Search

BACKGROUND: Abiraterone acetate received licencing for use in only "high-risk" metastatic hormone-naïve prostate cancer (mHNPC) following the LATITUDE trial findings. However, a "risk"-related effect was not seen in the STAMPEDE trial. There remains uncertainty as to whether men with LATITUDE "low-risk" M1 disease benefit from androgen deprivation therapy (ADT) combined with abiraterone acetate and prednisolone (AAP). OBJECTIVE: Evaluation of heterogeneity of effect between LATITUDE high- and low-risk M1 prostate cancer patients receiving ADT + AAP in the STAMPEDE trial. DESIGN, SETTING, AND PARTICIPANTS: A post hoc subgroup analysis of the 2017 STAMPEDE "abiraterone comparison". Staging scans for M1 patients contemporaneously randomised to ADT or ADT + AAP within the STAMPEDE trial were evaluated centrally and blind to treatment assignment. Stratification was by risk according to the criteria set out in the LATITUDE trial. Exploratory subgroup stratification incorporated the CHAARTED criteria. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome measure was overall survival (OS) and the secondary outcome measure was failure-free survival (FFS). Further exploratory analysis evaluated clinical skeletal-related events, progression-free survival (PFS), and prostate cancer-specific death. Standard Cox-regression and Kaplan-Meier survival estimates were employed for analysis. RESULTS AND LIMITATIONS: A total of 901 M1 STAMPEDE patients were evaluated after exclusions. Of the patients, 428 (48%) were identified as having a low risk and 473 (52%) a high risk. Patients receiving ADT + AAP had significantly improved OS (low-risk hazard ratio [HR]: 0.66, 95% confidence interval or CI [0.44-0.98]) and FFS (low-risk HR: 0.24, 95% CI [0.17-0.33]) compared with ADT alone. Heterogeneity of effect was not seen between low- and high-risk groups for OS or FFS. For OS benefit in low risk, the number needed to treat was four times greater than that for high risk. However, this was not observed for the other measured endpoints. CONCLUSIONS: Men with mHNPC gain treatment benefit from ADT + AAP irrespective of risk stratification for "risk" or "volume". PATIENT SUMMARY: Coadministration of abiraterone acetate and prednisolone with androgen deprivation therapy (ADT) is associated with prolonged overall survival and disease control, compared with ADT alone, in all men with metastatic disease starting hormone therapy for the first time.

14 Background: Docetaxel (DOC) and abiraterone (ABI) both improve overall survival (OS) in men with locally advanced or metastatic hormone-sensitive prostate cancer (HSPC) but no head to head trials compare the 2 agents. STAMPEDE, a multi-arm multi-stage platform trial, recruited patients (pts) to treatments including DOC or ABI between Nov-11 and Mar-13. There was no evidence OS differed between DOC or ABI, thus quality of life (QOL) may increasingly inform treatment options. Methods: QOL scores were analysed in pts contemporaneously randomised to receive DOC or ABI, in addition to standard of care treatment. Self-assessment QOL questionnaires EORTC QLQ C30 and PR25 were completed during treatment and follow-up. These analyses focus on average global QOL over the first 2 years after randomisation, using repeated measures analysis, plus cross-sectional analyses at 3, 6, 12 and 24 months. A score difference of ≥4 points was pre-defined as clinically meaningful. Results: 173 men randomised to DOC and 342 men randomised to ABI participated in the QOL sub-study and contributed to this analysis. Baseline characteristics and proportion of missing data were similar between groups. Baseline global QOL scores were similar (mean (sd): DOC 77.8 (20) and ABI 78.0 (19.3)). Average global QOL over 2 years was higher in pts randomised to ABI than DOC, although the difference was statistically significant it did not meet the pre-defined clinical parameter (+3.9, 95%CI 0.6 to 7.1, p=0.021). Cross-sectional analyses showed clinically meaningful superior QOL in the ABI group at 3 and 6 months (+6.6, 95%CI 2.6 to 10.7, p=0.001; +8.0, 95%CI 3.6 to 12.3, p

