Tyrrell 2006.

Methods	Start date, end date of recruitment: between November 1994 and September 1996 Follow‐up period: Mean duration of treatment in months was 27.6 (range 1.9 to 75.6) in the bicalutamide 300 mg group, 30.0 (range 2.0 to 78.7) in the 450 mg group and 29.2 (range 0.5 to 73.5) in the 600 mg group. Mean duration of treatment in the castration group was 33.5 (range 1.0 to 78.2) months; median follow‐up: 5 years Design: randomised controlled trial Trial registration number: ISRCTN16559899
Participants	Population/Inclusion criteria: Men with histologically or cytologically confirmed M0 (T3 or T4) or M1 prostate cancer were included in the trial, provided they had a PSA level ≥ 20 ng/mL, a life expectancy greater than 3 months and evaluable disease and were considered fit enough to receive any of the randomly assigned treatments Setting: multi‐centre Geographical location: conducted at 26 centres across Belgium, Denmark, Finland, France, Norway, Portugal, Spain, Sweden and the UK Exclusion criteria: any previous or concurrent systemic therapy for prostate cancer; previous radiotherapy to the prostate within 3 months before trial entry Total number randomly assigned: 248 Baseline imbalances: balanced Number of participants with non‐metastatic disease: 139 Number of participants with metastatic disease: 109 Age: bicalutamide 300 mg daily: mean 69.5 years (range 46 to 82 years); bicalutamide 450 mg daily: mean 71.2 years (range 52 to 89 years); bicalutamide 600 mg daily: mean 72.1 years (range 56 to 84 years); castration: mean 71.3 years (range 51 to 86 years) PSA: bicalutamide 300 mg daily: mean 76.5 ng/mL (range 21 to 545 ng/mL); bicalutamide 450 mg daily: mean 105.9 ng/mL (range 20 to 7008 ng/mL); bicalutamide 600 mg daily: mean 89.4 ng/mL (range 19 to 965 ng/mL); castration: mean 91.2 ng/mL (range 16 to 2000 ng/mL) Subgroup measured: Results are presented for the overall participant population and by disease stage (M0 or M1); however data for these subgroups were reported only for overall survival
Interventions	Intervention Description/Timing: bicalutamide 300 mg daily or 450 mg daily or 600 mg daily Number randomly assigned to this group: 21 participants received bicalutamide 300 mg daily, 95 participants received bicalutamide 450 mg daily and 43 participants received bicalutamide 600 mg daily Note: "Patients were initially recruited into a non‐randomised phase to assess the tolerability of oral bicalutamide 300 mg (two 150 mg tablets) given once daily. Tolerance was assessed in these patients after 6 weeks of treatment and, if acceptable, future patients were randomised on 1:1 to either bicalutamide 450 mg (three 150 mg tablets) or castration (bilateral orchidectomy or goserelin acetate 3.6 mg depot every 28 days). If, after 6 weeks, tolerance at the 450 mg dose was acceptable, further patients were to be randomised at 1:1:1 to bicalutamide 450 mg, bicalutamide 600 mg (four 150 mg tablets) or castration. However, if tolerance at the 450 mg dose was unacceptable, future patients were to be randomised to bicalutamide 300 mg or castration. If the 600 mg dose was acceptable (after 6 weeks of follow‐up), recruitment to the bicalutamide 450 mg dose was ended and all future patients entering the study were to be randomised at 1:1:1 to bicalutamide 600 mg, bicalutamide 750 mg (5 150 mg tablets) or castration. If tolerance at the 600 mg dose was unacceptable, new patients were to be randomised to bicalutamide 450 mg or castration. If tolerability at the 750 mg dose was acceptable, a further and final dose escalation to 900 mg (six 150 mg tablets) was to be done. Recruitment of 20 patients per treatment group was planned for each dose‐escalation stage"; "As patients who received bicalutamide at the 300 mg dose were not randomised, it was considered inappropriate to provide any comparisons with the other treatments" Control Description/Timing: goserelin acetate or bilateral orchidectomy Number randomly assigned to this group: Of 90 participants randomly assigned to castration, 82 received goserelin acetate and 8 underwent bilateral orchiectomy
