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BICALUTAMIDE 150 MG IN ADDITION TO STANDARD CARE IN PATIENTS WITH LOCALIZED OR LOCALLY ADVANCED PROSTATE CANCER: RESULTS FROM THE SECOND ANALYSIS OF THE EARLY PROSTATE CANCER PROGRAM AT MEDIAN FOLLOWUP OF 5.4 YEARS
0022-5347/04/1725-1865/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 172, 1865–1870, November 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000140159.94703.80
BICALUTAMIDE 150 MG IN ADDITION TO STANDARD CARE IN PATIENTS WITH LOCALIZED OR LOCALLY ADVANCED PROSTATE CANCER: RESULTS FROM THE SECOND ANALYSIS OF THE EARLY PROSTATE CANCER PROGRAM AT MEDIAN FOLLOWUP OF 5.4 YEARS MANFRED P. WIRTH,*, † WILLIAM A. SEE,‡ DAVID G. MCLEOD,§ PETER IVERSEN,㛳 TOM MORRIS㛳 AND KEVIN CARROLL㛳 ON BEHALF OF THE CASODEX EARLY PROSTATE CANCER TRIALISTS’ GROUP From the Department of Urology, Technical University of Dresden, Dresden, Germany, the Medical College of Wisconsin, Milwaukee, Wisconsin, the Walter Reed Army Medical Center, Washington, D. C., the Department of Urology, Rigshospitalet, Copenhagen, Denmark, and AstraZeneca, Macclesfield, United Kingdom
ABSTRACT
Purpose: We evaluated the efficacy and tolerability of 150 mg bicalutamide daily given in addition to standard care, in patients with localized or locally advanced prostate cancer. Materials and Methods: The bicalutamide Early Prostate Cancer program consists of 3 randomized, double blind, placebo controlled trials prospectively designed for combined analysis. A total of 8,113 men with T1b–T4, M0, any N (N0 in 1 trial) prostate cancer were randomized to bicalutamide 150 mg/day (4,052) or placebo (4,061) in addition to standard care (radical prostatectomy, radiotherapy or watchful waiting). Primary end points were objective progression-free survival (PFS) and overall survival. Results: At median 5.4 years of followup (21.6% progression events) bicalutamide significantly improved PFS in the overall population. This result was driven by positive results in trials 24 and 25, with the North American trial (trial 23) showing no difference. Patients with locally advanced disease gained most benefit from bicalutamide in terms of PFS, irrespective of underlying therapy. Overall survival was similar in the bicalutamide and placebo groups, across the program and in each trial. Among watchful waiting patients survival appeared to be improved with bicalutamide in those with locally advanced disease, whereas survival appeared to be reduced with bicalutamide in those with localized disease. The most common adverse events with bicalutamide were gynecomastia and breast pain. Other adverse events occurred with a similarly low incidence in the 2 treatment groups. Conclusions: This analysis confirms that bicalutamide provides benefit in patients with locally advanced disease. The current data suggest that early or adjuvant hormonal therapy for patients at low risk of disease progression, such as those with localized disease, is not appropriate. KEY WORDS: androgen antagonists, prostatic neoplasms
Standard management options for early (localized and locally advanced) prostate cancer include radical prostatectomy, radiotherapy and watchful waiting. However, patients with high risk disease, for example locally advanced disease, high Gleason scores or increased pretreatment prostate specific antigen (PSA) at diagnosis, remain at significant risk for disease progression/recurrence after primary therapy
alone.1–3 Since disease progression is associated with debilitating symptoms such as painful bone metastases, spinal cord compression, pathological fractures and urinary obstruction, additional treatment options are needed.4 The value of adding bicalutamide 150 mg/day to standard care for early prostate cancer is being investigated in the bicalutamide (Casodex, AstraZeneca, Wilmington, Delaware) Early Prostate Cancer (EPC) program, involving more than 8,000 patients worldwide. This program was designed to reflect global variability in clinical practice as far as possible at the time it was initiated, while minimizing the potential for bias, as well as to support a combined analysis. Results from the first per protocol analysis (median followup 3 years) were published previously.5 The EPC program is ongoing, and results of the second, combined per protocol analysis (minimum followup 4.5 years) are reported here.
Accepted for publication April 30, 2004. Study received Ethics Committee or Institutional Review Board approval at each center. * Correspondence: Department of Urology, Technical University of Dresden Medical School, Fetscherstrasse 74, Dresden D-01307, Germany (telephone: ⫹49 351 458 4447; FAX: ⫹49 351 458 4333; e-mail: [email protected]). † Financial interest and/or other relationship with AstraZeneca, Novartis, Praecis and GJK. ‡ Financial interest and/or other relationship with Abbott, Pfeiffer Foundation, Novartis, Merck, Therion Biologics, AstraZeneca, Intuitive Surgical, Pfizer, TAP Pharmaceutical Products Inc., National Cancer Institute, Southwest Oncology Group, Medical College of Wisconsin Cancer Center, Veterans Affairs Merit Review, University MATERIALS AND METHODS of Washington subcontract, National Measurement Laboratory, Antigenics, and National Institute for Diabetes and Digestive and KidStudy design and treatment. Detailed methods for the EPC ney Diseases. program have been described5 and are presented here in § Financial interest and/or other relationship with AstraZeneca, brief. The EPC program comprises 3 randomized, double Abbott, GlaxoSmithKline and Sanofi. blind, placebo controlled trials in North America (trial 23, 㛳 Financial interest and/or other relationship with AstraZeneca. 1865
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BICALUTAMIDE EARLY PROSTATE CANCER PROGRAM TABLE 1. Overall demographics Bicalutamide
Placebo
Trial 23
Trial 24
Trial 25
No. pts 4,052 4,061 3,292 3,603 1,218 Mean age (range) 66.9 (42–93) 66.9 (38–93) 64 (38–85) 69 (48–93) 69 (48–87) Disease stage (%):* T1/T2 67 68 73 65 60 T3 32 30 27 32 38 T4 2 2 0.2 3 2 Nodal status (%): N0 60 59 72 61 21 Nx 38 39 28 36 75 N⫹ 2 2 0 3 4 Gleason score (%): 2–4 22 22 5 31 43 5–6 44 45 48 41 44 7–10 33 32 47 26 12 Race (%): White 91 91 84 95 100 Black 5 5 12 1 0 Other 4 4 4 4 0 Standard care received (%): Radical prostatectomy 55 55 80 46 13 Radiotherapy 17 17 20 18 5 Watchful waiting 28 29 0 36 81 Neoadjuvant therapy (%) 17 17 22 18 0.5 Median ng/ml PSA before standard therapy 8.8 8.7 7.1 11.7 16.1 Median ng/ml PSA at baseline: Radical prostatectomy 1.0 1.0 Below limits of quantification Below limits of quantification 1.2 Radiotherapy 4.8 5.3 3.0 3.4 8.2 Watchful waiting 13.1 13.6 Not applicable 11.4 17.2 Median pt yrs of exposure 1.85 1.86 1.8 3.7 4.2 Median pt yrs of followup 5.43 5.42 5.7 5.1 5.3 * Disease stage determined pathologically for radical prostatectomy cases, but clinically for radiotherapy and watchful waiting.
