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Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

Summary Background Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. Methods Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m2) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). Findings 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60–71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23–184). Median follow-up was 43 months (IQR 30–60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79–1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66–0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69–0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3–5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. Interpretation Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. Funding Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.


Introduction
Since October, 2005, the STAMPEDE randomised controlled trial has recruited men with metastatic (M1), high-risk localised (N0), or node-positive (N+) prostate cancer who were newly diagnosed or had high-risk recurrent disease following previous local therapy. All were commencing fi rst-line long-term hormone therapy. Prognosis for these patient groups had altered little since the fi rst description of the eff ects of hormone therapy in the 1940s. This began to change in the early 21st century with licensing of agents that improved survival (ie, docetaxel, abiraterone, enzalutamide, cabazitaxel, radium-223, and sipuleucel-T), 1-8 and disease-modifying agents that reduced morbidity (zoledronic acid and denosumab). 9,10 However, these agents have all shown their benefi ts in the setting of castrate-refractory prostate cancer (ie, after fi rst-line hormone therapy has ceased working).
STAMPEDE uses a multiarm, multistage (MAMS) platform design to test whether the addition of treatments at the time of long-term hormone therapy initiation improves overall survival. Here, we evaluate and report fi ndings for zoledronic acid and docetaxel; data for celecoxib, abiraterone, enzalutamide in combination with abiraterone, and (in patients with newly diagnosed metastatic disease only) prostate radiotherapy will be reported elsewhere. We have previously reported the celecoxib-containing groups which closed to recruitment early after a pre-planned second intermediate analysis failed to show suffi cient eff ect on failure-free survival. 11 We have also previously reported control group outcome data for patients with metastatic 12 and non-metastatic 13 disease. We report here the fi rst survival data for the following original groups in this platform trial: zoledronic acid, docetaxel, and their combination. Other trials have also examined similar strategies, both in patients with non-metastatic disease and in those with metastatic disease, usually with single drugs. A meta-analysis with other docetaxel and zoledronic acid-containing trials has been conducted and is reported separately. 14 Zoledronic acid was licensed in 2002 on the basis of an improvement in a composite outcome measure of time to fi rst skeletal-related event, with a risk ratio of 0·64 (95% CI 0·49 to 0·85) in castrate-refractory prostate cancer, and subsequent reduction in further skeletalrelated events using the 4 mg schedule. 9 There was limited evidence of a benefi t in survival, although the study was underpowered. Two previous UK trials, PR04 and PR05, used sodium clodronate in patients with nonmetastatic and metastatic disease, respectively. The PR05 trial showed improved survival with concurrent hormone therapy plus clodronate but no evidence of benefi t was seen in PR04. 15 Docetaxel (75 mg/m²) 3-weekly (ie, given every 3 weeks) was licensed for metastatic castrate-refractory prostate cancer in 2004, on the basis of two trials comparing mitoxantrone and prednisone with docetaxel and either prednisone 2 or estramustine. 1 The median survival benefi t observed was about 3 months, with a hazard ratio (HR) of 0·76 (0·62-0·94) 2 for docetaxel compared with mitoxantrone.

Research in context
Evidence before this study Systemic treatment has changed little for newly diagnosed men with high-risk locally advanced or metastatic prostate cancer since the development of gonadotropin-releasing hormone analogues a generation ago. The only major change has been the use of radical radiotherapy for men whose disease had not spread. This century, new agents began to show valuable activity in relapsed, metastatic, castrate-refractory prostate cancer-including zoledronic acid, which was approved in 2002 on the basis of reduced morbidity in men with bone metastases (a site of spread in up to 90% of castrate-refractory prostate cancer), and docetaxel, with improved survival demonstrated in 2004. Several other trials in addition to STAMPEDE have assessed both drugs in the newly diagnosed setting, most notably GETUG-15 and CHAARTED, which assessed docetaxel in the metastatic setting (about 60% of the population used in our trial). A systematic review and meta-analysis was done in parallel to preparation of this report and contains details of the review strategy.

