the confirm study design , including eligibility criteria , exclusion criteria , and the calculation of sample size , has been described in detail elsewhere ( 9 ) . briefly , confirm was a randomized , phase iii , double - blind trial that evaluated two different doses of fulvestrant ( 500 mg vs 250 mg ) in postmenopausal patients who had either locally advanced or metastatic er - positive breast cancer ( clinicaltrials.gov identifier : nct00099437 ; http://www.clinicaltrials.gov/ct2/show/nct00099437 ) . the primary study endpoint was pfs ( the time elapsing between the date of randomization and the date of earliest evidence of objective disease progression or death from any cause ) . secondary endpoints included objective response rate , clinical benefit rate , duration of response , duration of clinical benefit , os , tolerability , and quality of life ( 9 ) . after initial analysis , all patients , regardless of whether they were still receiving randomized treatment , entered a survival follow - up phase . patients remaining on randomized treatment during this follow - up phase continued on blinded randomized treatment until progression and were assessed for serious adverse events ( saes ) and survival status . patients who had discontinued randomized treatment were assessed for their survival status and best response to their first subsequent systemic breast cancer therapy received after treatment discontinuation . the study was performed in accordance with the declaration of helsinki , consistent with international conference on harmonisation / good clinical practice requirements . all patients gave written informed consent before study entry , and the study protocol was approved by the institutional review board of each participating institution . patients were randomly assigned to treatment in balanced blocks using a computer - generated randomization schedule ; all study personnel were blinded to randomized treatment . eligible patients were randomly assigned 1:1 to either fulvestrant 500 mg administered as two 5-ml intramuscular injections on days 0 , 14 , and 28 and every 28 (  3 ) days thereafter or fulvestrant 250 mg administered as two 5-ml intramuscular injections ( one fulvestrant and one placebo [ identical in appearance to study drug ] ) on days 0 , 14 ( two placebo injections only ) , and 28 , and every 28 (  3 ) days thereafter ( 9 ) . each active prefilled syringe contained 250 mg of fulvestrant at a concentration of 50mg / ml in a volume of 5ml , designated fulvestrant 5% weight / volume injection . the placebo prefilled syringe was identical to the active prefilled syringe and also had a volume of 5ml . os was defined as the number of days from randomization to death from any cause . patients who died after the data cutoff or who were known to be alive after the data cutoff were right - censored at the date of the data cutoff . patients who were last known to be alive before the data cutoff or who were lost to follow - up before the data cutoff were right - censored at the date they were last known to be alive . after the initial analysis , patients on fulvestrant 250 mg were permitted to switch to 500 mg before entering the survival follow - up phase . irrespective of whether they were still receiving randomized treatment , all patients in the follow - up phase continued to have their survival status monitored every 122 weeks until cutoff for the final 75% os analysis ( october 31 , 2011 ) . details of the first subsequent systemic breast cancer therapy received after discontinuation of randomized treatment , and of the best response ( complete response , partial response , stable disease , progressive disease , not evaluable ) to this therapy were collected . saes were reported to the patient safety database and collated during the survival follow - up phase for those patients still receiving randomized treatment . os was first analyzed in 2009 , in parallel with the primary analysis of pfs , after the proportion of reported deaths exceeded 50% of the total number of patients randomized across the two treatment groups . an additional exploratory analysis , which used a cox proportional hazards model adjusting for six predefined covariables ( age at baseline , response to last endocrine therapy received before fulvestrant , receptor status at diagnosis , visceral involvement at baseline , last therapy before fulvestrant , and measurable disease at baseline ) was also performed to assess the robustness of the unadjusted os result . an updated analysis is presented here of more mature survival data , performed after the proportion of reported deaths exceeded 75% of the total number of patients randomized across the two treatment groups . the data