FIG. 1. Kaplan-Meier curves of objective progression-free survival in trials 23 to 25 and in overall population
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TABLE 2. Analysis of objective progression-free survival for the overall population by trial and by primary therapy/disease stage No. Pts Overall population Trial: 23 24 25 Adjuvant therapy: Localized disease Locally advanced disease Watchful waiting: Localized disease Locally advanced disease
No. Events (%)
HR
95% CI
959 (23.6)
0.73
0.66, 0.80
⬍0.0001
170 (10.3) 507 (28.1) 282 (46.2) 489 (16.9) 249 (13.2) 240 (24.2) 470 (40.1) 273 (32.2) 197 (61.2)
1.02 0.73 0.57 0.77 0.86 0.67 0.68 0.81 0.53
0.83, 1.26 0.64, 0.83 0.48, 0.68 0.67, 0.87 0.72, 1.03 0.56, 0.82 0.60, 0.78 0.68, 0.96 0.42, 0.65
0.824 ⬍0.0001 ⬍0.0001 0.00007 0.0971 0.00005 ⬍0.0001 0.018 ⬍0.0001
Bicalutamide
Placebo
8,113
797 (19.7)
3,292 3,603 1,218 5,824 3,799 2,024 2,285 1,627 657
177 (10.7) 405 (22.5) 215 (35.4) 419 (14.3) 229 (12.0) 191 (18.4) 377 (33.8) 229 (29.4) 148 (44.2)
p Value
End points. In each trial in the EPC program the end points included objective progression free survival (PFS) and overall survival. Objective PFS was defined as the time from randomization to the earliest occurrence of objective progression (confirmed by bone scan, computerized tomography/ultrasound/magnetic resonance imaging or histological evidence of distant metastases) or death from any cause without progression. Tolerability was a secondary end point and all adverse events were those reported spontaneously. Statistical analysis. The timing of the second analysis was based on the accrual of sufficient deaths across the program to allow detection of a 15% decrease in the overall mortality rate (80% power, 5% 2-sided significance). It was estimated that the required number of events (1,200) would occur by December 31, 2002, with 4.5 years’ minimum followup. Time to event data were analyzed on an intent to treat basis using the Cox proportional hazards regression model with covariates for trial, randomized treatment, primary therapy, baseline PSA, tumor grade and disease stage. This analysis estimates the hazard ratio (HR), the reduction in risk of an event. An alternative statistical analysis was also applied to objective PFS data to estimate the treatment benefit in terms of the relative increase in time to event (the event-to-time ratio [ETR]).6 As per protocol, data from the overall popula-
3,292 patients), Europe, South Africa, Australia, Israel and Mexico (trial 24, 3,603), and Scandinavia (trial 25, 1,218). The program was designed to support a combined analysis. Patients were randomized (1:1) to receive bicalutamide up to 150 mg or placebo once daily in addition to standard care (radical prostatectomy, radiotherapy, watchful waiting). According to protocol the duration of randomized therapy was 2 years in trial 23 and until disease progression in trials 24 (maximum 5 years recommended for adjuvant cases) and 25. Therapy upon disease progression was initiated at the investigators’ discretion, and all patients were followed for objective progression and death. The trials are conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and with Ethics Committee or Institutional Review Board approval at each center. An independent Data and Safety Monitoring Committee reviews safety and efficacy data on an ongoing basis. Although the study blind was broken at database level following the first analysis,5 it must be emphasized that the trials did not stop and all patients continued to be followed under the trial protocols. At this analysis 7% of patients in trials 24 and 25 had chosen to break the individual blind while still receiving randomized therapy (in total 10% of patients in trials 24 and 25 broke their blind). All patients in trial 23 had completed randomized therapy by the first analysis. Patients. Men 18 years old or older (upper limit 75 years in trial 25) with clinically or pathologically confirmed stage T1b–T4 prostate cancer and no distant metastases on bone scan were eligible. Trial 23 differed from trials 24 and 25 in that candidates for watchful waiting as well as patients with lymph node involvement were excluded from study.
TABLE 3. ETR analysis of objective PFS by underlying primary therapy/disease stage Primary Therapy/Disease Stage
ETR
95% CI
Adjuvant: 1.22 Localized 1.11 Locally advanced 1.37 Watchful waiting:* 1.31 Localized 1.16 Locally advanced 1.58 * In patients with locally advanced disease median objective and 44.1 months for bicalutamide and placebo, respectively.
1.11, 1.35 0.98, 1.26 1.18, 1.61 1.19, 1.45 1.03, 1.32 1.35, 1.86 PFS was 73.2
FIG. 2. Kaplan-Meier population.
curve
of
overall
survival
in
overall
TABLE 4. Analysis of objective progression-free survival for radical prostatectomy and radiotherapy populations by disease stage Population
No. Pts
Radical prostatectomy: Localized Locally advanced Radiotherapy: Localized Locally advanced
4,454 2,734 1,719 1,370 1,065 305
No. Events (%) Bicalutamide
Placebo
251 (11.2) 115 (8.4) 136 (15.6) 168 (24.0) 114 (21.2) 54 (33.5)
291 (13.1) 121 (8.8) 170 (20.0) 198 (29.5) 128 (24.3) 70 (48.6)
HR (95% CI; p value)
ETR (95% CI)
0.80 (0.68, 0.95; 0.0099) 0.93 (0.72, 1.20; 0.568) 0.71 (0.57, 0.89; 0.0034) 0.72 (0.59, 0.89; 0.002) 0.80 (0.62, 1.03; 0.088) 0.58 (0.41, 0.84; 0.00348)
1.19 (1.04, 1.37) 1.06 (0.87, 1.28) 1.32 (1.10, 1.59) 1.26 (1.09, 1.45) 1.16 (0.98, 1.37) 1.53 (1.16, 2.02)
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BICALUTAMIDE EARLY PROSTATE CANCER PROGRAM TABLE 5. Analysis of overall survival for overall population by trial and by primary therapy/disease stage No. Pts
Overall population Trial: 23 24 25 Adjuvant therapy: Localized disease Locally advanced disease Watchful waiting: Localized disease Locally advanced disease
No. Events (%)
95% CI
p Value
608 (15.0)
1.03
0.92, 1.15
0.582
134 (8.1) 316 (17.5) 158 (25.9) 301 (10.4) 182 (9.6) 119 (12.0) 307 (26.2) 174 (20.5) 133 (41.3)
1.07 1.03 0.99 1.01 1.01 1.04 1.04 1.23 0.81
0.84, 1.35 0.88, 1.20 0.79, 1.23 0.87, 1.19 0.82, 1.23 0.81, 1.33 0.89, 1.22 1.00, 1.50 0.63, 1.04
0.594 0.746 0.929 0.860 0.966 0.780 0.634 0.050 0.097
Placebo
8,113
628 (15.5)
3,292 3,603 1,218 5,824 3,799 2,024 2,285 1,627 657
145 (8.8) 320 (17.8) 163 (26.9) 318 (10.8) 187 (9.8) 131 (12.7) 309 (27.7) 196 (25.2) 113 (33.7)
TABLE 6. All adverse events (regardless of any relationship with trial therapy) with an incidence of greater than 5% in either treatment arm
Breast pain Gynecomastia Pharyngitis Asthenia Back pain Rash Constipation Hot flashes Impotence Arthralgia Urinary tract infection Hypertension Flu syndrome Abdominal pain Pain Urinary incontinence Pelvic pain Diarrhea Edema Urinary tract disorder Alopecia Wt gain Infection Hernia Accidental injury Bronchitis Hematuria Headache Arthritis
HR
Bicalutamide
% Bicalutamide (4,022 pts)
% Placebo (4,031 pts)
73.6 68.3 11.0 10.9 10.2 10.0 9.3 9.2 9.2 8.6 8.4 8.2 7.6 7.5 7.2 7.1 6.8 6.8 6.4 6.3 5.9 5.8 5.6 5.5 5.3 5.2 5.1 5.0 4.4
7.6 8.3 11.6 7.8 11.9 8.3 7.6 5.3 6.5 10.0 7.0 8.7 7.7 7.4 8.1 6.4 6.8 6.9 5.5 7.1 0.8 3.0 5.5 6.7 6.9 5.1 6.4 5.2 5.3
tion were analyzed by trial. Additional prospectively defined subgroup analyses were performed by underlying primary therapy and disease stage. The disease stage groupings were localized disease (disease not known to be outside the capsule; T1–2, N0 or Nx, M0) and locally advanced disease (known disease outside the capsule; T3– 4, any N, M0 or any T, N⫹, M0). Other efficacy data and the adverse event data are descriptive only. RESULTS