Added value of this study
Our results for zoledronic acid show no convincing evidence of worthwhile benefi t either on failure-free or overall survival.
These results are congruent with emerging results from other trials in men starting long-term hormone therapy. The docetaxel results showed an improvement in overall survival (HR 0·78; 95% CI 0·66-0·93; p=0·006). There was a notable improvement in survival for the metastatic subset, which is consistent with fi ndings from GETUG-15 and CHAARTED which both also showed gains in failure-free survival with docetaxel. GETUG-15 showed a non-signifi cant improvement in overall survival, and CHAARTED reported a statistically signifi cant improvement in overall survival.

Implications of all the available evidence
Together, these trials provide evidence that six cycles of docetaxel should be added to standard androgen deprivation therapy for men with metastatic disease commencing treatment. Men with non-metastatic disease had better prognoses, and failure-free survival was clearly improved by docetaxel; however, there were relatively few deaths in those with non-metastatic disease, so statements about overall survival in this population remain underpowered.
The STAMPEDE trial 16,17 used interim activity analyses, based on failure-free survival, to select groups to continue accrual for fully powered survival analysis. We report here overall, failure-free, and prostate-cancer-specifi c survival data from the zoledronic acid and docetaxel groups and their combination, together with adverse event data and treatment after relapse.

Study design and participants
We used a MAMS platform trial approach, incorporating a seamless phase 2/3 design. 18 The rationale and design have been described previously. 16,17,19 Full details are in the protocol. In summary, eligible patients had prostate cancer that was newly diagnosed as metastatic, node positive, or high-risk locally advanced (with at least two of T3/4, Gleason score of 8-10, and prostate-specifi c antigen ≥40 ng/mL); or previously treated with radical surgery, radiotherapy, or both and relapsing with high-risk features. All patients were intended for long-term hormone therapy, started no longer than 12 weeks before randomisation. There were no age restrictions; patients were required to be fi t for chemotherapy with no clinically signifi cant cardiovascular history.

Randomisation and masking
Patients were randomised centrally using a computerised algorithm, developed and maintained by the trials unit. Minimisation with a random element of 80% was used, stratifying for hospital, age at randomisation, presence of metastases, planned radiotherapy use, nodal involvement, WHO performance status, planned hormone therapy, and regular use of aspirin or another non-steroidal antiinfl ammatory drug. Allocation was in a 2:1:1:1 ratio to standard of care only (SOC-only), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care plus zoledronic acid and docetaxel (SOC + ZA + Doc). Masking to treatment allocation was considered impracticable and of limited value given the primary outcome measure.

Procedures
Standard of care was hormone therapy for at least 2 years with gonadotropin-releasing hormone agonists or antagonists or, only between 2006 and 2011 for patients with non-metastatic disease, oral anti-androgens alone. Orchidectomy was an allowable alternative to drug therapy. No recommendations around the use of granulocyte colony stimulating factor with docetaxel were given. Radiotherapy, at 6-9 months after randomisation, was  13 Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years. Docetaxel (75 mg/m²) was given for six 3-weekly cycles with prednisolone (10 mg) daily, and standard premedication before each injection. Dose modifi cations were described in the protocol. Trial therapy was discontinued after disease progression or intolerable adverse events. Patients were followed up 6-weekly to 6 months, 12-weekly to 2 years, 6-monthly to 5 years, then annually. Prostate-specifi c antigen was measured at every followup; further tests were at the clinician's discretion. Nadir prostate-specifi c antigen was the lowest value reported within 24 weeks after enrolment. Adverse events were graded with Common Toxicity Criteria (CTCAE) version 3.0; toxic eff ects and symptoms were reported at regular follow-up visits. Serious adverse events, including serious adverse reactions, were reported accordingly. The trial was done in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki, and had the relevant regulatory and ethics approvals (eg, in the UK we obtained national ethics approval, national regulatory approval, and local implementation). All patients gave written, informed consent.

