Abstract
Previous studies and meta-analyses have made it clear that some subgroups of prostate cancer patients who have received radiotherapy should benefit from immediate adjuvant hormonal therapy. A cohort totaling 1370 patients who received radiotherapy for early nonmetastatic prostate cancer is currently enrolled in three ongoing, randomized, double-blind, placebo-controlled trials investigating the role of bicalutamide (‘Casodex’) 150 mg/d as adjuvant to standard care (the bicalutamide Early Prostate Cancer program). At preliminary analysis, conducted after a median follow-up of 3 years, adjuvant therapy with bicalutamide 150 mg/d significantly reduced the risk of objective progression by 37% compared with radiotherapy alone (HR 0.63, 95% CI, 0.46–0.85, P = .0024). Initial results demonstrate that bicalutamide 150 mg/d given as immediate adjuvant therapy following radiotherapy in men with early nonmetastatic prostate cancer has benefits over radiotherapy alone.
Key words: Prostate cancer, Adjuvant hormonal therapy, Bicalutamide, Prostate-specific antigen
Acohort of 1370 patients who have received radiotherapy for localized (T1–T2, N0, M0) or locally advanced (T3–T4, any N, M0; or any T, N+, M0) prostate cancer is currently enrolled in three ongoing, randomized, double-blind, placebo-controlled trials investigating the role of bicalutamide (Casodex) 150 mg/d as adjuvant to standard care (the bicalutamide Early Prostate Cancer [EPC] program).1,2 This article will discuss the role of adjuvant hormonal therapy following radiotherapy and will present the preliminary results from this group of patients.
Several studies have evaluated hormonal therapy using a luteinizing hormone-releasing hormone (LHRH) analog or orchiectomy as adjuvant to radiotherapy in locally advanced prostate cancer. Bolla and colleagues3 have demonstrated improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin (Zoladex). Pilepich and colleagues4 have updated the results of the Radiation Therapy Oncology Group (RTOG) trial 85–31, showing improved results with androgen suppression following standard radiotherapy for locally advanced prostate cancer, including improved survival rates. Granfors and coworkers5 have demonstrated a significant reduction in mortality with orchiectomy and external radiotherapy combined, compared with radiotherapy alone in patients with, or without, pelvic lymph node involvement.
Roach and colleagues6 have performed a meta-analysis of five RTOG trials and identified four distinct prognostic risk groups based on Gleason score and clinical stage. There were major differences in overall and disease-specific survival, depending on these prognostic risk groups. Patients in Group 1 (Gleason score 2–6 and T1–T2, NX disease) had a disease-specific survival of 86% at 10 years, whereas patients in Group 4 (Gleason score 8–10 and T3, NX, or N+ disease) had a 34% disease-specific survival at 10 years. A further analysis using these subgroups assessed the impact of hormonal therapy (a LHRH analog, combined androgen blockade, diethylstilbestrol, or megestrol acetate) on outcome in men treated with radiotherapy.7 Patients in Group 3 (Gleason score 7 and T3, NX or N+ disease or Gleason score 8–10 and T1–T2, NX disease) and Group 4 had an approximately 20% higher disease-free survival at 8 years with the addition of long-term hormonal therapy (goserelin). The number of patients in Group 1 treated with hormonal therapy was small and, so far, no benefit in this group has been identified. Therefore, it is clear that some subgroups of radiotherapy patients should benefit from immediate adjuvant hormonal therapy; however, it may be extremely difficult to detect the benefit in patients with a very good prognosis.
The Bicalutamide EPC Program
Materials and Methods
The bicalutamide EPC program consists of three ongoing, prospective, randomized, double-blind, placebo-controlled trials in North America (Trial 23; n = 3292), Europe, South Africa, Israel, Australia, and Mexico (Trial 24; n = 3603), and Scandinavia (Trial 25; n = 1218).1 Eligible patients were randomized in a 1:1 ratio to receive bicalutamide 150 mg orally once daily or placebo in addition to standard care (radical prostatectomy, radiotherapy, or “watchful waiting”). The duration of randomized therapy was at least 2 years across the trials (2 years in Trial 23 and at least 5 years in Trials 24 and 25). Patients were followed in each trial until objective disease progression or death.