were analyzed using log - rank statistics , confirmed by cox proportional hazards model , and summarized by the method of kaplan  meier . p values presented are nominal without adjustment for multiplicity , and no alpha was retained for this analysis ( the 5% error was used at the initial os analysis ) . the confirm study design , including eligibility criteria , exclusion criteria , and the calculation of sample size , has been described in detail elsewhere ( 9 ) . briefly , confirm was a randomized , phase iii , double - blind trial that evaluated two different doses of fulvestrant ( 500 mg vs 250 mg ) in postmenopausal patients who had either locally advanced or metastatic er - positive breast cancer ( clinicaltrials.gov identifier : nct00099437 ; http://www.clinicaltrials.gov/ct2/show/nct00099437 ) . the primary study endpoint was pfs ( the time elapsing between the date of randomization and the date of earliest evidence of objective disease progression or death from any cause ) . secondary endpoints included objective response rate , clinical benefit rate , duration of response , duration of clinical benefit , os , tolerability , and quality of life ( 9 ) . after initial analysis , all patients , regardless of whether they were still receiving randomized treatment , entered a survival follow - up phase . patients remaining on randomized treatment during this follow - up phase continued on blinded randomized treatment until progression and were assessed for serious adverse events ( saes ) and survival status . patients who had discontinued randomized treatment were assessed for their survival status and best response to their first subsequent systemic breast cancer therapy received after treatment discontinuation . the study was performed in accordance with the declaration of helsinki , consistent with international conference on harmonisation / good clinical practice requirements . all patients gave written informed consent before study entry , and the study protocol was approved by the institutional review board of each participating institution . patients were randomly assigned to treatment in balanced blocks using a computer - generated randomization schedule ; all study personnel were blinded to randomized treatment . eligible patients were randomly assigned 1:1 to either fulvestrant 500 mg administered as two 5-ml intramuscular injections on days 0 , 14 , and 28 and every 28 (  3 ) days thereafter or fulvestrant 250 mg administered as two 5-ml intramuscular injections ( one fulvestrant and one placebo [ identical in appearance to study drug ] ) on days 0 , 14 ( two placebo injections only ) , and 28 , and every 28 (  3 ) days thereafter ( 9 ) . each active prefilled syringe contained 250 mg of fulvestrant at a concentration of 50mg / ml in a volume of 5ml , designated fulvestrant 5% weight / volume injection . the placebo prefilled syringe was identical to the active prefilled syringe and also had a volume of 5ml . os was defined as the number of days from randomization to death from any cause . patients who died after the data cutoff or who were known to be alive after the data cutoff were right - censored at the date of the data cutoff . patients who were last known to be alive before the data cutoff or who were lost to follow - up before the data cutoff were right - censored at the date they were last known to be alive . after the initial analysis , patients on fulvestrant 250 mg were permitted to switch to 500 mg before entering the survival follow - up phase . irrespective of whether they were still receiving randomized treatment , all patients in the follow - up phase continued to have their survival status monitored every 122 weeks until cutoff for the final 75% os analysis ( october 31 , 2011 ) . details of the first subsequent systemic breast cancer therapy received after discontinuation of randomized treatment , and of the best response ( complete response , partial response , stable disease , progressive disease , not evaluable ) to this therapy were collected . saes were reported to the patient safety database and collated during the survival follow - up phase for those patients still receiving randomized treatment . os was first analyzed in 2009 , in parallel with the primary analysis of pfs , after the proportion of reported deaths exceeded 50% of the total number of patients randomized across the two treatment groups . an additional exploratory analysis , which used a cox proportional hazards model adjusting for six predefined covariables ( age at baseline , response to last endocrine therapy received before fulvestrant , receptor status at diagnosis , visceral involvement at baseline , last therapy before fulvestrant , and measurable disease