Study 307.

Methods	Study 306 and Study 307 are individual randomised controlled trials, but with very similar methodology. These studies were planned for pooled analysis, and publications report mostly combined data analysis. We present therefore a summary of the 2 studies Start date, end date of recruitment: January 1992 to June 1993 Follow‐up period: non‐metastatic participants: 6.3 years; metastatic participants: 100 weeks Design: randomised controlled trial Trial registration number of study 307: ISRCTN44967321
Participants	Population/Inclusion criteria: PSA > 20 ng/mL and T3/4 M0 or M1; men with histologically or cytologically diagnosed stage who were considered candidates for palliative hormonal management; metastatic status was assessed for bone metastases by bone scan or x‐ray and for non‐skeletal metastases by x‐ray, computed tomography scan, clinical examination, ultrasound or other relevant test Setting: multi‐centre Geographical location: Study 306: Denmark, Norway, Finland, Sweden; Study 307: UK, South Africa, Austria, The Netherlands, Spain, Australia, Germany, Belgium, Italy Exclusion criteria: previous systematic therapy for prostate cancer; radiation therapy in previous 3 months; invasive malignancy in previous 5 years; ECOG 3 to 4; serum bilirubin ≥ 1.26 times the upper reference range Total number randomly assigned: 1450 (a total of 1453 men were recruited for the 2 studies (Study 306 and Study 307), of whom 1450 received their randomly assigned treatment (bicalutamide 100 mg daily: 165 participants; bicalutamide 150 mg daily: 862 participants; castration: 423 participants); of bicalutamide 150 mg and castration: 480 metastatic participants, 805 non‐metastatic participants) Baseline imbalances: balanced Number of participants with non‐metastatic disease: 480 Number of participants with metastatic disease: 805 Age: intervention: Study 306: mean 71.0 years (range 47 to 88 years), Study 307: mean 72.2 years (range 49 to 92 years); control: Study 306: mean 72.4 years (range 46 to 94 years), Study 307: mean 73.4 years (range 50 to 93 years) PSA: reported only for non‐metastatic participants: intervention (n = 320): range 0.1 to 7691 ng/mL, median 69.2 ng/mL, mean 173.2 ng/mL; control (n = 160): range 8.6 to 6267.7 ng/mL, median 65.3 ng/mL, mean 194.5 ng/mL Subgroup measured: non‐metastatic and metastatic participants (metastatic participants later withdrawn from study after 100 weeks—they received standard therapy; participants with non‐metastatic disease continued); data reported only for bicalutamide 150 mg versus castration
Interventions	Intervention Description/Timing: bicalutamide 100 mg daily or 150 mg daily Number randomly assigned to this group: 864; data reported only for bicalutamide 150 mg versus castration Note: "Initially patients were randomised on a 2:2:1 basis to receive either bicalutamide 100 mg daily, bicalutamide 150 mg daily or castration. The dose of bicalutamide was blinded. After 3 months the higher dose of bicalutamide showed a greater fall in PSA. This dose was selected for further investigation. Patients were then randomised to either bicalutamide 150 mg daily or castration on a 2:1 basis." Investigators presented no data for bicalutamide 100 mg daily Control Description/Timing: bilateral orchiectomy or goserelin acetate 3.6 mg every 28 days at the discretion of participants and investigators Number randomly assigned to this group: 424
Outcomes	Overall survival Comparison: non‐steroidal antiandrogen versus castration Subgroup: non‐metastatic and metastatic participants; data reported only for bicalutamide 150 mg versus castration Time points measured: Clinical visits were scheduled at 4, 8 and 12 weeks after random assignment and at 12‐week intervals thereafter until death occurred Time points reported: non‐metastatic and metastatic participants after 100 weeks; non‐metastatic participants after median follow‐up of 202 to 205 weeks and 6.3 years Number of participants randomly assigned: intervention: non‐metastatic participants: 320, metastatic participants: 544; control: non‐metastatic participants: 160, metastatic participants: 264 Number of participants in evaluation for ITT: intervention: non‐metastatic participants: 320, metastatic participants: 544; control: non‐metastatic participants: 160, metastatic participants: 264 Cancer‐specific mortality Outcome not measured/reported Treatment discontinuation due to adverse events Comparison: non‐steroidal antiandrogen versus castration Subgroup: reported only for non‐metastatic participants (data reported only for bicalutamide 150 mg vs castration) Time points measured: Clinical visits were scheduled at 4, 8 and 12 weeks after random assignment and at 12‐week intervals thereafter until death occurred Time points reported: at 6.3 years Number of participants randomly assigned: intervention: 320; control: 160 Number of participants in evaluation for ITT: intervention: 314; control: 160 Clinical progression Comparison: non‐steroidal antiandrogen versus castration Subgroup: non‐metastatic and metastatic participants (data reported only for bicalutamide 150 mg vs castration) Time points measured: Clinical visits were scheduled at 4, 8 and 12 weeks after random assignment and at 12‐week intervals thereafter