Outcomes	Overall survival Comparison: non‐steroidal antiandrogen versus castration Subgroup: non‐metastatic and metastatic participants Time points measured: median follow‐up of 5 years Time points reported: median follow‐up of 5 years Number of participants randomly assigned: intervention: bicalutamide 450 mg daily: 95; bicalutamide 600 mg daily: 43; control: 90 (non‐metastatic disease: bicalutamide 450/600 mg daily: 74, castration: 54; metastatic disease: bicalutamide 450/600 mg daily: 63; castration: 36) Number of participants in evaluation for ITT: intervention: bicalutamide 450 mg daily: 92; bicalutamide 600 mg daily: 42; control: 90 Cancer‐specific mortality Comparison: non‐steroidal antiandrogen versus castration Subgroup: non‐metastatic and metastatic participants (data reported only for combined population) Time points measured: median follow‐up of 5 years Time points reported: median follow‐up of 5 years Number of participants randomly assigned: intervention: bicalutamide 450 mg daily: 95; bicalutamide 600 mg daily: 43; control: 90 Number of participants in evaluation for ITT: intervention: bicalutamide 450 mg daily: 92; bicalutamide 600 mg daily: 42; control: 90 Treatment discontinuation due to adverse events Comparison: non‐steroidal antiandrogen versus castration Subgroup: non‐metastatic and metastatic participants (data reported only for combined population) Time points measured: median follow‐up of 5 years Time points reported: median follow‐up of 5 years Number of participants randomly assigned: intervention: bicalutamide 450 mg daily: 95; bicalutamide 600 mg daily: 43; control: 90 Number of participants in evaluation for ITT: intervention: bicalutamide 450 mg daily: 92; bicalutamide 600 mg daily: 42; control: 90 Clinical progression Comparison: non‐steroidal antiandrogen versus castration Subgroup: non‐metastatic and metastatic participants (data reported only for combined population) Time points measured: median follow‐up of 5 years Time points reported: median follow‐up of 5 years Outcome definition in report: Objective evidence for disease progression was considered to include any of the following: ≥ 50% increase in prostatic dimensions compared with the minimum dimensions recorded during the trial (provided 1 of the dimensions was > 3 cm at the time of assessment); the appearance of new or worsening of existing bone metastases on x‐ray or isotopic bone scan; or the appearance of new extraskeletal metastases or a ≥ 25% increase in the dimensions of any existing extraskeletal metastases compared with the minimum dimensions recorded during the trial Number of participants randomly assigned: intervention: bicalutamide 450 mg daily: 95; bicalutamide 600 mg daily: 43; control: 90 Number of participants in evaluation for ITT: intervention: bicalutamide 450 mg daily: 92; bicalutamide 600 mg daily: 42; control: 90 Biochemical progression Outcome not measured/reported Treatment failure Outcome not measured/reported Adverse events Comparison: non‐steroidal antiandrogen versus castration Subgroup: non‐metastatic and metastatic participants (data reported only for combined population) Time points measured: median follow‐up of 5 years Time points reported: median follow‐up of 5 years Number of participants randomly assigned: intervention: bicalutamide 450 mg daily: 95; bicalutamide 600 mg daily: 43; control: 90 Number of participants in evaluation for ITT: intervention: bicalutamide 450 mg daily: 92; bicalutamide 600 mg daily: 42; control: 90 Other outcomes reported Pharmacokinetic, change in serum PSA level from baseline after 12 weeks of treatment
Notes	Study funding source: AstraZeneca Possible conflict of interest: Five study investigators were funded by sponsor; author is a paid consultant to sponsor; another author is an employee of sponsor; editorial support was provided; financial assistance for this support was provided by AstraZeneca
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomly assigned treatment was assigned according to a scheme prepared by AstraZeneca using appropriate computer software. Random assignment was co‐ordinated in the UK by the Clinical Trials Unit, Queen Elizabeth Hospital, Birmingham; in Sweden, Denmark, Finland and Norway by the Randomisation Bureau, Danish Cancer Society, Aarhus, Denmark; and for all other centres by the local AstraZeneca Pharma Office
