Table 1 Descriptive of the 30 studies aiming to compare at least two interventions in a population of patients with or susceptible to have PC

multicentric, double-blind, phase 3, 2008–2011, follow-up of 48 months

adult, chemotherapy-naive, metastatic, castration-resistant PC, adequate organ function

dasatinib (n = 762) vs placebo (n = 760)

overall survival

proportion who achieved an objective response, time to first skeletal-related event, proportion with reduction > 35% in urinary N-telopeptide from baseline, progression-free survival, time to PSA progression, and proportion with reduction > 30% in pain intensity from baseline BPI-SF

stratified Cochran-Mantel-Haenszel

no

multicentric, double-blind, phase 3, 2009–2010, follow-up of 30 months

progressive, metastatic castration-resistant PC, BPI-SF score of zero to three, not previous chemotherapy

abiraterone (n = 546) vs placebo (n = 542)

time to pain progression (BPI-SF): increase ≥30% from baseline of the mean pain intensity, or increase ≥30% from baseline of the worst pain intensity, or increase ≥50% from baseline of the interference pain intensity

time to HRQoL deterioration (FACT-P) from baseline: decrease of the total score > 10%, or decrease of the general function > 9%, or decrease of the trial outcome index > 9%, or decrease of the prostate-specific-subscale > 3%, or decrease of the general function subscales > 3%

Kaplan-Meier

[47]

multicentric, double-blind, phase 3, 2010–2012, follow-up of 18 months

metastases and PSA progression, radiographic progression, or both in bone or soft tissue, despite receiving luteinizing hormone-releasing hormone analogue therapy or undergoing orchiectomy, serum testosterone level < 1·73 nmol/L, ECOG grade 0–1, BPI-SF score 0–3

enzalutamide (n = 872) vs placebo (n = 845)

radiographic progression-free survival and overall survival

time to initiation of cytotoxic chemotherapy, time to first skeletal-related event, best overall soft-tissue response, time to PSA decline > 50% or more from baseline, time to decline in QoL (FACT-P)

Kaplan-Meier

no

multicentric, open-label, phase 3, 1989–1999, follow-up of 18 years

younger than 75 years of age, life expectancy > 10 years, no other known cancers, localized tumor (T0d, T1, or T2, 1978 criteria of the International Union against Cancer)

radical-prostatectomy (n = 347) vs watchful-waiting (n = 348)

death from any cause, death from PC, and the risk of metastases

initiation of androgen deprivation therapy

no

no

multicentric, double-blind, phase 3, 1997–2010, follow-up of 24 months

radical prostatectomy for clinically localized (T1c or T2) PC less than 4 months before randomization, post-surgery PSA < 0.07 ng/mL confirmed by the assay used in this study, and fulfilled one or more following criteria: preoperative PSA > 20.0 ng/mL, final Gleason score ≥ 8, positive surgical margins, extracapsular extension, seminal vesicle invasion, or micro metastases in any removed pelvic lymph nodes

soy protein supplement (n = 86) vs placebo (n = 90)

2-year rate of biochemical cancer recurrence and time to recurrence for those in whom cancer recurred

adverse events (gastrointestinal, urinary tract, initiation of cholesterol or hypertension treatments, musculoskeletal pain)

no

no

multicentric, open-label, phase 3, 1998–2001, follow-up of 10 years

adult, histologically confirmed (T1b–T3a, N0, M0), PSA < 50 ng/mL, no contraindications for radical radiotherapy

escalated-dose (n = 422) vs control-doses (n = 421) radiotherapy

Biochemical progression-free survival and overall survival

biochemical failure, initiation of androgen deprivation therapy, progression-free survival, metastases-free survival, time to PC or non-PC death

no

no

multicentric, open-label, phase 3, 2003–2007, follow-up of 7 years

locally advanced PC (either T2a N0 M0, PSA ≥10 μg/L, Gleason score of ≥7) or T2b–4 N0 M0 tumors regardless of PSA and Gleason score

androgen suppression + leuprorelin (n = 268) or zoledronic acid (n = 268) or both (n = 267) vs standard (n = 268)