Assessments and Endpoints
Local and regional disease, clinical symptoms, and prostate-specific antigen (PSA) levels are assessed every 12 weeks. Bone scans are scheduled over 96 weeks and patients are followed up every 24 weeks until death following treatment withdrawal.
Primary efficacy endpoints are overall survival and time to objective progression, defined as the number of days between the date of randomization and objective progression. Objective progression is assessed by bone scan, magnetic resonance imaging, ultrasound, or computed tomography scan, and includes death without prior progression. PSA progression is not a primary endpoint.
Secondary endpoints include time to treatment failure that does not satisfy the above criteria, time to PSA progression, and tolerability.
Statistical Methods
The program is designed and powered on the basis of a combined analysis of all three trials to detect a 15% reduction in the rate of progression for bicalutamide 150 mg/d compared with standard care alone.
Overall time-to-event data were analyzed on an intent-to-treat basis using a Cox proportional hazard regression model with covariates for trial, randomized treatment, primary treatment of curative intent, initial PSA level, tumor grade, and stage.1
Data within the radiotherapy subgroup were also explored and treatment differences were presented descriptively in terms of hazard ratio (HR).2 A new analysis was also applied,8 which estimates the relative increase in the time to an event (the event time ratio [ETR]) conferred by the corresponding HR. For example, if the HR = 0.80 and the ETR = 1.30, then the risk of an event is reduced by 20% and the time to event is simultaneously increased by 30%. An ETR >1 indicates a benefit for bicalutamide 150 mg/d, while a 95% confidence interval (CI) excluding 1 indicates that the benefit was statistically significant. The time taken for any given percentage of patients to progress in each group can also be estimated using this model.
Results
Of the 1370 patients enrolled in the program who had received radiotherapy, 699 were randomized to bicalutamide 150 mg/d and 671 to placebo. Demographics of the patient populations are presented by group in Table 1.
Table 1.
Demography of Patients Receiving Radiotherapy, by Treatment Group9
| Bicalutamide 150 mg/d | Placebo | |
|---|---|---|
| (n = 699) | (n = 671) | |
| Mean age (range), y | 69.6 (48–85) | 69.3 (47–82) |
| Race (%) | ||
| Caucasian | 87.0 | 88.8 |
| Black | 6.3 | 5.7 |
| Other | 6.7 | 5.5 |
| Disease stage (%) | ||
| T1/T2 | 77.5 | 79.1 |
| T3 | 21.8 | 20.1 |
| T4 | 0.7 | 0.8 |
| Nodal status (%) | ||
| N− | 30.8 | 33.1 |
| NX | 68.2 | 65.9 |
| N+ | 1.0 | 1.0 |
| Tumor grade (Gleason score), % | ||
| Well differentiated (2–4) | 23.8 | 22.1 |
| Moderately differentiated (5–6) | 49.6 | 52.2 |
| Poorly differentiated (7–10) | 25.2 | 25.6 |
| Median PSA level (ng/mL) | ||
| Prior to radiotherapy | 11.3 | 11.2 |
| At randomization | 3.4 | 3.5 |
| Use of neoadjuvant therapy (%) | 30.0 | 32.5 |
| Patients (%) | ||
| Trial 23 | 46.5 | 47.7 |
| Trial 24 | 47.9 | 48.4 |
| Trial 25 | 5.6 | 3.9 |
The mean patient age was 69.6 years in the bicalutamide 150 mg/d group and 69.3 years in the placebo group. Treatment groups were balanced for racial origin and stage of disease, with 77.5% and 79.1% of patients having T1/T2 disease; 21.8% and 20.1% having T3 disease; and 0.7% and 0.8% having T4 disease in the bicalutamide 150 mg/d and placebo groups, respectively. Approximately 30% of patients had nodal staging and only 1% were nodal positive in both groups, while 68.2% and 65.9% of patients were of unknown nodal status in the bicalutamide 150 mg/d and placebo groups, respectively. Gleason scores were well balanced in the two groups, with approximately 25% poorly differentiated, 50% moderately differentiated, and just below 25% well differentiated. Median PSA levels were 11.3 ng/mL and 11.2 ng/mL in the bicalutamide 150 mg/d and placebo groups, respectively, prior to radiotherapy, and 3.4 ng/mL and 3.5 ng/mL, respectively, at randomization. Neoadjuvant therapy was used in 30.0% and 32.5% of patients in the bicalutamide 150 mg/d and placebo groups, respectively.