The EPC program recruited 8,113 patients, 4,052 randomized to bicalutamide and 4,061 to placebo. Overall treatment groups were well balanced with differences between trials relating to differences in entry criteria (table 1). Median followup at this analysis was 5.4 years. Efficacy. Objective PFS: Across the program 1,756 patients (21.6%) met the criteria for objective progression, with 797 (19.7%) in the bicalutamide group (205 confirmed by bone scan, 138 confirmed by other objective measures, 454 deaths in the absence of progression) and 959 (23.6%) in the placebo group (346 confirmed by bone scan, 221 confirmed by other objective measures, 392 deaths in the absence of progression). A significant improvement in objective PFS with bicalutamide was seen in trials 24 and 25 individually but there continues to be no difference between the treatment groups
in trial 23 (fig. 1 and table 2). In the overall population bicalutamide significantly improved objective PFS, reducing the risk of objective progression by 27% (HR 0.73, 95% CI 0.66, 0.80, p ⬍0.0001) compared with placebo (fig. 1 and table 2). Bicalutamide significantly improved objective PFS irrespective of underlying primary therapy (table 2). The benefit in terms of reducing the risk of disease progression was greatest in those patients with locally advanced disease in the adjuvant and watchful waiting populations (table 2). As with the overall population, the results in the adjuvant population were driven by positive results in trials 24 and 25. In the watchful waiting group, for patients with locally advanced disease median objective PFS was 73.2 months for bicalutamide and 44.1 months for placebo. As described previously to quantify the efficacy of bicalutamide in terms of the relative increase in time to objective progression, ETR values were calculated for each primary therapy/disease stage subgroup (table 3). For example in adjuvant cases of locally advanced disease the ETR of 1.37 indicated that the time to objective progression was 37% longer with bicalutamide than with placebo (while the HR of 0.67 indicated a reduced risk of progression of 33%). Both results were statistically significant (p ⬍0.05). Further exploration showed that results for the radical prostatectomy and radiotherapy subgroups reflected those for the adjuvant population overall (table 4). Overall Survival: At the time of analysis, 628 (15.5%) patients in the bicalutamide group and 608 (15.0%) in the
TABLE 7. Reasons for withdrawal from randomized therapy No. Pts (%) Reason for Withdrawal
Death Disease progression Lost to followup Adverse event Protocol noncompliance Patient unable or unwilling to continue Voluntary code break Other Totals
Bicalutamide (4,022 pts)
Placebo (4,031 pts)
150 (3.7) 200 (5.0) 20 (0.5) 1,154 (28.7) 22 (0.5) 311 (7.7) 112 (2.8) 101 (2.5)
108 (2.7) 508 (12.6) 31 (0.8) 397 (9.8) 34 (0.8) 305 (7.6) 219 (5.4) 377 (9.4)
2,070 (51.5)
1,979 (49.1)
TABLE 8. Most common (occurring with an incidence of 0.7% or greater in either treatment arm) causes of death
Prostate Ca Myocardial infarction Gastrointestinal Ca Cause unknown Cerebrovascular accident Lung Ca Heart failure Heart arrest Pneumonia
% Bicalutamide (4,022 pts)
% Placebo (4,031 pts)
4.3 1.3 0.9 0.8 0.8 0.8 0.7 0.7 0.5
4.9 1.5 0.7 0.6 0.9 0.8 0.3 0.4 0.8
BICALUTAMIDE EARLY PROSTATE CANCER PROGRAM
placebo group had died. There were no differences in overall survival among the 2 groups across the program (HR 1.03; 95% CI 0.92, 1.15; p ⫽ 0.582, fig. 2, table 5) or in any individual trial. However, in trial 25 planned statistical investigations revealed that the relative effect of bicalutamide on overall survival was dependent on disease stage. In patients with locally advanced disease survival appeared to be improved with bicalutamide, whereas in those with localized disease survival was reduced with bicalutamide. Trial 25 findings are discussed in this issue.7 In light of these trial 25 findings, exploratory analyses of overall survival were undertaken in each primary therapy/ disease stage subgroup. Given the lack of significant difference in survival overall, the risk of false-positive results increases when data are explored in this manner, which must be considered when interpreting p values and CI. These exploratory analyses indicated no significant differences in survival between bicalutamide and placebo in patients with localized or locally advanced disease who received adjuvant therapy (table 5). However, in the watchful waiting population there was a trend towards improved survival with bicalutamide in patients with locally advanced disease but a trend towards reduced survival with bicalutamide in those with localized disease (table 5). These trends arose largely from the watchful waiting patients in trial 25. The median duration of bicalutamide therapy in the watchful waiting group was 4.4 years in patients with localized disease and in those with locally advanced disease. Safety and tolerability. Adverse Events: The overall tolerability profile of bicalutamide was consistent with that at the first analysis. The most commonly reported adverse events in patients receiving bicalutamide were breast pain (73.6%) and gynecomastia (68.3%, table 6). These events occurred at a similar frequency to that reported in the first analysis and were mild to moderate in more than 90% of cases. Other adverse events were reported with a similar low incidence in both treatment groups, including hot flashes (9.2% with bicalutamide versus 5.3% with placebo), decreased libido (3.6% versus 1.2%), impotence (9.2% versus 6.5%) and abnormal liver function tests (reported as an adverse event, 3.1% versus 1.7%). Overall withdrawal rates were similar in the bicalutamide and placebo groups (51.5% versus 49.1%), and withdrawal rates due to adverse events were 28.7% and 9.8%, respectively (table 7). The withdrawal rate due to breast pain and/or gynecomastia was 16.7% with bicalutamide versus 0.7% with placebo. Fewer patients with locally advanced disease withdrew from bicalutamide due to breast pain and/or gynecomastia (12.9%) than patients with localized disease (18.6%). The withdrawal rate due to liver function abnormalities was low with bicalutamide (1.2%) and placebo (0.5%). Deaths: In the overall safety population (8,053) fewer patients died of prostate cancer in the bicalutamide group than in the placebo group (172 [4.3%] versus 198 [4.9%]), whereas the opposite was observed for nonprostate cancer deaths (455 [11.3%] versus 406 [10.1%], table 8). No consistent pattern of nonprostate cancer related deaths was apparent in either group (table 8). DISCUSSION
Given the serious clinical consequences of disease progression which include bone pain, spinal cord compression, pathological fractures and urinary obstruction,4 the improvement in objective PFS afforded by bicalutamide is not just statistically significant but is also clinically important. Patients with locally advanced disease who were at higher risk of disease progression gained the most from therapy in terms of objectives PFS. This was the case in the adjuvant setting and in patients who would otherwise have undergone watchful waiting.