PC-specific mortality

PSA progression, local progression, distant progression, bone progression, time to secondary therapeutic intervention, all-cause mortality

no

no

multicentric, double-blind, phase 3, 2008–2011, follow-up of 38 months

adult, histologically or cytologically confirmed PC, surgically castrated or continuously medically castrated, serum testosterone levels ≤ 2·4 nmol/L

oral zibotentan (524) vs placebo (528)

overall survival

time to pain and PSA progression, progression-free survival, safety, time to deterioration of symptoms (FACT-P Symptom Index-8), time to deterioration of HRQoL (FACT-P total scores)

Log-rank

no

multicentric, open-label, phase 2, 2011–2013, 108 weeks

progressive metastatic castration-resistant PC, castrate concentrations of testosterone, ECOG grade 0–1

1400 (n = 35) or 400 (n = 37) mg daily doses of ODM-201 vs standard (n = 38)

PSA response at week 12, defined as a decrease of 50% or more in serum PSA from baseline

objective disease response (RECIST for soft tissue and PCWG2 criteria for bone), time to PSA progression analyzed (PCWG2 criteria), and time to radiographic disease progression (RECIST and PCWG2 criteria)

no

no

multicentric, double-blind, phase 3, 2009–2010, follow-up of 24 months

histologically or cytologically confirmed PC, undergone orchiectomy or received gonadotropin-releasing hormone agonist therapy, castrate testosterone levels, ECOG grade 0–2, previously received docetaxel, progressive disease (PCWG2 criteria)

enzalutamide (n = 800) vs placebo (n = 399)

overall survival

time to first skeletal-related event, change in pain severity and interference from baseline to week 13, pain palliation at week 13, pain progression at week 13, time to pain progression, overall improvement in HRQoL, improvements in individual HRQoL domains, time to HRQoL deterioration (FACT-P)

Kaplan-Meier, Log-Rank, stratified Cochran-Mantel-Haenszel

no

multicentric, double-blind, phase 3, follow-up of 30 months

adult, histologically or cytologically confirmed PC, radiographically documented metastatic disease with evidence of disease progression after receiving docetaxel

orteronel (n = 734) vs placebo (n = 365)

overall survival

radiographic progression-free survival, PSA decrease > 50% at 12 weeks, pain response at 12 weeks, response by RECIST 1·1, time to PSA progression, duration of pain response, time to pain progression, safety

no

no

simulation-based study, follow-up of 11 years

between the ages of 55 and 75 years

screening vs non-screening

incremental cost-effectiveness ratio

life-years gained, costs, gained in quality-adjusted life-years

no

no

multicentric, double-blind, phase 3, 2008–2011, follow-up of 36 months

histologically confirmed, progressive castration-resistant PC, two or more bone metastases detected on skeletal scintigraphy and no known visceral metastases, baseline PSA level ≥ 5 ng/mL, evidence of progressively increasing PSA values, ECOG grade 0–2, life expectancy ≥ 6 months, adequate hematologic, renal, and liver function

radium-223 (n = 614) vs placebo (n = 307)

overall survival

time to first symptomatic skeletal event, time to increase in PSA concentration, time to increase in total alkaline phosphatase concentration, confirmed reduction of at least 30% in total alkaline phosphataseponse, normalization of total alkaline phosphatase concentration

no

[42, 48]

multicentric, open-label, phase 3, 1996–1999, follow-up of 12 years

born between 1929 and 1944 (aged 55, 59, 63, or 67 years at entry), identified from the Finnish population Registry, no previous PC diagnosis

screening (n = 31,866) vs non-screening (n = 48,278)

overall mortality and prostate-specific mortality

no

no

no

multicentric, double-blind, phase 3, 2009–2012, follow-up of 36 months

at least one bone metastasis from castration-resistant PC, progression after docetaxel treatment