Allocation concealment (selection bias)	High risk	Participant numbers were allocated sequentially by entry as participants entered the trial
Blinding of participants and personnel (performance bias) overall survival, cancer‐specific mortality, biochemical progression	Unclear risk	No blinding for overall survival and cancer‐specific mortality. Blinding was not possible because of different interventions provided. It might be conceivable that outcomes such as overall survival and cancer‐specific mortality are influenced by lack of blinding. We finally judge that risk of bias regarding these outcomes is unclear
Blinding of participants and personnel (performance bias) treatment discontinuation due to adverse events, clinical progression, treatment failure, adverse events	High risk	No blinding for clinical progression, treatment discontinuation due to adverse events and adverse events. Blinding was not possible because of different interventions provided. We judge that outcomes such as clinical progression, treatment discontinuation due to adverse events and adverse events are likely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) overall survival, cancer‐specific mortality, biochemical progression	Low risk	No blinding for overall survival and cancer‐specific mortality. Blinding was not possible because of different interventions provided, and study authors reported insufficient information only. However, we judge that it is not likely that outcome assessment for overall survival and cancer‐specific mortality is influenced by lack of blinding
Blinding of outcome assessment (detection bias) treatment discontinuation due to adverse events, clinical progression, treatment failure, adverse events	High risk	No blinding. Blinding was not possible because of different interventions provided, and study authors reported insufficient information only. We judge that it is likely that outcome assessment for clinical progression, treatment failure, adverse events and treatment discontinuation due to adverse events is influenced by lack of blinding
Incomplete outcome data (attrition bias) overall survival, cancer‐specific mortality	Low risk	Proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate (all participants were evaluable except for 3 in the bicalutamide 450 mg group and 1 in the bicalutamide 600 mg group, who received no study treatment)
Incomplete outcome data (attrition bias) treatment discontinuation due to adverse events, adverse events	Low risk	Proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate (all participants were evaluable except for 3 in the bicalutamide 450 mg group and 1 in the bicalutamide 600 mg group, who received no study treatment)
Incomplete outcome data (attrition bias) clinical progression, biochemical progression	Low risk	Proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate (all participants were evaluable except for 3 in the bicalutamide 450 mg group and 1 in the bicalutamide 600 mg group, who received no study treatment)
Incomplete outcome data (attrition bias) treatment failure	Unclear risk	Not measured/reported
Selective reporting (reporting bias)	Low risk	Study protocol was not available, but it was clear that published reports included all expected outcomes
Other bias	Unclear risk	Unclear risk for conflict of interest Note: Allocation of bicalutamide 300 mg was not randomly assigned in this trial, and random assignment to the higher doses was done in 2 sections. Consequently, although the similar demographics of the treatment groups offer reassurance as to the validity of the results, the efficacy data should still be interpreted with some caution. Analysis of time to death was one of the endpoints not specified in the protocol that were analysed retrospectively to compare the effect of high doses (450 mg to 600 mg) of bicalutamide or castration on survival rates of participants with advanced prostate cancer

BMD, bone mineral density; CgA, chromogranin A; DMSC, Data Management Sub‐Committee; ECOG, Eastern Cooperative Oncology Group; FFM, fat‐free mass; HDL, high‐density lipoprotein; ITT, intention‐to‐treat; LDL, low‐density lipoprotein; LHRH, luteinising hormone–releasing hormone; PSA, prostate‐specific antigen; SD, standard deviation; VLDL, very low‐density lipoprotein; x‐ray, x‐radiation.