate that bicalutamide 150 mg has a similar efficacy to goserelin in patients with locally advanced disease. This is consistent with previous findings from Iversen and colleagues who showed that there was no significant difference in overall survival between castration (orchiectomy or goserelin) and bicalutamide in patients with locally advanced disease (median follow-up of 6.3 years) (Iversen et al. 2000).

The European Organisation for Research and Treatment of Cancer (EORTC) 22863 trial has also shown a significant overall survival benefit in patients receiving goserelin adjuvant to radiotherapy in patients with locally advanced disease (Table 1) (Bolla et al. 2002). In this study, at a median follow-up of 5.5 years, goserelin adjuvant to radiotherapy significantly reduced the risk of death by 49% compared with radiotherapy alone (HR 0.51; 95% CI 0.36, 0.73; P < 0.0001; n = 412) (Bolla et al. 2002). This reduction in the risk of death is higher than that observed in the present analysis and the RTOG 85-31 trial. There are, however, notable differences between the trials. In the EORTC 22863 trial, goserelin was initiated on the first day of radiotherapy and continued for 3 years (Bolla et al. 2002). In the EPC program drug therapy was only administered after completion of radiotherapy. It is, therefore, possible that the greater reduction in the risk of death in the EORTC 22863 trial compared with the present analysis and the RTOG 85-31 trial could be due to the addition of concomitant hormonal therapy to radiotherapy. Patients in the EORTC 22863 trial, however, also appear to be at a higher risk of death compared with the present analysis and the RTOG 85-31 trials. This is shown by a numerically higher number of deaths in patients who received radiotherapy alone in the EORTC 22863 trial compared with those who received radiotherapy alone in the present analysis and in the RTOG 85-31 trial (Bolla et al. 2002).

The dose of radiotherapy used in the EPC program (median 64 Gy) was in line with radiotherapy guidelines when the trial was started in 1995. The RTOG 85-31 trials administered a total prescribed dose of 65–70 Gy (Pilepich et al. 2005), while the EORTC 22863 trial administered a total prescribed dose of 70 Gy (Bolla et al. 2002). While current guidelines now recommend a higher dose of 78 Gy (Aus et al. 2005), the results from the three trials would be expected to be applicable given that radiotherapy cannot eradicate distant disease although the magnitude of benefit obtained may be different.

These differences between the EORTC 22863 trial, the present analysis and the RTOG 85-31 trial therefore suggest that in terms of trial design the RTOG 85-31 trial is more comparable to the EPC program when examining the effects of adding hormonal therapy adjuvant to radiotherapy.

Advancing disease is associated with debilitating symptoms such as painful metastases, spinal cord compression, pathological fractures, and urinary dysfunction (Smith et al. 1999). Patients with locally advanced disease are at highest risk of developing these symptoms due to disease progression compared with those with localized disease (Soloway and Roach 2005). In this analysis, bicalutamide 150 mg adjuvant to radiotherapy significantly reduced the risk of objective progression by 44% compared with radiotherapy alone in patients with locally advanced disease. In addition, bicalutamide significantly reduced the risk of PSA–PFS by 59% in these patients compared with radiotherapy alone. This reduction in PSA progression is of particular importance given that PSA is widely used to monitor disease status and is often used as a marker to drive further therapy. Moreover, from a patient’s perspective, PSA recurrence and elevated clinical symptoms can cause psychological distress (Ullrich et al. 2003). Therefore, a delay in time to objective and PSA progression may benefit prostate cancer patients by reducing their anxiety.

In patients with localized disease, the analysis presented here showed no significant difference in overall survival or objective PFS. Therefore, coupled with the findings from the EPC program overall, in which patients with localized disease do not appear to derive clinical benefit from the addition of bicalutamide irrespective of the standard care received (McLeod et al. 2006), we conclude that bicalutamide 150 mg is not recommended in this setting.

Quality-of-life issues are becoming increasingly important for men with prostate cancer who wish to maintain an active lifestyle. For these patients, maintenance of sexual function, vitality and mobility are often a high priority. Although these issues were not addressed in the EPC program, other studies have demonstrated additional quality-of-life benefits with bicalutamide relative to castration. In a study pooling two open-label, multicenter trials of identical design, bicalutamide has shown significant benefits in terms of maintaining sexual interest and physical capacity compared with castration in patients with locally advanced disease (Iversen et al. 2000). Furthermore, bicalutamide has been shown to have no effect on bone mineral density, and to have fewer adverse events, such as hot flashes, compared with castration (Iversen et al. 2000; Sieber et al. 2004). However, patients receiving non-steroidal antiandrogens do have a higher incidence of gynecomastia and breast pain (mild to moderate in > 90% of cases) than those receiving castration (Iversen et al. 2000), and these symptoms do lead to withdrawal of therapy in approximately 16% of locally advanced adjuvant patients (McLeod et al. 2006).

Many of the symptoms of castration therapy can be managed. For example, loss of bone mineral density can be reduced with bisphosphonates (Smith et al. 2001; Smith 2003; Aus et al. 2005) and hot flashes can be treated with diethylstilbestrol, cyproterone acetate, venlafaxine or clonidine (Aus et al. 2005). Similarly, bicalutamide-induced gynecomastia and breast pain can be effectively managed with either radiotherapy (therapeutic or prophylactic) or tamoxifen (Tyrrell et al. 2004; Boccardo et al. 2005; Van Poppel et al. 2005). However, two recent studies comparing tamoxifen with radiotherapy for the prevention and treatment of bicalutamide-induced gynecomastia and breast pain have shown tamoxifen to be more effective than radiotherapy (Di Lorenzo et al. 2005; Perdona et al. 2005). The symptoms of bicalutamide-induced gynecomastia and breast pain are often reversible upon discontinuation of treatment (Moul et al. 2003). Following cessation of LHRH agonist treatment, however, the median time to testosterone recovery is reported to be 7–16 months (Pickles et al. 2002). Nonetheless, these different profiles of bicalutamide and LHRH agonist treatment should be considered for each individual patient.

In conclusion, the findings from the radiotherapy subgroup of patients within the EPC program demonstrate a significant overall survival benefit for bicalutamide 150 mg compared with radiotherapy alone in patients with locally advanced disease. This is the first evidence of an overall survival benefit for any non-castration-based therapy in this setting. Moreover, this benefit compares favorably with the overall survival benefit observed with goserelin adjuvant to radiotherapy (the only other hormonal therapy with a proven overall survival benefit in patients with locally advanced disease) in the RTOG 85-31 trial. Bicalutamide, however, has additional quality-of-life benefits relative to castration in terms of maintaining sexual interest, physical ability, and bone mineral density. Therefore, for locally advanced patients treated with radiotherapy, adjuvant bicalutamide 150 mg is an attractive alternative to castration.