ZAPCA.

Study characteristics
Methods	Recruitment period: May 2008 to December 2010 Outcomes: overall survival, SREs, disease progression, adverse events Pain assessment tool: not reported Randomization: intervention vs control
Participants	Eligibility criteria: men age ≥ 20 years histopathologically or cytologically confirmed prostate cancer bone metastasis on bone scan sensitivity to androgen blockade therapy ECOG performance status ≤ 2 PSA level ≥ 30 ng/mL leukocyte count ≥ 3000/µL hemoglobin ≥ 9.0 g/dL platelet count 7.5 × 104/µL serum creatinine level ≤ 3.0 mg/dL corrected serum calcium ≥ 8.5 mg/dL and ≤ 11.5 mg/dL total bilirubin ≤ 1.8 mg/dL AST level ≤ 90 IU/L ALT level ≤ 100 IU/L Exclusion criteria: poorly controlled dental caries poorly controlled hypertension or cardiovascular disease double cancer requiring treatment systematical use of steroid drugs active HIV or hepatitis virus infections prior androgen blockade therapy prior or concurrent other anticancer therapy prior or concurrent immunologic adjuvant therapy prior or concurrent use of bisphosphonates (excluding zoledronic acid) prior systemic chemotherapy Participants randomized: 227 randomized, 115 intervention, 112 control Median age: 72.0 years, 73.0 years intervention, 71.5 years control Country of participants: Japan
Interventions	Previous interventions: all participants were treatment‐naive Interventions during study period: intervention: zoledronic acid 4 mg IV every 4 weeks from study entry and androgen blockade therapy with LHRH analogue + bicalutamide for 2 years control: androgen blockade therapy with LHRH analogue + bicalutamide for 2 years
Outcomes	Reported and analyzed in this review: none
Funding sources	Funding sources: "The ZAPCA trial was supported by Grant for Urologic Research No. 200040700148 from Kyoto University Hospital."
Declarations of interest	Conflicts of interest: Tomomi Kamba: honorarium from Astellas Pharma Toshiyuki Kamoto: research funding and honoraria from Astellas Pharma Fuminori Sato: research funding from Janssen Pharmaceutical and Astellas Pharma Naoya Masumori: honoraria from Novartis Pharma and Daiichi Sankyo, and research funding from Daiichi Sankyo Shin Egawa: research funding from Astellas Pharma and Takeda Pharmaceutical Hideki Sakai: research funding from Astellas Pharma and Takeda Pharmaceutical, and honoraria from Astellas Pharma and AstraZeneca Osamu Ogawa: honorarium from Astellas Pharma
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Computer‐based randomization was conducted at the Translational Research Informatics Center (TRI; Kobe, Japan) with stratification according to the treatment institution, baseline PSA concentration (<200 or ≥200 ng/mL), baseline extent of disease (EOD) grade [13] (≤2 or ≥3), and biopsy Gleason score (≤7 or ≥8). [...] The system automatically evaluated the eligibility of each patient and randomly assigned participants to each group."
Allocation concealment (selection bias)	Low risk	"Computer‐based randomization was conducted at the Translational Research Informatics Center (TRI; Kobe, Japan) with stratification according to the treatment institution, baseline PSA concentration (<200 or ≥200 ng/mL), baseline extent of disease (EOD) grade [13] (≤2 or ≥3), and biopsy Gleason score (≤7 or ≥8). [...] The system automatically evaluated the eligibility of each patient and randomly assigned participants to each group."
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Open‐label trial
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Open‐label trial
Blinding of outcome assessment (detection bias) Outcomes subjective to participants	High risk	Open‐label trial
Blinding of outcome assessment (detection bias) Outcomes subjective to outcome assessors	Unclear risk	Insufficient information on blinding of outcome assessor
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	No known reason for bias
Incomplete outcome data (attrition bias) Time‐to‐event data	Low risk	"Eight patients did not obtain evaluable efficacy data and were excluded from the full analysis set—three were found to be ineligible, two in the CZ group did not receive ZA, and three in the CZ group did not receive any treatment since the beginning of the study. Therefore, 110 patients in the CAB group and 109 in the CZ group were included in the full analysis set." 165 participants discontinued intervention, most due to progression (reasons clearly given).
Incomplete outcome data (attrition bias) Patient‐reported outcomes (other than safety data)	Low risk	"Eight patients did not obtain evaluable efficacy data and were excluded from the full analysis set—three were found to be ineligible, two in the CZ group did not receive ZA, and three in the CZ group did not receive any treatment since the beginning of the study. Therefore, 110 patients in the CAB group and 109 in the CZ group were included in the full analysis set." 165 participants discontinued intervention, most due to progression (reasons clearly given).
Incomplete outcome data (attrition bias) Safety data	Low risk	"All 224 patients who received at least one dose of LH–RH agonist were included in the Safety Assessment Set (SAS)."
Incomplete outcome data (attrition bias) Other outcomes	Low risk	"Eight patients did not obtain evaluable efficacy data and were excluded from the full analysis set—three were found to be ineligible, two in the CZ group did not receive ZA, and three in the CZ group did not receive any treatment since the beginning of the study. Therefore, 110 patients in the CAB group and 109 in the CZ group were included in the full analysis set." 165 participants discontinued intervention, most due to progression (reasons clearly given).
Selective reporting (reporting bias)	High risk	Study investigators initially planned to analyze QoL and pain as outcomes, but the authors did not provide any data on these endpoints in their publications. Protocol available (NCT00685646).
Other bias	Low risk	None identified