at baseline ) was also performed to assess the robustness of the unadjusted os result . an updated analysis is presented here of more mature survival data , performed after the proportion of reported deaths exceeded 75% of the total number of patients randomized across the two treatment groups . the data were analyzed using log - rank statistics , confirmed by cox proportional hazards model , and summarized by the method of kaplan  meier . p values presented are nominal without adjustment for multiplicity , and no alpha was retained for this analysis ( the 5% error was used at the initial os analysis ) . in total , 736 women ( median age = 61.0 years ) were randomly assigned between february 2005 and august 2007 from 128 centers in 17 countries ( belgium , brazil , chile , colombia , czech republic , hungary , india , italy , malta , mexico , poland , russia , slovakia , spain , the united states , ukraine , and venezuela ) ( fulvestrant 500 mg : n = 362 ; fulvestrant 250 mg : n = 374 ) ( figure 1 ) . baseline patient and tumor characteristics , reported previously , were comparable between the treatment groups ( 9 ) . at the time of the final analysis , 63 patients ( 8.6% ) were lost to follow - up , 16 patients ( 2.2% ) had withdrawn consent , 103 patients ( 14.0% ) were still being followed up ( n = 21 [ 2.9% ] on treatment ; n = 82 [ 11.1% ] not on treatment ) , and 554 patients ( 75.3% ) had died . eight patients ( 2.1% ) crossed over from fulvestrant 250 mg to fulvestrant 500 mg . at the initial data cutoff , 378 of 736 patients ( 51.4% ) had died ( n = 175 [ 48.3% ] in the fulvestrant 500 mg group ; n = 203 [ 54.3% ] in the fulvestrant 250 mg group ) ( table 1 ) . there was a trend for improved os for patients in the fulvestrant 500 mg group compared with those in the fulvestrant 250 mg group ( 25.1 months vs 22.8 months , respectively ; hazard ratio ( hr ) = 0.84 , 95% confidence interval ( ci ) = 0.69 to 1.03 , p = .09 for the unadjusted analysis ; hr = 0.81 , 95% ci = 0.66 to 1.00 , p = .049 for the retrospective adjusted analysis ) ( table 1 ; figure 2a ) . b ) overall survival for when 75% of patients had died . analysis by log - rank test . all rights reserved ( 9 ) . at the final survival update , 554 of 736 patients ( 75.3% ) had died ( n = 261 [ 72.1% ] in the fulvestrant 500 mg group ; n = 293 [ 78.3% ] in the fulvestrant 250 mg group ) ( table 1 ) . there was continued separation of the survival curves for fulvestrant 500 mg compared with fulvestrant 250 mg . the median time to death for patients in the fulvestrant 500 mg group vs the fulvestrant 250 mg group was 26.4 months vs 22.3 months , respectively ( hr = 0.81 , 95% ci = 0.69 to 0.96 , nominal p = .02 for the unadjusted analysis ; hr = 0.79 , 95% ci = 0.67 to 0.94 , nominal p = .007 for the adjusted analysis ) ( table 1 ; figure 2b ) . no statistically significant interaction was observed between the six predefined variables indicated in the method section and fulvestrant activity ( global interaction test p = .62 ) , indicating that the overall treatment effect was consistent across the predefined covariables . information on first subsequent therapies was available for 230 ( 63.5% ) and 239 ( 63.9% ) patients treated with fulvestrant 500 mg or 250 mg , respectively . best response to subsequent therapy is detailed in table 2 . for those randomized patients who had subsequent therapy , response to subsequent therapies was similar between treatment groups : 8.3% vs 8.4% of patients had either complete response or partial response in the fulvestrant 500 mg vs 250 mg groups , respectively ; 24.8% and 32.2% of patients had stable disease in the fulvestrant 500 mg vs 250 mg groups , respectively ; and 33.5% and 28.5% of patients had progressive disease in the fulvestrant 500 mg vs 250 mg groups , respectively . best response to subsequent therapy * * subsequent endocrine therapy included : anastrozole , exemestane , letrozole , medroxy progesterone , megestrol acetate , and tamoxifen . fulvestrant was either given at a dose of 250 mg or the dose was not specified . a summary of patients with an sae during the entire treatment period ( main trial plus follow - up phase ) is shown in table 3 . during the entire treatment period , a total of 35 ( 9.7% ) and 27 ( 7.2% ) patients had at least one sae in the fulvestrant 500 mg and fulvestrant 250 mg groups , respectively . saes that were causally related to study treatment were reported for eight ( 2.2% ) and four ( 1.1% ) patients , and saes with an outcome of death were reported for five ( 1.4% ) and seven ( 1.9% ) patients in the fulvestrant 500 mg and fulvestrant 250 mg groups , respectively , during the entire treatment period . overall , there