Outcomes
The defi nitive and intermediate primary outcome measures were overall survival and failure-free survival, respectively. Overall survival was defi ned as time from randomisation to death from any cause. Failure-free survival, which is commonly used to drive decisions in the clinic, was selected because it is on the causal pathway to death from prostate cancer and was not required to be a surrogate for overall survival. It was defi ned as time from randomisation to fi rst evidence of at least one of: biochemical failure; progression either locally, in lymph nodes, or in distant metastases; or death from prostate cancer. Biochemical failure was defi ned as a rise of 50% above the within-24-week nadir and above 4 ng/mL and confi rmed by retest or treatment. 12 We expected prostate-specifi c antigen failure to be the most common manifestation of failure-free survival events. Cause of death was determined by masked central review. Death from prostate cancer was recorded when classifi ed by the reviewer as "defi nitely" or "probably" prostate cancer. The site investigator's determination was used for deaths not yet reviewed.

Statistical analysis
The sample size was calculated using nstage and its predecessor programmes in Stata, which enables design of MAMS trials. 20 Assuming, for the control group, 2 years' median failure-free survival, and median overall survival between 4 and 5 years, we targeted a 25% relative improvement (HR 0·75) in both failure-free survival and overall survival for each comparison of research group with control. Accumulating data were reviewed by an Independent Data Monitoring Committee, guided by lack-of-benefi t stopping guidelines. [16][17][18] The effi cacy stage analysis of each pairwise comparison of research against control for overall survival required around 400 deaths in the control arm for 90% power and 2·5% one-sided α (corresponding to a two-sided α of 5%), accounting for three intermediate analyses on failure-free survival (analysed March, 2010, April, 2011, and May, 2012). The research groups within STAMPEDE were seen to test distinct hypotheses, and the trial was purposely not designed as a factorial trial. 17 In this situation, many methodologists would not be concerned about the familywise error rate. 3,21-23 However, for completeness we calculated the maximum family-wise error rate as 6·75% for these three research groups.
Patients without the event of interest were censored at the time last known to be event free. Standard survival analysis methods were used to analyse time-to-event data. Cox proportional hazards regression models were used to estimate most relative treatment eff ects. This model was adjusted for stratifi cation factors (except hospital and planned hormone therapy), and stratifi ed by time periods defi ned by addition of a new research group or end in recruitment to an ongoing research group. An HR below 1·00 favoured the research group. Flexible parametric models were constructed with 4 degrees of freedom for each of the baseline hazard function and time-dependent eff ect, and adjusted for stratifi cation factors and time periods. 24 Medians and 5-year estimates come from the fl exible parametric model fi tted to the data; these are more reliable than reading the Kaplan-Meier curves. The proportional hazards assumption was tested; restricted mean survival time was emphasised in the presence of non-proportionality. Fine and Gray regression models were used for competing risk analysis of prostate-cancerspecifi c survival (non-metastatic prostate-cancer-specifi c survival analyses did not adjust for time period due to lack of convergence). Prespecifi ed analyses looked at consistency of treatment eff ect within stratifi cation factors, over time period, and also by categorised Gleason score (≤7, 8+, unknown), recurrent disease, and prostatespecifi c antigen values before hormone therapy. The statistical analysis plan was modifi ed to include an analysis of the subset of patients with metastatic disease at randomisation after the presentation of CHAARTED 25 and GETUG-15 26 and before this primary analysis was performed. All tests were two-sided, with confi dence intervals given at the 95% level.