At the time of this preliminary analysis, median follow-up was 3 years and median exposure for those patients who received treatment was 1.8 years for both treatment groups.
Time to Objective Progression
In this first analysis of 1370 radiotherapy patients, 178 (13.0%) showed evidence of objective progression: 75 (10.7%) in the bicalutamide 150 mg/d group and 103 (15.4%) in the placebo group. In the bicalutamide 150 mg/d group, progression was confirmed by bone scan in 28 patients and was objectively confirmed by other means in 11 patients. In the placebo group, progression was confirmed by bone scan in 45 patients and was objectively confirmed by other means in 20 patients. There have been 36 deaths without prior progression in the bicalutamide 150 mg/d group and 38 in the placebo group. The HR for objective disease progression is 0.63 (95% CI, 0.46–0.85, P = .0024; Figure 1).
Figure 1.
Kaplan-Meier analysis of time to objective progression in the bicalutamide 150 mg/d and placebo groups.
Therefore the risk of disease progression with a median follow-up of 3 years has been reduced by 37% with bicalutamide 150 mg/d compared with placebo. This translates into a 36% increase in objective progression-free survival (ETR 1.36, 95% CI, 1.11–1.67). The estimated time taken for the first 10% of patients to progress was 2.9 years in the bicalutamide 150 mg/d group compared with 2.2 years in the placebo group, a difference at this point on the Kaplan-Meier curve of 8.4 months.
Data from the radiotherapy patients have been further explored in terms of stage, grade, nodal status, PSA level prior to and after radiotherapy, and trial (Figure 2 and Table 2).
Figure 2.
Forest plot analysis of objective progression by stage, grade, nodal status, and PSA level.
Table 2.
Analysis of Objective Progression by Stage, Grade, Nodal Status, PSA Level, and Trial9
| Time Taken for First 10% | |||||
|---|---|---|---|---|---|
| of Patients to Progress (y) | |||||
| Risk Group | No. Patients | HR (95% CI) | ETR (95% CI) | Bicalutamide 150 mg/d | Placebo |
| Overall population | 1370 | 0.63 (0.46–0.85) | 1.36 (1.11–1.67) | 2.9 | 2.2 |
| Disease stage | |||||
| Localized disease | 1065 | 0.80 (0.55–1.17) | 1.16 (0.91–1.74) | 3.2 | 2.9 |
| Locally advanced disease | 305 | 0.39 (0.24–0.66) | 1.93 (1.32–2.82) | 2.2 | 1.2 |
| Gleason score | |||||
| 2–4 | 314 | 0.89 (0.45–1.79) | 1.10 (0.74–1.63) | 2.9 | 2.9 |
| 5–6 | 697 | 0.59 (0.39–0.92) | 1.37 (1.05–1.79) | 3.2 | 2.3 |
| 7–10 | 348 | 0.63 (0.37–1.08) | 1.47 (0.95–2.29) | 2.4 | 1.7 |
| Nodal status | |||||
| N0 | 437 | 0.53 (0.31–0.89) | 1.54 (1.09–2.19) | 2.5 | 1.9 |
| NX | 919 | 0.69 (0.47–1.00) | 1.28 (1.00–1.64) | 3.1 | 2.5 |
| N+ | 14 | —* | —* | —* | —* |
| Preradiotherapy PSA level | |||||
| ≤4 ng/mL | 105 | —* | —* | —* | —* |
| > 4–10 ng/mL | 491 | 0.49 (0.27–0.87) | 1.70 (1.10–2.63) | 4.1 | 2.4 |
