Study 0301.

Methods	Start date, end date of recruitment: June 1990 to February 1992 Follow‐up period: follow‐up of a minimum of 12 months; mean duration for all 376 participants was 67 weeks for intervention and 75 weeks for control (for all analyses except survival, a data cutoff point was used when a minimum follow‐up of 3 months was reached for the first 306 participants; for the analyses of survival, information from all 376 participants was used with a minimum follow‐up of 12 months) Design: randomised controlled trial
Participants	Population/Inclusion criteria: histologically or cytologically diagnosed prostate cancer with evaluable distant metastases and suitable for orchiectomy Setting: multi‐centre Geographical location: Denmark, Norway, Sweden Exclusion criteria: Men who had received or were receiving systemic treatment for prostate cancer (including radiotherapy, antiandrogen, oestrogen, LHRH analogue, ketoconazole or cytotoxic therapy) or who had previously received radiotherapy to the prostate within 3 months of entry into the study were excluded. Other exclusion criteria were history or presence of an invasive malignancy within the past 5 years (other than prostate cancer or squamous/basal cell carcinoma of the skin), an ECOG performance score of 3 or 4, a bilirubin value 1.26 times the upper limit of the reference range or greater and any severe concomitant medical condition that would limit participation in the study. No other treatment for prostate cancer or drugs that could affect sex hormone status were allowed during the follow‐up period Total number randomly assigned: 376 Baseline imbalances: balanced Number of participants with non‐metastatic disease: 0 Number of participants with metastatic disease: 376 Age: intervention: mean 71.5 years (range 54 to 80 years); control: mean 70.3 years (range 49 to 85 years) PSA: not reported Subgroup measured: no
Interventions	Intervention Description/Timing: bicalutamide 50 mg once daily Number randomly assigned to this group: 186 Control Description/Timing: bilateral orchiectomy Number randomly assigned to this group: 190
Outcomes	Overall survival Comparison: non‐steroidal antiandrogen versus castration Subgroup: no Time points measured: For analyses of survival, information from all 376 participants was used, with a minimum follow‐up of 12 months Time points reported: For analyses of survival, information from all 376 participants was used, with a minimum follow‐up of 12 months Number of participants randomly assigned: intervention: 186; control: 190 Number of participants in evaluation for ITT: intervention: 186; control: 190 Cancer‐specific mortality Comparison: non‐steroidal antiandrogen versus castration Subgroup: no Time points measured: For analyses of survival, information from all 376 participants was used, with a minimum follow‐up of 12 months Time points reported: For analyses of survival, information from all 376 participants was used, with a minimum follow‐up of 12 months Number of participants randomly assigned: intervention: 186; control: 190 Number of participants in evaluation for ITT: intervention: 186; control: 190 Treatment discontinuation due to adverse events Comparison: non‐steroidal antiandrogen versus castration Subgroup: no Time points measured: minimum follow‐up of 3 months Time points reported: mean duration for all 376 participants was 67 weeks for intervention and 75 weeks for control Number of participants randomly assigned: intervention: 186; control: 190 Number of participants in evaluation for ITT: intervention: 153; control: 153 Clinical progression Comparison: non‐steroidal antiandrogen versus castration Subgroup: no Time points measured: minimum follow‐up of 3 months Time points reported: mean duration for all 376 participants was 67 weeks for intervention and 75 weeks for control Outcome definition in report: an increase in prostatic dimensions (product of 2 greatest perpendicular diameters) by 50% or more (1 initial diameter at least 3 cm) compared with the minimum dimensions recorded during the study; appearance of any new or worsening of existing bone metastases on x‐ray or isotope bone scan; appearance of any new extraskeletal metastasis or an increase in dimensions (by 25% or more) of any existing extraskeletal metastasis compared with the minimum dimensions recorded during the study; death occurring before evidence of objective progression Number of participants randomly assigned: intervention: 186; control: 190 Number of participants in evaluation for ITT: intervention: 153; control: 153 Biochemical progression Outcome not measured/reported Treatment failure Comparison: non‐steroidal antiandrogen versus castration Subgroup: no Time points measured: minimum follow‐up of 3 months Time points reported: Mean duration for all 376 participants was 67 weeks for intervention and 75 weeks for control Outcome definition in report: death (in the absence of disease progression); objective disease progression; addition of any recognised systemic treatment for prostate cancer before objective progression; patient lost to follow‐up; cessation of therapy because of adverse event, at the discretion of the investigator or at the request of the participant (applicable only to participants receiving bicalutamide) Number of participants randomly assigned: intervention: 186; control: 190 Number of participants in evaluation for ITT: intervention: 153; control: 153 Adverse events Comparison: non‐steroidal antiandrogen versus castration Subgroup: no Time points measured: minimum follow‐up of 3 months Time points reported: mean duration for all 376 participants was 67 weeks for intervention and 75 weeks for control Number of participants randomly assigned: intervention: 186; control: 190 Number of participants in evaluation for ITT: intervention: 153; control: 150 (3 refused surgery) Other outcomes reported Subjective response, quality of life
Notes	Study funding source: not reported Possible conflict of interest: not reported; the assistance of a member of Zeneca in preparation of the manuscript was gratefully acknowledged
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
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, adverse events and treatment failure. Blinding was not possible because of different interventions provided. We judge that outcomes such as clinical progression, treatment discontinuation due to adverse events, adverse events and treatment failure 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 for clinical progression, treatment discontinuation due to adverse events, adverse events and treatment failure. 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	Intention‐to‐treat analysis and therefore low risk of bias for incomplete outcome data for overall survival
Incomplete outcome data (attrition bias) treatment discontinuation due to adverse events, adverse events	High risk	'As‐treated' analysis on adverse events done with substantial departure of the intervention received from that assigned at randomisation (participants included who had at least 3 months of follow‐up)
Incomplete outcome data (attrition bias) clinical progression, biochemical progression	High risk	'As‐treated' analysis on clinical progression done with substantial departure of the intervention received from that assigned at randomisation (participants included who had at least 3 months of follow‐up)
Incomplete outcome data (attrition bias) treatment failure	High risk	'As‐treated' analysis on treatment failure done with substantial departure of the intervention received from that assigned at randomisation (participants included who had at least 3 months of follow‐up)
Selective reporting (reporting bias)	Low risk	Study protocol is not available, but it is clear that published reports include all expected outcomes
Other bias	Unclear risk	Unclear risk for conflict of interest