ipilimumab (n = 399) vs placebo (n = 400)

overall survival

progression-free survival, pain response, safety profile

no

no

multicentric, double-blind, phase 3, 2008–2010, follow-up of 36 months

histologically or cytologically confirmed PC, metastatic and castration-resistant (refractory to androgen ablation), surgical or ongoing chemical castration, baseline testosterone level < 50 ng/dL

sunitinib (n = 584) vs placebo (n = 289)

overall survival

progression-free survival, objective response rate, safety

no

no

open-label, pilot study, follow-up of 3 months

localized PC (T1c-T3,N0/NX), Gleason score > 6, risk of nodal involvement > 10%, no prior therapy for PC, no history of thrombosis, no unstable angina, no heart failure, serum testosterone > 280 ng/dL, normal blood counts, creatinine, and transaminases

goserelin (n = 12) or bicalutamide (n = 10) + dutasteride vs bicalutamide, dutasteride, and ketoconazole (n = 13)

Prostate tissue androgen levels

serum androgen levels, prostate androgen receptor program activity, PSA nadir, pathologic outcomes

no

no

multicentric, double-blind, phase 3, 2008–2011, follow-up of 38 months

histologically confirmed, progressive castration-resistant PC, two or more bone metastases detected on skeletal scintigraphy and no known visceral metastases, baseline PSA level ≥ 5 ng/mL, evidence of progressively increasing PSA values, ECOG grade 0–2, life expectancy ≥ 6 months, adequate hematologic, renal, and liver function

radium-223 (n = 614) vs placebo (n = 307)

overall survival

time to the first symptomatic skeletal event, clinically evaluated symptomatic skeletal events, total alkaline phosphatase and PSA concentrations, adverse events, mean change in the FACT-P total score at week 16

Student

[37, 48]

multicentric, double-blind, phase 3, 2009–2012, follow-up of 52 weeks

adult, clinical stage II (T1b-T2bN0M0) PC, with i) Gleason score < seven and the serum PSA level < 20 ng/mL, or ii) Gleason score ≥ seven and PSA < 15 ng/mL, ability to achieve erection at least half the time (International Index of Erectile Function question one response 3–5), Zubrod Performance Status score < 2, serum testosterone within normal limits, and no prior bilateral orchiectomy, chemotherapy, external radiotherapy, brachytherapy, surgical, or other ablative therapy for PC

tadalafil (n = 121) vs placebo (n = 31)

maintaining spontaneous erections between weeks 28 and 30 after the start of radiotherapy

overall sexual function, sexual satisfaction, marital adjustment and their partners’ sexual satisfaction, adverse events (NCI Common Terminology Criteria for Adverse Events, version 4)

Fisher, Student, Wilcoxon, generalized estimation equation, logistic, Spearman

no

multicentric, open-label, phase 3, 2000–2004, follow-up of 10 years

adult, PC with one of the following criteria: clinical classification T1b-4 (American Joint Committee on Cancer staging system, 5th edition), Gleason grade 2–6 and PSA > 10 but < 100 ng/mL, T1b-4 Gleason grade seven and PSA < 20 ng/mL, or T1b-1c Gleason score 8–10 and PSA < 20 ng/mL

28 weeks (n = 737) vs 8 weeks (n = 752) of androgen suppression

PC-specific mortality

overall and disease-free survival, time to loco regional progression or distant metastatic progression, time to biochemical failure and to biochemical failure on secondary androgen suppression, adverse events

no

no

phase 3, 2002–2006, follow-up of 7 years

favorable- to high-risk PC

hypofractionated external-beam radiotiony (n = 151) vs conventional fractionation intensity-modulated radiation (n = 152)