until death occurred Time points reported: metastatic participants after 12 months and 24 months; non‐metastatic and metastatic participants after 100 weeks; non‐metastatic participants after median follow‐up of 202 to 205 weeks and 6.3 years Outcome definition in report: time of random assignment to 50% or greater increase in prostatic dimension (product of the 2 largest perpendicular dimensions) from the minimum recorded during the trial, bony metastases on x‐ray or isotope bone scan or appearance of extraskeletal metastases Number of participants randomly assigned: intervention: non‐metastatic participants: 320, metastatic participants: 544; control: non‐metastatic participants: 160, metastatic participants: 264 Number of participants in evaluation for ITT: intervention: non‐metastatic participants: 320, metastatic participants: 544; control: non‐metastatic participants: 160, metastatic participants: 264 Biochemical progression Outcome not measured/reported Treatment failure Comparison: non‐steroidal antiandrogen versus castration Subgroup: non‐metastatic and metastatic participants (data reported only for bicalutamide 150 mg vs castration) Time points measured: Clinical visits were scheduled at 4, 8 and 12 weeks after random assignment and at 12‐week intervals thereafter until death occurred Time points reported: median 202 to 205 weeks Outcome definition in report: death from any cause; objective progression; addition of other systemic therapy for prostate cancer; loss to follow‐up; refusal to take or continue with randomly assigned therapy; cessation due to adverse events or other reasons (bicalutamide and medical castration only) Number of participants randomly assigned: intervention: non‐metastatic participants: 320; metastatic participants: 544; control: non‐metastatic participants: 160; metastatic participants: 264 Number of participants in evaluation for ITT: intervention: non‐metastatic participants: 320; metastatic participants: 544; control: non‐metastatic participants: 160; metastatic participants: 264 Adverse events Comparison: non‐steroidal antiandrogen versus castration Subgroup: non‐metastatic and metastatic participants (data reported only for bicalutamide 150 mg vs castration) Time points measured: Clinical visits were scheduled at 4, 8 and 12 weeks after random assignment and at 12‐week intervals thereafter until death occurred Time points reported: after 100 weeks, at 202 to 205 weeks and after 6.3 years Number of participants randomly assigned: intervention: 320; control: 160 Number of participants in evaluation for ITT: intervention: 314; control: 160 Other outcomes reported Subjective response, quality of life, bone mineral density (evaluated in only 29 non‐metastatic participants)
Notes	Study funding source: not reported Possible conflict of interest: Seven study authors had a financial interest and/or relationship with AstraZeneca; co‐author is a member of sponsor (AstraZeneca)
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. Blinding was not possible because of different interventions provided. It might be conceivable that overall survival is influenced by lack of blinding. We finally judge that risk of bias regarding this outcome is unclear Note: Comparison of bicalutamide 100 mg daily versus 150 mg daily was blinded, but participants receiving bicalutamide 100 mg daily discontinued
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 Note: Comparison of bicalutamide 100 mg daily versus 150 mg daily was blinded, but participants receiving bicalutamide 100 mg daily discontinued
Blinding of outcome assessment (detection bias) overall survival, cancer‐specific mortality, biochemical progression	Low risk	No blinding for overall survival. 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 overall survival 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	Data are reported on intention‐to‐treat
Incomplete outcome data (attrition bias) treatment discontinuation due to adverse events, adverse events	Low risk	Data are reported on intention‐to‐treat. Proportions of missing outcomes for safety data compared with observed event risk were not enough to have a clinically relevant impact on the intervention effect estimate
Incomplete outcome data (attrition bias) clinical progression, biochemical progression	Low risk	Data are reported on intention‐to‐treat
Incomplete outcome data (attrition bias) treatment failure	Low risk	Data are reported on intention‐to‐treat
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 Note: A protocol interim analysis after a median of approximately 100 weeks revealed a statistically significant qualitative interaction between randomly assigned treatment group and stage of disease at entry (M0 and M1); consequently, data from these subgroups were analysed separately. At that time, the M1 data were considered mature (43% deaths, combined trials) and indicated a significant survival advantage of 6 weeks for participants treated by castration. In accordance with DMSC advice, M1 participants were withdrawn from the trial, and no further data for this subgroup are presented here. The M0 data, at that time, were considered immature (13% of cases resulting in death, combined trials), and so these participants remained in the trial