Median follow-up was determined through the standard approach of reverse-censoring on death, in which survival is treated as the event and death as censoring. All patients are included in the effi cacy analyses according to allocated treatment on an intention-to-treat basis. Adverse event data are shown for the safety population, comprising patients who received any study drug and underwent adverse event assessment, and analysed according to treatment initiated irrespective of study group assignment; a sensitivity analysis of safety was done on an intention-totreat basis. Safety data were assessed continuously; we also present a safety analysis at 1 year, chosen to assess whether chemotherapy side-eff ects had ameliorated by this timepoint. A formal comparison of those research groups showing a survival advantage, compared with SOC-only,  Median time to starting zoledronic acid was about 2 weeks after randomisation, and about 8 weeks from starting hormone therapy (most patients started hormone therapy before randomisation). Median duration of zoledronic acid was 16·6 months (IQR 7·8-23·2) for SOC + ZA and 19·5 months (IQR 9·1-23·4) for SOC + ZA + Doc, with the diff erence in duration being driven by diff erences in time to progression (table 2). Of patients allocated to receive zoledronic acid as part of trial treatment, overall about 40% of patients completed 2 years of zoledronic acid therapy (table 2). When less than 2 years of treatment was received, progression was the most common reason for stopping. Zoledronic acid was not started in eight (1%) patients assigned to SOC + ZA and 49 (8%) patients assigned to SOC + ZA + Doc, mostly due to treatment refusal.
Comparing the two research groups that demonstrated a survival advantage over the control group (SOC + Doc and SOC + ZA + Doc), we noted no evidence of an advantage when adding zoledronic acid to docetaxel (HR 1·06, 95% CI 0·86-1·30; p=0·592). In an exploratory analysis of the eff ect of docetaxel on survival in the context of zoledronic acid (ie, comparing SOC + ZA with SOC + ZA + Doc), the hazard ratio was 0·87 (95% CI 0·71-1·06). Analysis of the main eff ects of zoledronic acid and docetaxel in a single factorial model, without a treatment-interaction term, showed docetaxel to be associated with a survival advantage (HR 0·82, 95% CI 0·72-0·93; p=0·003), but not zoledronic acid (HR 0·98, 95% CI 0·86-1·11; p=0·726). An exploratory factorial model, including an interaction term, found no evidence of treatment interaction (p=0·401); the individual treatment eff ects were the same as in the pairwise comparisons. Figure 2 shows the failure-free survival plot for each research comparison, and the appendix page 10 shows the form of that failure-free survival event. There were 761 events in patients on SOC-only; median failure-free survival 20 months; 5-year failure-free survival 28%. With 374 events there was no evidence of improvement in failure-free survival with SOC + ZA (HR 0·92, 95% CI 0·81-1·04; p=0·198); median failure-free survival was 22 months and 5-year failure-free survival was 31%.
Amongst patients randomly assigned to SOC-only, 328 of 1184 reported at least one skeletal-related event. Time to fi rst skeletal-related event was improved with SOC + Doc (112 patients reported skeletal-related event; HR 0·60, 95% CI 0·48-0·74; p=0·127 × 10 -⁵) and SOC + ZA + Doc (108 patients; HR 0·55, 95% CI 0·44-0·69; p=0·277 × 10 -⁷), but not SOC + ZA (153 patients; HR 0·89, 95% CI 0·73-1·07; p=0·221). There was strong evidence of non-proportional hazards for both comparisons showing improvement in time to fi rst skeletal-related event (SOC + Doc and SOC + ZA + Doc). In these cases, restricted mean survival time is preferred for summarising treatment eff ect. Mean time to skeletal-related event, restricted to within the fi rst 84 months on trial, was 61·4 months (95% CI 59·5-63·2) on SOC-only, compared with 68·0 months on SOC + Doc (diff erence 6·6 months, 95% CI 3·6-9·6; 1·2 1·4   In the patient group with bone metastases at presentation, SOC + ZA similarly had no evidence of an eff ect (HR 0·94, 95% CI 0·76-1·16; p=0·564). Figure 4 shows time to fi rst of any treatment after a failure-free survival event and time to fi rst life-extending therapy (defi ned as available agents with proven survival gain in castrate-refractory prostate cancer: docetaxel, abiraterone, cabazitaxel, enzalutamide, and radium-223). There were no obvious diff erences either in time to any therapy or life-extending therapies between groups. There were however, diff erences in the pattern of therapy depending on whether patients were docetaxel-exposed upfront (fi gure 4). Analysis of zoledronic acid use after relapse is provided in the appendix page 7. Overall exposure to treatment for progression is summarised in table 4, showing slightly higher rates of exposure to subsequent therapy in the control group. Use of cabazitaxel, enzalutamide, and radium-223 were low across all groups (appendix page 6).