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There were important differences in outcome across the EPC program, with no difference in clinical outcome evident in trial 23. The low progression rate and absence of a difference in progression in trial 23 may reflect the good prognosis of the patients enrolled in this trial as well as the shorter duration of therapy. It should be noted that since the EPC program was designed to reflect clinical practice worldwide, surgical and radiotherapy techniques or other procedures such as neoadjuvant therapy were not specified in the protocol, and pathological specimens were assessed at the investigational site with no central review. However, any resulting differences among trial centers apply equally to both treatment arms and do not bias the size of treatment effects. The HR for objective PFS in the second analysis is closer to 1 than that observed in the first analysis. It is important to remember that objective PFS reflects not only disease progression events but also deaths without evidence of disease progression. An aging population, as in the EPC program, would be expected to be increasingly at risk from competing causes of death, and such deaths would tend to dilute the treatment effect for disease progression. As expected with current followup, overall survival did not differ between the treatment groups (15% mortality), with fewer prostate cancer related deaths in the bicalutamide than the placebo group. A thorough investigation of the nonprostate cancer deaths failed to reveal any specific cause for the imbalance across the overall population. The imbalance was principally a reflection of findings in the watchful waiting group, where (with 27% mortality) overall survival was improved with bicalutamide in patients with locally advanced disease but reduced with bicalutamide in those with localized disease. Again, this latter trend appears to be due to an increase in nonprostate cancer deaths of patients who received bicalutamide. No specific cause for this finding could be identified. Given the small number of excess deaths, it is not possible at this stage to make any conclusions relating to the duration of therapy. No overall survival treatment differences were apparent in patients receiving adjuvant therapy. However, as would be expected for these patients with a relatively good prognosis (many of whom were enrolled in trial 23), these data are still relatively immature (11% mortality). At this analysis approximately 50% of patients in each treatment group had withdrawn from randomized therapy (including all patients in trial 23, in which randomized therapy was scheduled for 2 years only). However, all patients are still being followed for objective progression and death since the intent is to compare time to event data irrespective of withdrawal from randomized therapy. Findings relating to objective PFS are supported by results from previous studies of adjuvant hormonal therapy (medical or surgical castration) in high risk prostate cancer.8 –14 In many of these trials improvements in PFS translated into improved overall survival on further followup.8 –10, 12–14 However, castration is associated with side effects including decreased libido, sexual dysfunction, fatigue, hot flashes, loss of bone mineral density and osteoporotic fractures.15, 16 Unlike castration, nonsteroidal antiandrogens such as bicalutamide do not suppress testosterone production, offering potential quality of life benefits.17 In men with locally advanced disease, bicalutamide monotherapy provides similar survival advantages to castration while conferring significant benefits in terms of sexual interest and physical capacity.18 Recent findings also suggest that bone mineral density is preserved during bicalutamide therapy.19 The observed objective PFS benefits with bicalutamide must be balanced against the possible risk of adverse events, the costs of treatment and the results of trial 25, which revealed the apparent reduction in survival with bicalutamide treatment in low risk patients. Nonetheless, the with-
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drawal rate due to these events was relatively low, indicating that many patients are willing to tolerate the side effects of antiandrogen therapy. Although patients in the EPC program were not offered any prophylaxis or treatment for gynecomastia or breast pain, options are available including surgery, radiation therapy and antiestrogen therapy.20, 21
10.
CONCLUSIONS
At a median of 5.4 years of followup reduction in risk of objective progression was seen in patients with locally advanced disease in trials 24 and 25 irrespective of primary therapy, and there was no difference in trial 23 (the North American trial). In the watchful waiting population there was a trend towards improved survival with bicalutamide in patients with locally advanced disease but a trend towards reduced survival with bicalutamide in those with localized disease. Overall, the findings of this analysis confirm that bicalutamide provides benefit in patients with locally advanced disease. However, the current data suggest that early or adjuvant hormonal therapy for patients at low risk of disease progression, such as those with localized disease, is not appropriate. The EPC program is ongoing and followup will provide further clarification for the role of bicalutamide in prostate cancer treatment.
11.
12.
13.