cumulative incidence of biochemical and/or clinical disease failure

toxicity (modified LENT and RTOG) criteria, PC mortality, overall survival

no

no

multicentric, double-blind, phase3, 2006–2010, follow-up of 60 months

pathologically confirmed PC with evidence of bone metastases on a bone scan, judged to be unresponsive or refractory to hormone treatment

atrasentan (n = 498) vs placebo (n = 496)

progression-free survival and overall survival

toxicities

no (results will be reported separately)

no

multicentric, double-blind, phase 3, 2009–2010, follow-up of 60 months

PSA progression (PCWG2 criteria) or radiographic progression in soft tissue or bone, ongoing androgen deprivation therapy with a serum testosterone level < 50 ng/dL, ECOG grade 0–1, BPI-SF score 0–3

abiraterone acetate (n = 546) vs placebo (n = 542)

radiographic progression-free survival and overall survival

time to opiate use for cancer-related pain, long-term safety

no

[27]

multicentric, double-blind, phase 3, 2008–2011, follow-up of 32 months

histologically confirmed, progressive castration-resistant PC, two or more bone metastases detected on skeletal scintigraphy and no known visceral metastases, baseline PSA level ≥ 5 ng/mL, evidence of progressively increasing PSA values, ECOG grade 0–2, life expectancy ≥ 6 months, adequate hematologic, renal, and liver function

radium-223 (n = 614) vs placebo (n = 307)

overall survival

time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture, occurrence of spinal cord compression, occurrence of tumor-related orthopedic surgical intervention

no

[37, 42]

multicentric, open-label, phase 3, 1994–2013, follow-up of 13 years

aged 50–74 years from population registries and randomly assigned by computer generated random numbers

PSA screening (n = 7408) vs no intervention (n = 6107)

PC-specific mortality

no

no

no

multicentric, double-blind, phase 3, 2006–2008, follow-up of 42 months

adult, histologically confirmed, non-metastatic castration-resistant PC at high risk for developing bone metastasis, as characterized by PSA ≥ 8.0 ng/mL within 3 months before random assignment, PSA doubling time ≤ 10 months at baseline, or both

denosumab (n = 716) vs placebo (n = 716)

time to first occurrence of bone metastasis or death resulting from any cause

time to first bone metastasis excluding deaths, overall survival

no

no

phase 3, blind, 2004–2012, follow-up of 36 months

adult, histologically confirmed PC, at least one bone metastasis by radiographic imaging, with ECOG grade 0–2, creatinine clearance (Cockroft-Gault) > 30 mL/min

zoledronic acid (n = 323) vs placebo (n = 322)

time to first skeletal-related event

overall survival, progression-free survival, safety

no

no

multicentric, double-blind, phase 3, 2007–2010, follow-up of 54 months

metastatic castrate-resistant PC, adequate organ function, no prior chemotherapy

aflibercept (n = 612) vs placebo (n = 612)

overall survival

PSA response, time to skeletal-related event, progression-free survival

no (results will be reported separately)

no

multicentric, open-label, phase 2, 2009–2011, follow-up of 24 weeks

intermediate- and high-risk patients had histologically confirmed localized PC (> three positive biopsies) and one of the following criteria: PSA > 10 ng/mL, PSA velocity > 2 ng/mL per year, Gleason score > 7

24-week (n = 30) vs 12-week (n = 28) abiraterone acetate

12-week prostate tissue testosterone and dihydrotestosterone levels

12- and 24-week intra prostatic hormones, serum hormones, monthly serum PSA, and prostate pathologic assessment

no

no

multicentric, double-blind, phase 3, 2007–2010, follow-up of 12 weeks

moderate to severe hot flashes ≥ four per day, life expectancy > 9 months, no history of hepatic dysfunction, no allergies to soy or dairy, no uncontrolled hypertension, no history of seizures, no history of intolerance to venlafaxine

venlafaxine + milk powder or placebo + soy powder or venlafaxine + soy powder vs placebo + milk powder

number of hot flashes times severity

12-week QoL level (FACT-P), adverse events

ANalysis Of VAriances

no