SOC vs SOC + Doc
The proportion of patients reporting worst adverse event ever as grade 3 or higher was highest with SOC + Doc (288 patients [52%]) and SOC + ZA + Doc (269 [52%]; table 5). This was mostly due to events during the fi rst 6 months on trial, when the proportions were 17% (n=203) for SOC-only, 15% (n=91) for SOC + ZA, 36% (n=198) for SOC + Doc, and 39% (n=202) for SOC + ZA + Doc, with docetaxel seeming to contribute the most toxicity. For 1998 patients with adverse event data around 1 year after randomisation (ie, worst adverse event grade reported at 48 or 60 weeks of follow-up), the proportions of grade 3 or higher toxic eff ects were balanced, with 10% (n=76) patients reporting a worst adverse event as grade 3 or higher with SOC-only, 10% (n=41) with SOC + ZA, 10% with (n=43) SOC + Doc, and 12% (n=49) with SOC + ZA + Doc. The pattern and levels of adverse events were similar in the safety and intention-to-treat populations. There were ten   (2%) reported cases of osteonecrosis of the jaw on SOC + ZA and 20 (4%) on SOC + ZA + Doc. There were eight deaths probably or possibly related to the research treatment: one on SOC + Doc (neutropenic sepsis), and seven on SOC + ZA + Doc (four neutropenic sepsis, one pneumocystic pneumonia, one interstitial pneumonitis, and one pneumonia).