| > 10 ng/mL | 726 | 0.68 (0.46–1.01) | 1.28 (0.99–1.66) | 2.5 | 2.1 |
| Postradiotherapy PSA level | |||||
| ≤4 ng/mL | 766 | 0.76 (0.48–1.20) | 1.21 (0.88–1.66) | 3.5 | 2.8 |
| > 4 ng/mL | 578 | 0.60 (0.40–0.89) | 1.39 (1.07–1.81) | 2.4 | 1.8 |
| Trial | |||||
| 23 | 645 | 0.84 (0.50–1.40) | 1.13 (0.79–1.61) | 3.8 | 3.4 |
| 24 | 660 | 0.56 (0.37–0.86) | 1.45 (1.10–1.92) | 2.7 | 1.8 |
| 25 | 65 | —* | —* | —* | —* |
Too few events to calculate hazard ratio (HR) and event time ratio (ETR).
It was found that patients at higher risk of progression received clearest benefit. Obviously, patients with locally advanced disease have a higher rate of progression than those with localized disease. The HR for locally advanced disease is 0.39 (95% CI, 0.24–0.66) compared with 0.80 (95% CI, 0.55–1.17) for localized disease. In patients with Gleason scores 2–4, too few events have occurred to date to draw any conclusions on the presence or absence of a treatment effect, but the HR is 0.59 (95% CI, 0.39–0.92) for higher risk patients with a Gleason score of 5–6 and 0.63 (95% CI, 0.37–1.08) for those with a Gleason score of 7–10. Similarly, in patients with a baseline PSA level < 4.0 ng/mL, too few events have occurred to date to assess treatment effect, but the HR is 0.49 (95% CI, 0.27–0.87) for patients with a PSA level of 4.0–10.0 ng/mL and 0.68 (95% CI, 0.46–1.01) for patients with a PSA level of ≤10.0 ng/mL.
Survival
A total of 52 deaths occurred in each of the two treatment groups; a quarter of these were considered related to prostate cancer. This endpoint is considered immature.
PSA Progression
Bicalutamide 150 mg/d significantly reduced the risk of PSA progression (HR 0.42, 95% CI, 0.33–0.53; P ≪ .0001) (Figure 3). This translates into a 99% increase in PSA progression-free survival (ETR 1.99, 95% CI, 1.65–2.40).
Figure 3.
Kaplan-Meier analysis of time to PSA progression in the bicalutamide 150 mg/d and placebo groups (radiotherapy cohort). Data from Tyrrell et al,2 reproduced with permission.
The estimated time taken for 10% of patients to progress was 1.9 years in the bicalutamide 150 mg/d group compared with 1.0 years in the placebo group, a difference on the Kaplan-Meier curve of 10.8 months. At 3 years, the number of patients who had experienced PSA progression, objective progression, or who had died was 119 (17.0%) in the bicalutamide 150 mg/d group compared with 213 (31.7%) in the placebo group. This is important, as a rising PSA level is known to precede relapse following radiotherapy.10
PSA progression data from radiotherapy patients have been further explored in terms of stage, grade, nodal status, PSA level prior to and after radiotherapy, and trial (Figure 4 and Table 3).
Figure 4.
Forest plot analysis of PSA progression by stage, grade, nodal status, and PSA level.
Table 3.