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1. Zagars, G. K., Pollack, A. and von Eschenbach, A. C.: Management of unfavorable locoregional prostate carcinoma with radiation and androgen ablation. Cancer, 80: 764, 1997 2. Hull, G. W., Rabbani, F., Abbas, F., Wheeler, T. M., Kattan, M. W. and Scardino, P. T.: Cancer control with radical prostatectomy alone in 1,000 consecutive patients. J Urol, 167: 528, 2002 3. Albertsen, P. C., Fryback, D. G., Storer, B. E., Kolon, T. F. and Fine, J.: Long-term survival among men with conservatively treated localized prostate cancer. JAMA, 274: 626, 1995 4. Smith, J. A., Jr., Soloway, M. S. and Young, M. J.: Complications of advanced prostate cancer. Urology, suppl., 54: 8, 1999 5. See, W. A., Wirth, M. P., McLeod, D. G., Iversen, P., Klimberg, I., Gleason, D. et al: Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program. J Urol, 168: 429, 2002 6. Carroll, K. J.: On the use and utility of the Weibull model in the analysis of survival data. Control Clin Trials, 24: 682, 2003 7. Iversen, P., Johansson, J.-E., Lodding, P., Lukkarinen, O., Lundmo, P., Klarskov, P. et al: Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curvative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6. J Urol, 172: 1871, 2004 8. Bolla, M., Collette, L., Blank, L., Warde, P., Dubois, J. B., Mirimanoff, R. O. 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, 360: 103, 2002 9. Lawton, C. A., Winter, K., Murray, K., Machtay, M., Mesic, J. B.,
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Hanks, G. E. et al: Updated results of the Phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys, 49: 937, 2001 Pilepich, M. V., Winter, K., Lawton, C., Krisch, R. E., Wolkov, H., Movsas, B. et al: Phase III trial of androgen suppression adjuvant to definitive radiotherapy. Long term results of RTOG study 85-31. Proc Am Soc Clin Oncol, 22: 381, abstract 1530, 2003 Hanks, G. E., Lu, J., Machtay, V., Venkatesan, V., Pinover, W., Byhardt, R. et al: RTOG protocol 92-02: a phase III trial of the use of long term androgen suppression following neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate. Proc Am Soc Clin Oncol, 19: 327a, 2000 Messing, E., Manola, J., Sarosdy, M., Wilding, G., Crawford, E. D. and Trump, D.: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node positive prostate cancer: results at 10 years of EST 3886. J Urol, suppl., 169: 396, abstract 1480, 2003 Hanks, G. E., Pajak, T. F., Porter, A., Grignon, D., Brereton, H., Venkatesan, V. et al: 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 9202. J Clin Oncol, 21: 3972, 2003 Granfors, T., Modig, H., Damber, J.-E. and Tomic, R.: Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study. J Urol, 159: 2030, 1998 Kirby, R.: Treatment options for early prostate cancer. Urology, 52: 948, 1998 Daniell, H. W., Dunn, S. R., Ferguson, D. W., Lomas, G., Niazi, Z. and Stratte, P. T.: Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol, 163: 181, 2000 Iversen, P., Melezinek, I. and Schmidt, A.: Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function. BJU Int, 87: 47, 2001 Iversen, P., Tyrrell, C. J., Kaisary, A. V., Anderson, J. B., Van Poppel, H., Tammela, T. L. J. et al: Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup. J Urol, 164: 1579, 2000 Sieber, P. R., Keiller, D. L., Kahnoski, R. J., Gallo, J. and McFadden, S.: Bicalutamide 150 mg maintains bone mineral density during monotherapy for localized or locally advanced prostate cancer. J Urol, 171: 2272, 2004 Payne, H., Tyrrell, C., Tammela, T., Bakke, A., Lodding, P., Goedhals, L. et al: Prophylactic breast irradiation significantly reduces the incidence of bicalutamide (‘Casodex’)-induced gynecomastia. Int J Radiat Oncol Biol Phys, 54: 135, abstract 230, 2002 Saltzstein, D., Cantwell, A., Sieber, P., Ross, J. R., Silvay-Mandeau, O. and Gallo, J.: Prophylactic tamoxifen significantly reduces the incidence of bicalutamide-induced gynaecomastia and breast pain. BJU Int, suppl., 90: 120, abstract PD-4.07, 2002
Vol. 172, 1865–1870, November 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000140159.94703.80
BICALUTAMIDE 150 MG IN ADDITION TO STANDARD CARE IN PATIENTS WITH LOCALIZED OR LOCALLY ADVANCED PROSTATE CANCER: RESULTS FROM THE SECOND ANALYSIS OF THE EARLY PROSTATE CANCER PROGRAM AT MEDIAN FOLLOWUP OF 5.4 YEARS MANFRED P. WIRTH,*, † WILLIAM A. SEE,‡ DAVID G. MCLEOD,§ PETER IVERSEN,㛳 TOM MORRIS㛳 AND KEVIN CARROLL㛳 ON BEHALF OF THE CASODEX EARLY PROSTATE CANCER TRIALISTS’ GROUP From the Department of Urology, Technical University of Dresden, Dresden, Germany, the Medical College of Wisconsin, Milwaukee, Wisconsin, the Walter Reed Army Medical Center, Washington, D. C., the Department of Urology, Rigshospitalet, Copenhagen, Denmark, and AstraZeneca, Macclesfield, United Kingdom
ABSTRACT
Purpose: We evaluated the efficacy and tolerability of 150 mg bicalutamide daily given in addition to standard care, in patients with localized or locally advanced prostate cancer. Materials and Methods: The bicalutamide Early Prostate Cancer program consists of 3 randomized, double blind, placebo controlled trials prospectively designed for combined analysis. A total of 8,113 men with T1b–T4, M0, any N (N0 in 1 trial) prostate cancer were randomized to bicalutamide 150 mg/day (4,052) or placebo (4,061) in addition to standard care (radical prostatectomy, radiotherapy or watchful waiting). Primary end points were objective progression-free survival (PFS) and overall survival. Results: At median 5.4 years of followup (21.6% progression events) bicalutamide significantly improved PFS in the overall population. This result was driven by positive results in trials 24 and 25, with the North American trial (trial 23) showing no difference. Patients with locally advanced disease gained most benefit from bicalutamide in terms of PFS, irrespective of underlying therapy. Overall survival was similar in the bicalutamide and placebo groups, across the program and in each trial. Among watchful waiting patients survival appeared to be improved with bicalutamide in those with locally advanced disease, whereas survival appeared to be reduced with bicalutamide in those with localized disease. The most common adverse events with bicalutamide were gynecomastia and breast pain. Other adverse events occurred with a similarly low incidence in the 2 treatment groups. Conclusions: This analysis confirms that bicalutamide provides benefit in patients with locally advanced disease. The current data suggest that early or adjuvant hormonal therapy for patients at low risk of disease progression, such as those with localized disease, is not appropriate. KEY WORDS: androgen antagonists, prostatic neoplasms
Standard management options for early (localized and locally advanced) prostate cancer include radical prostatectomy, radiotherapy and watchful waiting. However, patients with high risk disease, for example locally advanced disease, high Gleason scores or increased pretreatment prostate specific antigen (PSA) at diagnosis, remain at significant risk for disease progression/recurrence after primary therapy
alone.1–3 Since disease progression is associated with debilitating symptoms such as painful bone metastases, spinal cord compression, pathological fractures and urinary obstruction, additional treatment options are needed.4 The value of adding bicalutamide 150 mg/day to standard care for early prostate cancer is being investigated in the bicalutamide (Casodex, AstraZeneca, Wilmington, Delaware) Early Prostate Cancer (EPC) program, involving more than 8,000 patients worldwide. This program was designed to reflect global variability in clinical practice as far as possible at the time it was initiated, while minimizing the potential for bias, as well as to support a combined analysis. Results from the first per protocol analysis (median followup 3 years) were published previously.5 The EPC program is ongoing, and results of the second, combined per protocol analysis (minimum followup 4.5 years) are reported here.