Discussion
The STAMPEDE randomised controlled trial is investigating the eff ectiveness of the front-line use of various treatments in men commencing long-term hormone therapy for newly diagnosed locally advanced or metastatic prostate cancer, or who have relapsed after local therapy with poor prognosis features. The MAMS design used in STAMPEDE has allowed us to address multiple treatment questions simultaneously within a single trial platform. 18 We will report further randomised comparisons from STAMPEDE in the coming years (appendix page 2), meaning that, through this single protocol, we will have answered at least eight diff erent primary questions in 15 years. To have addressed as many questions in separate, sequential trials would have taken many decades and far more patients, notably allocated to control groups. We recommend that academic and industry researchers consider this design in the future, to make faster progress and good use of limited trial resources. These are the fi rst mature, comparative, randomised data to emerge from the trial. We found that the addition of docetaxel to standard of care was associated with improved survival, with an HR of 0·78 and a diff erence in median survival of 10 months, as well as improvements in prostate-cancer-specifi c survival, failure-free survival, and skeletal-related events. The combination of zoledronic acid and docetaxel was associated with similar improvements, although the benefi t observed was smaller. We will report cost-eff ectiveness and patientreported outcomes separately.
Docetaxel is a widely used drug with a familiar toxicity profi le. Docetaxel was well tolerated in this population, with most patients completing all six cycles in a timely fashion and good dose intensity. Predictable chemotherapy toxic eff ects, including neutropenia and febrile neutropenia, were observed but few patients stopped treatment because of side-eff ects. Toxic eff ects in both docetaxel-containing groups seemed higher than in previous studies of this drug in patients with castraterefractory prostate cancer (eg, TAX327), but the studies have used diff erent populations. 27,28 The protocol made no recommendations about growth factor support, and we have not collected information about its use. 29,30 Docetaxel signifi cantly prolonged failure-free and overall survival across the trial population with no evidence that the eff ect varied across diff erent groups in the population; in particular, there is no evidence of a diff erence of the eff ect of docetaxel by metastatic status, for either of these outcome measures. The benefi cial eff ect on survival is clear in the larger metastatic subpopulation, which accounted for 61% of patients in the trial and 84% of deaths. There were fewer patients with non-metastatic disease and, with their generally more favourable prognosis, there were relatively few deaths in this group; all survival analyses for this subset are currently underpowered. In this non-metastatic subset of men, death from causes other than prostate cancer was more common than in men with metastatic disease, and therefore any eff ect of docetaxel on overall survival will be diluted. We will report longer-term follow-up in due course, but note that estimates of the treatment eff ect in failure-free survival and prostate-cancer-specifi c survival are extremely similar for patients with and without metastases at presentation.
For zoledronic acid, the results show no evidence of effi cacy on failure-free survival, skeletal-related events, or overall survival, despite good compliance with therapy and good levels of exposure, with target duration of 2 years. Few patients stopped treatment for sideeff ects; the most frequent reason for stopping trial therapy within 2 years was disease progression. This diff ered between the SOC + ZA and SOC + ZA + Doc groups because failure-free survival was increased in the latter group by docetaxel, indirectly leading to increased exposure to zoledronic acid as well. Despite this increased exposure, zoledronic acid showed no Cox-2 inhibition 0 (0%) 1 (0%) 0 (0%) 0 (0%) *Not docetaxel or cabazitaxel. †Not zoledronic acid Table 4: Treatments ever used at relapse, at the discretion of the treating clinician evidence of an advantage when added to docetaxel (HR 1·06). The eff ect of docetaxel on survival was positive, but clinically signifi cant toxicity did occur; in clinical practice, consideration could be given to early use of growth factor support to enable treatment delivery. There was one treatment-related death in the SOC + Doc group and seven in the combination group. This diff erence, combined with a more modest survival benefi t for the combination treatment, raises the possibility of some interaction (or antagonism) between docetaxel and zoledronic acid in the treatment of this group of men.
A number of trials have now examined docetaxel in the hormone-naive context in both the non-metastatic and metastatic settings, of which STAMPEDE is the largest. 25,26,[31][32][33][34] These fi ndings are discussed elsewhere but consistently show an improvement in failure-free survival. 14 The CHAARTED trial 25 recently reported improved survival in metastatic disease whereas GETUG-15, 26 a similar trial, did not report a diff erential eff ect. Taken with our results, there is compelling evidence that front-line docetaxel substantially improves survival in patients with metastatic disease. In the non-metastatic setting, there are insuffi cient mature survival results in the literature, so further follow-up and engagement in planned meta-analyses are needed to further delineate the eff ect of docetaxel on survival in this setting. The impact on failure-free survival is both clear and large in favour of docetaxel in STAMPEDE.
The case mix of patients joining the trial included men with newly diagnosed disease and a small proportion of patients with recurrent disease. The recurrent disease subset is small and thus it is unrealistic to look for statistically reliable results in such men; however, we note that estimates of the eff ect of docetaxel are consistent with that seen in the population as a whole.
For zoledronic acid, there are now several trials showing no evidence of a survival gain with upfront use, 14 Grade 5 adverse events were not necessarily treatment-related; similarly treatment-related deaths were not always grade 5 adverse events. ITT=intention-to-treat.*Analysis by actual treatment initiated (irrespective of assigned study arm) in patients who underwent adverse event assessment. †Analysis by assigned study arm in patients who underwent adverse event assessment. companion non-metastatic trial showed no evidence of an eff ect on survival with the same agent. 15 Men in the STAMPEDE trial did better than we had expected in terms of survival. We believe this resulted from second-line and third-line treatments which were unavailable when the trial was designed. The timing of second-line therapy after relapse was similar across groups, but choice of which treatment to use was at the investigator's discretion, and, consequently, was varied. This choice would have been aff ected by local practice and availability of newer treatments over time, such as abiraterone, enzalutamide, radium-223, and cabazitaxel, as well as allocated treatment in the trial.
There are several strengths to note in the STAMPEDE trial and specifi cally for the analyses reported here. First, the data were prospectively collected and randomised, from nearly 3000 men with patient characteristics that were well balanced by group, and we achieved good median follow-up (43 months). Second, the data were very recently frozen (May, 2015) at a pre-planned analysis point of roughly 400 control group deaths, meaning the primary outcome results are both well powered and have been reported promptly. Third, the patients contributing to these analyses came from more than 100 sites across the UK and Switzerland, suggesting the results to be generalisable. Fourth, the design allows easy understanding of eff ect across multiple randomisations. Finally, treatment compliance among patients starting treatment was good.
We are aware that there are also limitations within the data. First, the proportion of patients not starting treatment, especially docetaxel, will have a small diluting eff ect. Linkage to hospital records is required to report more detailed information on skeletal-related events. The impact of therapies that do not target androgen receptors on recurrence (as assessed by prostate-specifi c antigen) is likely to be complex. Finally, power for assessing the consistency of eff ects across subsets is inevitably low; we will report long-term follow-up in due course when the maturity will be much greater both across the trial and particularly in the non-metastatic subset.
In conclusion, we have shown improved survival across a population of men commencing fi rst-line long-term hormone therapy through the addition of docetaxel chemotherapy but not by adding zoledronic acid. Therefore, zoledronic acid should not become part of standard of care. Standard of care should be updated to include docetaxel chemotherapy in suitable patients with metastatic disease, and docetaxel may be considered for men with high-risk non-metastatic prostate cancer with or without radiotherapy.