Analysis of PSA Progression by Stage, Grade, Nodal Status, PSA Level, and Trial9
| Time Taken for First 10% | |||||
|---|---|---|---|---|---|
| of Patients to Progress (y) | |||||
| Risk Group | No. Patients | HR (95% CI) | ETR (95% CI) | Bicalutamide 150 mg/d | Placebo |
| Overall population | 1370 | 0.42 (0.33–0.53) | 1.99 (1.65–2.40) | 1.9 | 1.0 |
| Disease stage | |||||
| Localized disease | 1065 | 0.51 (0.38–0.67) | 1.72 (1.37–2.15) | 2.2 | 1.3 |
| Locally advanced disease | 305 | 0.29 (0.19–0.43) | 2.62 (1.89–3.65) | 1.4 | 0.5 |
| Gleason score | |||||
| 2–4 | 314 | 0.47 (0.28–0.79) | 1.66 (1.17–2.35) | 2.0 | 1.4 |
| 5–6 | 697 | 0.42 (0.31–0.58) | 1.92 (1.49–2.49) | 2.0 | 1.1 |
| 7–10 | 348 | 0.43 (0.28–0.65) | 2.16 (1.47–3.18) | 1.5 | 0.7 |
| Nodal status | |||||
| N0 | 437 | 0.33 (0.22–0.51) | 2.33 (1.65–3.27) | 1.9 | 1.0 |
| NX | 919 | 0.46 (0.35–0.60) | 1.89 (1.50–2.37) | 1.9 | 1.0 |
| N+ | 14 | –* | –* | –* | –* |
| Preradiotherapy PSA level | |||||
| ≤ 4 ng/mL | 105 | –* | –* | –* | –* |
| > 4–10 ng/mL | 491 | 0.44 (0.29–0.67) | 2.07 (1.39–3.08) | 2.5 | 1.2 |
| > 10 ng/mL | 726 | 0.40 (0.29–0.53) | 2.04 (1.61–2.58) | 1.6 | 0.9 |
| Postradiotherapy PSA level | |||||
| ≤ 4 ng/mL | 766 | 0.48 (0.36–0.65) | 1.81 (1.41–2.33) | 1.8 | 1.0 |
| > 4 ng/mL | 578 | 0.35 (0.24–0.51) | 2.06 (1.58–2.70) | 2.1 | 1.2 |
| Trial | |||||
| 23 | 645 | 0.59 (0.42–0.83) | 1.59 (1.17–2.17) | 2.1 | 1.3 |
| 24 | 660 | 0.38 (0.27–0.53) | 2.06 (1.59–2.68) | 2.0 | 0.9 |
| 25 | 65 | 0.21 (0.10–0.42) | 2.95 (1.86–4.68) | 1.2 | 0.4 |
Too few events to calculate hazard ratio (HR) and event time ratio (ETR).
Safety and Tolerability
The adverse events reported among patients who received radiotherapy are similar to those reported for the trial program as a whole.1 As expected from its pharmacology, the most commonly reported adverse events with bicalutamide 150 mg/d were breast pain and gynecomastia. The trial program did not evaluate potential prophylactic or treatment options for breast pain and gynecomastia, but it is important that such adverse effects are effectively managed and several options are available.11 The only reported adverse event in this study not otherwise noted in the trial population as a whole was rectal hemorrhage, which occurred in approximately 10% of patients in each study group (Table 4).
Table 4.
Adverse Events, Regardless of Causality, Occurring in > 10% of Radiotherapy Patients in Either Treatment Group9
| Patients (%) | ||
|---|---|---|
| Bicalutamide 150 mg/d | Placebo | |
| (n = 694) | (n = 664) | |
| Breast pain | 74.4 | 9.0 |
| Gynecomastia | 65.6 | 10.1 |
| Diarrhea | 14.4 | 13.4 |
| Asthenia | 12.8 | 8.6 |
| Impotence | 12.7 | 9.3 |
| Back pain | 10.8 | 12.3 |
| Rectal hemorrhage | 10.4 | 10.2 |
| Pharyngitis | 10.4 | 9.3 |
| Rash | 10.1 | 8.1 |
| Hematuria | 8.1 | 10.7 |
| Arthralgia | 7.5 | 11.1 |
Overall Withdrawals
The overall withdrawal rate for patients receiving radiotherapy was 41.8% in the bicalutamide 150 mg/d group and 34.9% in the placebo group (Table 5). There were 201 withdrawals (29.0%) for adverse events in the bicalutamide 150 mg/d group and 59 (8.9%) in the placebo group. However, there were more withdrawals for disease progression in the placebo group: 56 (8.4%) patients in the placebo group compared with 20 (2.9%) patients in the bicalutamide 150 mg/d group.