Accepted for publication April 30, 2004. Study received Ethics Committee or Institutional Review Board approval at each center. * Correspondence: Department of Urology, Technical University of Dresden Medical School, Fetscherstrasse 74, Dresden D-01307, Germany (telephone: ⫹49 351 458 4447; FAX: ⫹49 351 458 4333; e-mail: [email protected]). † Financial interest and/or other relationship with AstraZeneca, Novartis, Praecis and GJK. ‡ Financial interest and/or other relationship with Abbott, Pfeiffer Foundation, Novartis, Merck, Therion Biologics, AstraZeneca, Intuitive Surgical, Pfizer, TAP Pharmaceutical Products Inc., National Cancer Institute, Southwest Oncology Group, Medical College of Wisconsin Cancer Center, Veterans Affairs Merit Review, University MATERIALS AND METHODS of Washington subcontract, National Measurement Laboratory, Antigenics, and National Institute for Diabetes and Digestive and KidStudy design and treatment. Detailed methods for the EPC ney Diseases. program have been described5 and are presented here in § Financial interest and/or other relationship with AstraZeneca, brief. The EPC program comprises 3 randomized, double Abbott, GlaxoSmithKline and Sanofi. blind, placebo controlled trials in North America (trial 23, 㛳 Financial interest and/or other relationship with AstraZeneca. 1865
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BICALUTAMIDE EARLY PROSTATE CANCER PROGRAM TABLE 1. Overall demographics Bicalutamide
Placebo
Trial 23
Trial 24
Trial 25
No. pts 4,052 4,061 3,292 3,603 1,218 Mean age (range) 66.9 (42–93) 66.9 (38–93) 64 (38–85) 69 (48–93) 69 (48–87) Disease stage (%):* T1/T2 67 68 73 65 60 T3 32 30 27 32 38 T4 2 2 0.2 3 2 Nodal status (%): N0 60 59 72 61 21 Nx 38 39 28 36 75 N⫹ 2 2 0 3 4 Gleason score (%): 2–4 22 22 5 31 43 5–6 44 45 48 41 44 7–10 33 32 47 26 12 Race (%): White 91 91 84 95 100 Black 5 5 12 1 0 Other 4 4 4 4 0 Standard care received (%): Radical prostatectomy 55 55 80 46 13 Radiotherapy 17 17 20 18 5 Watchful waiting 28 29 0 36 81 Neoadjuvant therapy (%) 17 17 22 18 0.5 Median ng/ml PSA before standard therapy 8.8 8.7 7.1 11.7 16.1 Median ng/ml PSA at baseline: Radical prostatectomy 1.0 1.0 Below limits of quantification Below limits of quantification 1.2 Radiotherapy 4.8 5.3 3.0 3.4 8.2 Watchful waiting 13.1 13.6 Not applicable 11.4 17.2 Median pt yrs of exposure 1.85 1.86 1.8 3.7 4.2 Median pt yrs of followup 5.43 5.42 5.7 5.1 5.3 * Disease stage determined pathologically for radical prostatectomy cases, but clinically for radiotherapy and watchful waiting.
FIG. 1. Kaplan-Meier curves of objective progression-free survival in trials 23 to 25 and in overall population
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BICALUTAMIDE EARLY PROSTATE CANCER PROGRAM
TABLE 2. Analysis of objective progression-free survival for the overall population by trial and by primary therapy/disease stage No. Pts Overall population Trial: 23 24 25 Adjuvant therapy: Localized disease Locally advanced disease Watchful waiting: Localized disease Locally advanced disease
No. Events (%)
HR
95% CI
959 (23.6)
0.73
0.66, 0.80
⬍0.0001
170 (10.3) 507 (28.1) 282 (46.2) 489 (16.9) 249 (13.2) 240 (24.2) 470 (40.1) 273 (32.2) 197 (61.2)
1.02 0.73 0.57 0.77 0.86 0.67 0.68 0.81 0.53
0.83, 1.26 0.64, 0.83 0.48, 0.68 0.67, 0.87 0.72, 1.03 0.56, 0.82 0.60, 0.78 0.68, 0.96 0.42, 0.65
0.824 ⬍0.0001 ⬍0.0001 0.00007 0.0971 0.00005 ⬍0.0001 0.018 ⬍0.0001
Bicalutamide
Placebo
8,113
797 (19.7)
3,292 3,603 1,218 5,824 3,799 2,024 2,285 1,627 657
177 (10.7) 405 (22.5) 215 (35.4) 419 (14.3) 229 (12.0) 191 (18.4) 377 (33.8) 229 (29.4) 148 (44.2)
p Value
End points. In each trial in the EPC program the end points included objective progression free survival (PFS) and overall survival. Objective PFS was defined as the time from randomization to the earliest occurrence of objective progression (confirmed by bone scan, computerized tomography/ultrasound/magnetic resonance imaging or histological evidence of distant metastases) or death from any cause without progression. Tolerability was a secondary end point and all adverse events were those reported spontaneously. Statistical analysis. The timing of the second analysis was based on the accrual of sufficient deaths across the program to allow detection of a 15% decrease in the overall mortality rate (80% power, 5% 2-sided significance). It was estimated that the required number of events (1,200) would occur by December 31, 2002, with 4.5 years’ minimum followup. Time to event data were analyzed on an intent to treat basis using the Cox proportional hazards regression model with covariates for trial, randomized treatment, primary therapy, baseline PSA, tumor grade and disease stage. This analysis estimates the hazard ratio (HR), the reduction in risk of an event. An alternative statistical analysis was also applied to objective PFS data to estimate the treatment benefit in terms of the relative increase in time to event (the event-to-time ratio [ETR]).6 As per protocol, data from the overall popula-
3,292 patients), Europe, South Africa, Australia, Israel and Mexico (trial 24, 3,603), and Scandinavia (trial 25, 1,218). The program was designed to support a combined analysis. Patients were randomized (1:1) to receive bicalutamide up to 150 mg or placebo once daily in addition to standard care (radical prostatectomy, radiotherapy, watchful waiting). According to protocol the duration of randomized therapy was 2 years in trial 23 and until disease progression in trials 24 (maximum 5 years recommended for adjuvant cases) and 25. Therapy upon disease progression was initiated at the investigators’ discretion, and all patients were followed for objective progression and death. The trials are conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and with Ethics Committee or Institutional Review Board approval at each center. An independent Data and Safety Monitoring Committee reviews safety and efficacy data on an ongoing basis. Although the study blind was broken at database level following the first analysis,5 it must be emphasized that the trials did not stop and all patients continued to be followed under the trial protocols. At this analysis 7% of patients in trials 24 and 25 had chosen to break the individual blind while still receiving randomized therapy (in total 10% of patients in trials 24 and 25 broke their blind). All patients in trial 23 had completed randomized therapy by the first analysis. Patients. Men 18 years old or older (upper limit 75 years in trial 25) with clinically or pathologically confirmed stage T1b–T4 prostate cancer and no distant metastases on bone scan were eligible. Trial 23 differed from trials 24 and 25 in that candidates for watchful waiting as well as patients with lymph node involvement were excluded from study.
TABLE 3. ETR analysis of objective PFS by underlying primary therapy/disease stage Primary Therapy/Disease Stage
ETR
95% CI
Adjuvant: 1.22 Localized 1.11 Locally advanced 1.37 Watchful waiting:* 1.31 Localized 1.16 Locally advanced 1.58 * In patients with locally advanced disease median objective and 44.1 months for bicalutamide and placebo, respectively.