Declaration of interests
GA reports personal fees from Sanofi -Aventis; personal fees and non-fi nancial support from Astellas; personal fees from Novartis; grants, personal fees, and non-fi nancial support from Janssen, personal fees and non-fi nancial support from Roche/Ventana, personal fees and nonfi nancial support from Medivation, personal fees from Millennium Pharmaceuticals, personal fees and non-fi nancial support from Abbott Laboratories, personal fees from Essa Pharmaceuticals, personal fees and non-fi nancial support from Bayer Healthcare Pharmaceuticals, personal fees from Takeda, and grants from AstraZeneca. AJB reports other support from Janssen, Sanofi , and Astellas, outside the submitted work. RC reports personal fees as a Consultant for Sanofi -Aventis, outside the submitted work. SC reports grants and personal fees from Sanofi -Aventis, outside the submitted work. JdB reports advisory boards and paid participation for Sanofi -Aventis. DPD reports grants from Cancer Research UK, during the conduct of the study; personal fees from Takeda Pharmaceuticals, outside the submitted work. TE reports that patients entering this study received docetaxel free of charge (Sanofi ) and has previously received per-patient payment for entering patients in other commercial trials investigating docetaxel. JDG reports other support as a local principal investigator for a study of radium-223 in prostate cancer funded by Bayer, and other support as a local principal investigator for a study of LHRH antagonist in prostate cancer funded by Millennium Pharmaceuticals, outside the submitted work. NDJ reports grants and personal fees from Sanofi , and grants and personal fees from Novartis, during the conduct of the study; grants and personal fees from Janssen, grants and personal fees from Astellas, and grants and personal fees from Bayer, outside the submitted work. RJJ reports grants from Sanofi , and grants and non-fi nancial support from Novartis, during the conduct of the study; grants, personal fees, and non-fi nancial support from Sanofi , grants, personal fees, and non-fi nancial support from Novartis, outside the submitted work. MDM reports personal fees from Sanofi , personal fees from Bayer, personal fees from Dendreon, personal fees from Bristol-Myers, and personal fees from Janssen, outside the submitted work. CCP reports personal fees from Sanofi -Aventis, research funding and speaker's honoraria from Bayer, and Bavarian Nordic and Janssen, outside the submitted work. MKBP reports funding from