Table 5.
Reasons for Withdrawal of Patients Receiving Radiotherapy9
| Patients (%) | ||
|---|---|---|
| Bicalutamide 150 mg/d | Placebo | |
| (n= 694)* | (n= 664)* | |
| Adverse event | 201 (29.0) | 59 (8.9) |
| Disease progression | 20 (2.9) | 56 (8.4) |
| Death | 13 (1.9) | 12 (1.8) |
| Other reason† | 56 (8.1) | 105 (15.8) |
| Total | 290 (41.8) | 232 (34.9) |
Five patients in the bicalutamide 150 mg/d group and 7 patients in the placebo group did not receive randomized treatment.
Includes patients lost to follow-up, protocol noncompliance, patient unwilling or unable to continue, or investigator's decision.
Discussion
First results from the EPC program have demonstrated a significant overall treatment effect for immediate therapy with bicalutamide 150 mg/d as adjuvant to standard care in patients with localized or locally advanced prostate cancer.1 Analysis of the radiotherapy group as reported here, and elsewhere,2 showed that treatment with bicalutamide 150 mg/d resulted in a significant reduction in the risk of objective disease progression in patients who received radiotherapy.
Further analysis by risk group demonstrated that the overall effect was consistent across important prognostic subgroups, indicating those patients most likely to benefit. It is too early to expect any survival difference, but other studies3–5 have shown survival benefits over long follow-up, and it is suggested that early androgen blockade is better than deferred hormonal therapy for these patients. It is hoped that improvements in objective progression will lead to improvements in survival.
Conclusions
Initial results from this large group of radiotherapy patients (n = 1370) demonstrate that bicalutamide 150 mg/d, when given as immediate adjuvant therapy following radiotherapy in men with early nonmetastatic prostate cancer, has benefits over radiotherapy alone. Highly significant reductions in the risk of objective and PSA progression were observed. Results by patients risk group show that, over 3 years’ follow-up, these benefits are clearest in those patients at higher risk, such as those with locally advanced disease. Longer follow-up will determine whether the observed reduction in the risk of disease progression translates into a survival benefit.
Main Points.
The bicalutamide (Casodex) Early Prostate Cancer program consists of three ongoing, randomized, double-blind, placebo-controlled trials in which men with early nonmetastatic prostate cancer received bicalutamide 150 mg daily as immediate therapy, either alone or as adjuvant to treatment of curative intent.
At first analysis, conducted after a median follow-up of 3 years, 178 (13.0%) patients showed evidence of objective progression: 75 (10.7%) in the bicalutamide 150 mg/d group and 103 (15.4%) in the placebo group.
Adjuvant therapy with bicalutamide 150 mg/d significantly reduced the risk of objective progression by 37% compared with placebo (HR 0.63; 95% CI 0.46–0.85; P = .0024). This translates into a 36% increase in objective progression-free survival (ETR 1.36; 95% CI 1.11–1.67).
Data from the radiotherapy patients have been further explored in terms of stage, grade, nodal status, PSA level prior to and after radiotherapy, and trial. Those at higher risk of progression were found to receive the clearest benefit.
Adjuvant bicalutamide 150 mg/d also significantly reduced the risk of PSA progression by 58% compared with placebo (HR 0.42; 95% CI 0.33–0.53; P ≪ .0001). This translates into a 99% increase in PSA progression-free survival (ETR 1.99; 95% CI 1.65–2.40).
First results from this program have demonstrated a significant overall treatment effect for immediate therapy with bicalutamide 150 mg/d as adjuvant to radiotherapy in patients with early nonmetastatic prostate cancer.
References
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