1.11, 1.35 0.98, 1.26 1.18, 1.61 1.19, 1.45 1.03, 1.32 1.35, 1.86 PFS was 73.2
FIG. 2. Kaplan-Meier population.
curve
of
overall
survival
in
overall
TABLE 4. Analysis of objective progression-free survival for radical prostatectomy and radiotherapy populations by disease stage Population
No. Pts
Radical prostatectomy: Localized Locally advanced Radiotherapy: Localized Locally advanced
4,454 2,734 1,719 1,370 1,065 305
No. Events (%) Bicalutamide
Placebo
251 (11.2) 115 (8.4) 136 (15.6) 168 (24.0) 114 (21.2) 54 (33.5)
291 (13.1) 121 (8.8) 170 (20.0) 198 (29.5) 128 (24.3) 70 (48.6)
HR (95% CI; p value)
ETR (95% CI)
0.80 (0.68, 0.95; 0.0099) 0.93 (0.72, 1.20; 0.568) 0.71 (0.57, 0.89; 0.0034) 0.72 (0.59, 0.89; 0.002) 0.80 (0.62, 1.03; 0.088) 0.58 (0.41, 0.84; 0.00348)
1.19 (1.04, 1.37) 1.06 (0.87, 1.28) 1.32 (1.10, 1.59) 1.26 (1.09, 1.45) 1.16 (0.98, 1.37) 1.53 (1.16, 2.02)
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BICALUTAMIDE EARLY PROSTATE CANCER PROGRAM TABLE 5. Analysis of overall survival for overall population by trial and by primary therapy/disease stage No. Pts
Overall population Trial: 23 24 25 Adjuvant therapy: Localized disease Locally advanced disease Watchful waiting: Localized disease Locally advanced disease
No. Events (%)
95% CI
p Value
608 (15.0)
1.03
0.92, 1.15
0.582
134 (8.1) 316 (17.5) 158 (25.9) 301 (10.4) 182 (9.6) 119 (12.0) 307 (26.2) 174 (20.5) 133 (41.3)
1.07 1.03 0.99 1.01 1.01 1.04 1.04 1.23 0.81
0.84, 1.35 0.88, 1.20 0.79, 1.23 0.87, 1.19 0.82, 1.23 0.81, 1.33 0.89, 1.22 1.00, 1.50 0.63, 1.04
0.594 0.746 0.929 0.860 0.966 0.780 0.634 0.050 0.097
Placebo
8,113
628 (15.5)
3,292 3,603 1,218 5,824 3,799 2,024 2,285 1,627 657
145 (8.8) 320 (17.8) 163 (26.9) 318 (10.8) 187 (9.8) 131 (12.7) 309 (27.7) 196 (25.2) 113 (33.7)
TABLE 6. All adverse events (regardless of any relationship with trial therapy) with an incidence of greater than 5% in either treatment arm
Breast pain Gynecomastia Pharyngitis Asthenia Back pain Rash Constipation Hot flashes Impotence Arthralgia Urinary tract infection Hypertension Flu syndrome Abdominal pain Pain Urinary incontinence Pelvic pain Diarrhea Edema Urinary tract disorder Alopecia Wt gain Infection Hernia Accidental injury Bronchitis Hematuria Headache Arthritis
HR
Bicalutamide
% Bicalutamide (4,022 pts)
% Placebo (4,031 pts)
73.6 68.3 11.0 10.9 10.2 10.0 9.3 9.2 9.2 8.6 8.4 8.2 7.6 7.5 7.2 7.1 6.8 6.8 6.4 6.3 5.9 5.8 5.6 5.5 5.3 5.2 5.1 5.0 4.4
7.6 8.3 11.6 7.8 11.9 8.3 7.6 5.3 6.5 10.0 7.0 8.7 7.7 7.4 8.1 6.4 6.8 6.9 5.5 7.1 0.8 3.0 5.5 6.7 6.9 5.1 6.4 5.2 5.3
tion were analyzed by trial. Additional prospectively defined subgroup analyses were performed by underlying primary therapy and disease stage. The disease stage groupings were localized disease (disease not known to be outside the capsule; T1–2, N0 or Nx, M0) and locally advanced disease (known disease outside the capsule; T3– 4, any N, M0 or any T, N⫹, M0). Other efficacy data and the adverse event data are descriptive only. RESULTS
The EPC program recruited 8,113 patients, 4,052 randomized to bicalutamide and 4,061 to placebo. Overall treatment groups were well balanced with differences between trials relating to differences in entry criteria (table 1). Median followup at this analysis was 5.4 years. Efficacy. Objective PFS: Across the program 1,756 patients (21.6%) met the criteria for objective progression, with 797 (19.7%) in the bicalutamide group (205 confirmed by bone scan, 138 confirmed by other objective measures, 454 deaths in the absence of progression) and 959 (23.6%) in the placebo group (346 confirmed by bone scan, 221 confirmed by other objective measures, 392 deaths in the absence of progression). A significant improvement in objective PFS with bicalutamide was seen in trials 24 and 25 individually but there continues to be no difference between the treatment groups
in trial 23 (fig. 1 and table 2). In the overall population bicalutamide significantly improved objective PFS, reducing the risk of objective progression by 27% (HR 0.73, 95% CI 0.66, 0.80, p ⬍0.0001) compared with placebo (fig. 1 and table 2). Bicalutamide significantly improved objective PFS irrespective of underlying primary therapy (table 2). The benefit in terms of reducing the risk of disease progression was greatest in those patients with locally advanced disease in the adjuvant and watchful waiting populations (table 2). As with the overall population, the results in the adjuvant population were driven by positive results in trials 24 and 25. In the watchful waiting group, for patients with locally advanced disease median objective PFS was 73.2 months for bicalutamide and 44.1 months for placebo. As described previously to quantify the efficacy of bicalutamide in terms of the relative increase in time to objective progression, ETR values were calculated for each primary therapy/disease stage subgroup (table 3). For example in adjuvant cases of locally advanced disease the ETR of 1.37 indicated that the time to objective progression was 37% longer with bicalutamide than with placebo (while the HR of 0.67 indicated a reduced risk of progression of 33%). Both results were statistically significant (p ⬍0.05). Further exploration showed that results for the radical prostatectomy and radiotherapy subgroups reflected those for the adjuvant population overall (table 4). Overall Survival: At the time of analysis, 628 (15.5%) patients in the bicalutamide group and 608 (15.0%) in the
TABLE 7. Reasons for withdrawal from randomized therapy No. Pts (%) Reason for Withdrawal
Death Disease progression Lost to followup Adverse event Protocol noncompliance Patient unable or unwilling to continue Voluntary code break Other Totals
Bicalutamide (4,022 pts)
Placebo (4,031 pts)
150 (3.7) 200 (5.0) 20 (0.5) 1,154 (28.7) 22 (0.5) 311 (7.7) 112 (2.8) 101 (2.5)
108 (2.7) 508 (12.6) 31 (0.8) 397 (9.8) 34 (0.8) 305 (7.6) 219 (5.4) 377 (9.4)
2,070 (51.5)
1,979 (49.1)
TABLE 8. Most common (occurring with an incidence of 0.7% or greater in either treatment arm) causes of death
Prostate Ca Myocardial infarction Gastrointestinal Ca Cause unknown Cerebrovascular accident Lung Ca Heart failure Heart arrest Pneumonia
% Bicalutamide (4,022 pts)
% Placebo (4,031 pts)
4.3 1.3 0.9 0.8 0.8 0.8 0.7 0.7 0.5
4.9 1.5 0.7 0.6 0.9 0.8 0.3 0.4 0.8
BICALUTAMIDE EARLY PROSTATE CANCER PROGRAM
placebo group had died. There were no differences in overall survival among the 2 groups across the program (HR 1.03; 95% CI 0.92, 1.15; p ⫽ 0.582, fig. 2, table 5) or in any individual trial. However, in trial 25 planned statistical investigations revealed that the relative effect of bicalutamide on overall survival was dependent on disease stage. In patients with locally advanced disease survival appeared to be improved with bicalutamide, whereas in those with localized disease survival was reduced with bicalutamide. Trial 25 findings are discussed in this issue.7 In light of these trial 25 findings, exploratory analyses of overall survival were undertaken in each primary therapy/ disease stage subgroup. Given the lack of significant difference in survival overall, the risk of false-positive results increases when data are explored in this manner, which must be considered when interpreting p values and CI. These exploratory analyses indicated no significant differences in survival between bicalutamide and placebo in patients with localized or locally advanced disease who received adjuvant therapy (table 5). However, in the watchful waiting population there was a trend towards improved survival with bicalutamide in patients with locally advanced disease but a trend towards reduced survival with bicalutamide in those with localized disease (table 5). These trends arose largely from the watchful waiting patients in trial 25. The median duration of bicalutamide therapy in the watchful waiting group