were no clinically important differences in the profiles of saes between the treatment groups , and no clustering of saes could be detected in either treatment group . summary of patients experiencing saes during the treatment period * * saes = serious adverse events . all patients experiencing an sae with nonfatal outcome ( regardless of whether they later had a fatal sae ) . in total , 736 women ( median age = 61.0 years ) were randomly assigned between february 2005 and august 2007 from 128 centers in 17 countries ( belgium , brazil , chile , colombia , czech republic , hungary , india , italy , malta , mexico , poland , russia , slovakia , spain , the united states , ukraine , and venezuela ) ( fulvestrant 500 mg : n = 362 ; fulvestrant 250 mg : n = 374 ) ( figure 1 ) . baseline patient and tumor characteristics , reported previously , were comparable between the treatment groups ( 9 ) . at the time of the final analysis , 63 patients ( 8.6% ) were lost to follow - up , 16 patients ( 2.2% ) had withdrawn consent , 103 patients ( 14.0% ) were still being followed up ( n = 21 [ 2.9% ] on treatment ; n = 82 [ 11.1% ] not on treatment ) , and 554 patients ( 75.3% ) had died . eight patients ( 2.1% ) crossed over from fulvestrant 250 mg to fulvestrant 500 mg . at the initial data cutoff , 378 of 736 patients ( 51.4% ) had died ( n = 175 [ 48.3% ] in the fulvestrant 500 mg group ; n = 203 [ 54.3% ] in the fulvestrant 250 mg group ) ( table 1 ) . there was a trend for improved os for patients in the fulvestrant 500 mg group compared with those in the fulvestrant 250 mg group ( 25.1 months vs 22.8 months , respectively ; hazard ratio ( hr ) = 0.84 , 95% confidence interval ( ci ) = 0.69 to 1.03 , p = .09 for the unadjusted analysis ; hr = 0.81 , 95% ci = 0.66 to 1.00 , p = .049 for the retrospective adjusted analysis ) ( table 1 ; figure 2a ) . b ) overall survival for when 75% of patients had died . analysis by log - rank test . all rights reserved ( 9 ) . at the final survival update , 554 of 736 patients ( 75.3% ) had died ( n = 261 [ 72.1% ] in the fulvestrant 500 mg group ; n = 293 [ 78.3% ] in the fulvestrant 250 mg group ) ( table 1 ) . there was continued separation of the survival curves for fulvestrant 500 mg compared with fulvestrant 250 mg . the median time to death for patients in the fulvestrant 500 mg group vs the fulvestrant 250 mg group was 26.4 months vs 22.3 months , respectively ( hr = 0.81 , 95% ci = 0.69 to 0.96 , nominal p = .02 for the unadjusted analysis ; hr = 0.79 , 95% ci = 0.67 to 0.94 , nominal p = .007 for the adjusted analysis ) ( table 1 ; figure 2b ) . no statistically significant interaction was observed between the six predefined variables indicated in the method section and fulvestrant activity ( global interaction test p = .62 ) , indicating that the overall treatment effect was consistent across the predefined covariables . information on first subsequent therapies was available for 230 ( 63.5% ) and 239 ( 63.9% ) patients treated with fulvestrant 500 mg or 250 mg , respectively . best response to subsequent therapy is detailed in table 2 . for those randomized patients who had subsequent therapy , response to subsequent therapies was similar between treatment groups : 8.3% vs 8.4% of patients had either complete response or partial response in the fulvestrant 500 mg vs 250 mg groups , respectively ; 24.8% and 32.2% of patients had stable disease in the fulvestrant 500 mg vs 250 mg groups , respectively ; and 33.5% and 28.5% of patients had progressive disease in the fulvestrant 500 mg vs 250 mg groups , respectively . best response to subsequent therapy * * subsequent endocrine therapy included : anastrozole , exemestane , letrozole , medroxy progesterone , megestrol acetate , and tamoxifen . fulvestrant was either given at a dose of 250 mg or the dose was not specified . a summary of patients with an sae during the entire treatment period ( main trial plus follow - up phase ) is shown in table 3 . during the entire treatment period , a total of 35 ( 9.7% ) and 27 ( 7.2% ) patients had at least one sae in the fulvestrant 500 mg and fulvestrant 250 mg groups , respectively . saes that were causally related to study treatment were reported for eight ( 2.2% ) and four ( 1.1% ) patients , and saes with an outcome of death were reported for five ( 1.4% ) and seven ( 1.9% ) patients in the fulvestrant 500 mg and fulvestrant 250 mg groups , respectively , during the entire treatment period . overall , there were no clinically important differences in the profiles of saes between the treatment groups , and no clustering of saes could be detected in either treatment group . summary of patients experiencing saes during the treatment period * * saes = serious adverse events . all patients experiencing an sae with nonfatal outcome ( regardless of whether they later had a fatal sae ) . preclinical and preliminary clinical data prompted the activation of the confirm trial comparing fulvestrant 500 mg with fulvestrant 250 mg in postmenopausal patients with er - positive advanced breast cancer ( 1,5,6,10 ) . the pfs analysis ( primary study endpoint of the confirm trial ) demonstrated the superiority of 500 mg over 250 mg ( 9 ) . at the time of the pfs analysis , a first os analysis was also performed , and approximately 50% of events had been reported . the os analysis suggested a numerical trend in favor of 500 mg over 250 mg despite the lack of a statistically significant difference ( 9 ) . this observed numerical trend favoring fulvestrant 500 mg led to a decision by the study steering committee to plan for a second os analysis at 75% maturity . this article reports the results of the final 75% os analysis and suggests that fulvestrant 500 mg is superior to fulvestrant 250 mg , with a 19% relative reduction in the risk of death and a 4.1-month increase in median os . however , a limitation of this study is that the 75% os analysis is considered exploratory because it was planned after the results of the pfs and 50% os events analyses were available ; accordingly , no alpha was retained for this analysis and no adjustment for multiplicity was possible . nevertheless , the reported results are consistent with the previously reported pfs and 50% os events results ( 9 ) . in the attempt to rule out the hypothesis that the observed difference in os in favor of fulvestrant 500 mg was mainly the consequence of an imbalance in subsequent therapies delivered after progression on the study drug , an investigation of first subsequent therapies after progression on fulvestrant information on first subsequent therapies was available for approximately two - thirds ( 64% ) of the study population , with 153 and 165 patients treated with fulvestrant 500 mg and 250 mg , respectively , evaluable for best response . the findings show that there was no imbalance in type of first subsequent therapies given after progression on fulvestrant . last but not least , the analysis shows that the objective response rate and stable disease rate for first subsequent therapies are very similar between the two treatment groups . in summary , the analysis on first subsequent therapies suggests that the observed improvement in os in favor of the 500 mg dose was not due to an imbalance in subsequent treatments delivered after progression on fulvestrant . an additional investigation carried out in this study focused on the cross - over rate for patients initially treated with 250 mg . the study design did not initially allow for a cross - over after progression on fulvestrant 250 mg . however , when the pfs results were available , the study protocol was amended , and patients on treatment with 250 mg were offered the option to cross over to 500 mg . most patients had already progressed on fulvestrant by the time the pfs results were available and the study protocol had been amended . accordingly , fulvestrant dose was unblinded after progression to the study drug for only 34 of the 736 patients . twenty - four patients were eligible for crossover ( per protocol amendment ) , but the actual cross - over rate was low , with only eight of 374 patients ( 2.1% ) receiving fulvestrant 500 mg after prior treatment with 250 mg . considering that there is no clinical evidence on the activity of fulvestrant 500 mg in patients pretreated with 250 mg , it seems unlikely that the suggested os benefit of 500 mg over 250 mg is due to the low cross - over rate in this trial . with regard to the safety profile , the reported results do not support any clinically relevant difference either in the rate or causality of related saes between the two treatment groups . furthermore , the number of saes with an outcome of death was very similar between the two groups ( five events for the 500 mg group vs seven events for the 250 mg group ) . in addition , the 500-mg safety profile reported in this article is comparable with the safety profile of the same dose observed at the time of the pfs analysis . the results of this study raise a number of questions that need to be addressed in future trials . is fulvestrant given at the 500 mg dose a better option than aromatase inhibitors as a first - line therapy for postmenopausal patients with er - positive advanced breast cancer ? results from a phase ii randomized trial appear to suggest that this might be the case ( 11,12 ) . a phase iii trial ( the falcon trial ) is currently ongoing ( clinicaltrials.gov identifier : nct01602380 ) in an attempt to address this question . a trial recently reported by the southwest oncology group ( swog ) has suggested that a poly - endocrine therapy approach , consisting of the combination of fulvestrant 250 mg with an aromatase inhibitor , is superior to single - agent treatment with the same aromatase inhibitor ( 13 ) . no clinical data on the comparison between the poly - endocrine therapy and fulvestrant 500 mg are available . ideally , it would be important to have markers driving our treatment decisions when a first - line endocrine therapy approach has to be started . interestingly , a subgroup analysis run in the context of the swog trial seems to suggest that most of the benefit from poly - endocrine therapy is observed in patients with no prior exposure to endocrine therapy , either in the adjuvant or in the advanced setting ( 13 ) . this subgroup analysis might explain the contradictory results reported in another poly - endocrine therapy trial ( the fulvestrant and anastrozole combination therapy [ fact ] trial ) whose design completely overlaps with the swog trial but where a significantly higher proportion of patients were previously exposed to endocrine therapies ( 14,15 ) . last but not least , our results provide a rationale that if fulvestrant is to be combined with other nonendocrine agents targeting molecular pathways involved in the induction of primary or secondary endocrine resistance , then the dose should be 500 mg . results of the breast cancer trials of oral everolimus 2 ( bolero-2 ) show that the combination of an endocrine treatment with a compound targeting the pi3k pathway can improve the antitumor activity of single - agent endocrine therapy ( 16 ) . fulvestrant might be an ideal partner for future combination studies considering that its unique mechanism of action leads to er downregulation , thus preventing not only the er - mediated transcription of several genes but also the cross - talks between cytoplasmic er and several downstream effectors of molecular pathways involved in resistance to endocrine therapies ( 17,18 ) . in summary , based on the final results of the confirm trial , which suggest an os benefit for fulvestrant 500 mg over 250 mg , and taking into account that the previously reported pfs results were statistically significantly in favor of fulvestrant 500 mg , we believe that whenever treatment with fulvestrant should be initiated , this should be at the dose of 500 mg , according to the same schedule of this trial . this study was designed and funded by astrazeneca pharmaceuticals , macclesfield , uk , which was involved in the reviewing and interpretation of data , the writing of the manuscript , and the decision to submit for publication .
backgroundat the time of the initial analysis of overall survival ( os ) for the comparison of faslodex in recurrent or metastatic breast cancer ( confirm ) randomized , double - blind , phase iii trial , approximately 50% of patients had died . 
 a final analysis of os was subsequently planned for when 75% of patients had died.methodspatients were randomly assigned 1:1 to fulvestrant 500 mg administered as two 5-ml intramuscular injections on days 0 , 14 , and 28 and every 28 ( 3 ) days thereafter or fulvestrant 250 mg administered as two 5-ml intramuscular injections ( one fulvestrant and one placebo [ identical in appearance to study drug ] ) on days 0 , 14 ( two placebo injections only ) , and 28 and every 28 ( 3 ) days thereafter . 
 os was analyzed using an unadjusted log - rank test . 
 no adjustments were made for multiplicity . 
 serious adverse events ( saes ) and best response to subsequent therapy were also reported . 
 all statistical tests were two-sided.resultsin total , 736 women ( median age = 61.0 years ) were randomly assigned to fulvestrant 500 mg ( n = 362 ) or 250 mg ( n = 374 ) . at the final survival analysis , 554 of 736 ( 75.3% ) patients had died . 
 median os was 26.4 months for fulvestrant 500 mg and 22.3 months for 250 mg ( hazard ratio = 0.81 ; 95% confidence interval = 0.690.96 ; nominal p = .02 ) . 
 there were no clinically important differences in sae profiles between the treatment groups ; no clustering of saes could be detected in either treatment group . 
 type of first subsequent therapy and objective responses to first subsequent therapy were well balanced between the two treatment groups.conclusionsin patients with locally advanced or metastatic estrogen receptor  positive breast cancer , fulvestrant 500 mg is associated with a 19% reduction in risk of death and a 4.1-month difference in median os compared with fulvestrant 250 mg . fulvestrant 500 mg was well tolerated , and no new safety concerns were identified .