was 4.4 years in patients with localized disease and in those with locally advanced disease. Safety and tolerability. Adverse Events: The overall tolerability profile of bicalutamide was consistent with that at the first analysis. The most commonly reported adverse events in patients receiving bicalutamide were breast pain (73.6%) and gynecomastia (68.3%, table 6). These events occurred at a similar frequency to that reported in the first analysis and were mild to moderate in more than 90% of cases. Other adverse events were reported with a similar low incidence in both treatment groups, including hot flashes (9.2% with bicalutamide versus 5.3% with placebo), decreased libido (3.6% versus 1.2%), impotence (9.2% versus 6.5%) and abnormal liver function tests (reported as an adverse event, 3.1% versus 1.7%). Overall withdrawal rates were similar in the bicalutamide and placebo groups (51.5% versus 49.1%), and withdrawal rates due to adverse events were 28.7% and 9.8%, respectively (table 7). The withdrawal rate due to breast pain and/or gynecomastia was 16.7% with bicalutamide versus 0.7% with placebo. Fewer patients with locally advanced disease withdrew from bicalutamide due to breast pain and/or gynecomastia (12.9%) than patients with localized disease (18.6%). The withdrawal rate due to liver function abnormalities was low with bicalutamide (1.2%) and placebo (0.5%). Deaths: In the overall safety population (8,053) fewer patients died of prostate cancer in the bicalutamide group than in the placebo group (172 [4.3%] versus 198 [4.9%]), whereas the opposite was observed for nonprostate cancer deaths (455 [11.3%] versus 406 [10.1%], table 8). No consistent pattern of nonprostate cancer related deaths was apparent in either group (table 8). DISCUSSION
Given the serious clinical consequences of disease progression which include bone pain, spinal cord compression, pathological fractures and urinary obstruction,4 the improvement in objective PFS afforded by bicalutamide is not just statistically significant but is also clinically important. Patients with locally advanced disease who were at higher risk of disease progression gained the most from therapy in terms of objectives PFS. This was the case in the adjuvant setting and in patients who would otherwise have undergone watchful waiting.
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There were important differences in outcome across the EPC program, with no difference in clinical outcome evident in trial 23. The low progression rate and absence of a difference in progression in trial 23 may reflect the good prognosis of the patients enrolled in this trial as well as the shorter duration of therapy. It should be noted that since the EPC program was designed to reflect clinical practice worldwide, surgical and radiotherapy techniques or other procedures such as neoadjuvant therapy were not specified in the protocol, and pathological specimens were assessed at the investigational site with no central review. However, any resulting differences among trial centers apply equally to both treatment arms and do not bias the size of treatment effects. The HR for objective PFS in the second analysis is closer to 1 than that observed in the first analysis. It is important to remember that objective PFS reflects not only disease progression events but also deaths without evidence of disease progression. An aging population, as in the EPC program, would be expected to be increasingly at risk from competing causes of death, and such deaths would tend to dilute the treatment effect for disease progression. As expected with current followup, overall survival did not differ between the treatment groups (15% mortality), with fewer prostate cancer related deaths in the bicalutamide than the placebo group. A thorough investigation of the nonprostate cancer deaths failed to reveal any specific cause for the imbalance across the overall population. The imbalance was principally a reflection of findings in the watchful waiting group, where (with 27% mortality) overall survival was improved with bicalutamide in patients with locally advanced disease but reduced with bicalutamide in those with localized disease. Again, this latter trend appears to be due to an increase in nonprostate cancer deaths of patients who received bicalutamide. No specific cause for this finding could be identified. Given the small number of excess deaths, it is not possible at this stage to make any conclusions relating to the duration of therapy. No overall survival treatment differences were apparent in patients receiving adjuvant therapy. However, as would be expected for these patients with a relatively good prognosis (many of whom were enrolled in trial 23), these data are still relatively immature (11% mortality). At this analysis approximately 50% of patients in each treatment group had withdrawn from randomized therapy (including all patients in trial 23, in which randomized therapy was scheduled for 2 years only). However, all patients are still being followed for objective progression and death since the intent is to compare time to event data irrespective of withdrawal from randomized therapy. Findings relating to objective PFS are supported by results from previous studies of adjuvant hormonal therapy (medical or surgical castration) in high risk prostate cancer.8 –14 In many of these trials improvements in PFS translated into improved overall survival on further followup.8 –10, 12–14 However, castration is associated with side effects including decreased libido, sexual dysfunction, fatigue, hot flashes, loss of bone mineral density and osteoporotic fractures.15, 16 Unlike castration, nonsteroidal antiandrogens such as bicalutamide do not suppress testosterone production, offering potential quality of life benefits.17 In men with locally advanced disease, bicalutamide monotherapy provides similar survival advantages to castration while conferring significant benefits in terms of sexual interest and physical capacity.18 Recent findings also suggest that bone mineral density is preserved during bicalutamide therapy.19 The observed objective PFS benefits with bicalutamide must be balanced against the possible risk of adverse events, the costs of treatment and the results of trial 25, which revealed the apparent reduction in survival with bicalutamide treatment in low risk patients. Nonetheless, the with-
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BICALUTAMIDE EARLY PROSTATE CANCER PROGRAM
drawal rate due to these events was relatively low, indicating that many patients are willing to tolerate the side effects of antiandrogen therapy. Although patients in the EPC program were not offered any prophylaxis or treatment for gynecomastia or breast pain, options are available including surgery, radiation therapy and antiestrogen therapy.20, 21
10.
CONCLUSIONS
At a median of 5.4 years of followup reduction in risk of objective progression was seen in patients with locally advanced disease in trials 24 and 25 irrespective of primary therapy, and there was no difference in trial 23 (the North American trial). In the watchful waiting population there was a trend towards improved survival with bicalutamide in patients with locally advanced disease but a trend towards reduced survival with bicalutamide in those with localized disease. Overall, the findings of this analysis confirm that bicalutamide provides benefit in patients with locally advanced disease. However, the current data suggest that early or adjuvant hormonal therapy for patients at low risk of disease progression, such as those with localized disease, is not appropriate. The EPC program is ongoing and followup will provide further clarification for the role of bicalutamide in prostate cancer treatment.
11.
12.
13.
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