5012 Background: STAMPEDE (www.stampedetrial.org) recruits men with newly-diagnosed or rapidly relapsing prostate cancer (PCa) that is metastatic (M1) or high-risk locally advanced, all commencing long-term androgen ablation therapy (AAT) for the first time. This is now the largest therapeutic RCT in PCa. We report survival outcomes for newly-diagnosed M1 control arm men in order to inform future trials in this setting. Methods: Newly-diagnosed men with M1 disease in the trial’s control arm (standard of care: AAT alone for at least 2yr), diagnosed up to 6 months prior to randomisation, were identified from trial records in Dec-2012. We report overall survival (OS) and failure-free survival (FFS) from randomisation by primary disease characteristics. Results: 3703 men were recruited to STAMPEDE Oct-2005 to Dec-2012, including a control arm cohort of 630 M1 men with newly-diagnosed disease. This cohort has median age at randomisation 66yr (quartiles 60-71), median PSA 105 (quartiles 34-379) IU/l; metastases to bone only (B) 393 (62%), soft tissue only (ST) 78 (13%) or bone and soft tissue (B+ST) 159 (25%). ST was mainly lymph nodes. Median time from diagnosis to randomisation is 69 days (max 180 days). Median duration of AAT prior to randomisation is 46 days (max 105 days). There were 129 deaths, of which 111 were from PCa. Median OS from randomisation is 42 months, with 2-yr OS 74% (95%CI 68, 78) in this cohort; B 77% (95%CI 71, 83), ST 85% (95%CI 70, 93), B+ST 57% (95%CI 45, 68). Median FFS is 12 months, driven by rising PSA; 2-yr FFS 32% (95%CI 27-37). Median time from FFS event to death was 22 months. Additional data on relapse therapies will be presented. Conclusions: Survival, and particularly FFS, remains relatively poor for men presenting with M1 disease starting long-term AAT, despite potential access when castration-resistant (CRPC) to docetaxel and other newer therapies. Better first-line therapy is required; STAMPEDE will report many comparisons in the future. Different M1 patterns may vary prognostically. Men with M1 disease will now spend most time in a state of CRPC, which has important implications for clinicians and trialists. Clinical trial information: NCT00268476.

27 Background: STAMPEDE ( NCT00268476 ) is a multi-centre, RCT using novel multi‐arm, multi‐stage (MAMS) methods. We describe the methodological and practical issues arising with early stopping of recruitment to some arms following an intermediate analysis and the issues in adding new research arms during the trial. Methods: The trial recruits men with locally advanced or metastatic prostate cancer starting standard long-term hormone therapy. There are 5 research and 1 control arm assessed over 3 intermediate activity stages I-III [outcome measure: failure-free survival (FFS)] and a final efficacy stage IV [outcome measure: overall survival]. At the end of each stage, research arms are formally compared to the control arm. Accrual of further patients is discontinued early for research arms not showing sufficient evidence of activity or with adverse safety considerations; accrual continues to the other arms; this interim hurdle is increasingly stringent at each stage. The addition of new research arm(s) can be actively considered when sufficiently interesting agents emerge. New research arms are compared only to contemporaneously-recruited control arm pts using the same intermediate guidelines in a time-delayed manner. Results: (1) After the second intermediate activity analysis (Mar-2011), the IDMC recommended and the Trial Steering Committee ratified discontinuation of recruitment to two research arms for lack-of-sufficient activity. Nearly 100 recruiting centres in UK and Switzerland had to promptly implement changes. Detailed advanced preparation meant that activation was swift and recruitment continued seamlessly into Activity Stage III. (2) An application to add a new research arm, abiraterone, has been agreed by funders, industry partner and ethics committee; regulatory approval awaited. Details on methodological and practical issues and implementation of these changes will be presented. Conclusions: The STAMPEDE experiences shows that recruitment to MAMS trials is achievable and that mid-flow changes to trial design are practicable and encouraged.

26 Background: Long-term hormone therapy (HT) alone is standard of care for men with metastatic or high-risk non-metastatic prostate cancer (PCa). STAMPEDE investigates whether early use of additional therapies improves overall survival. It is an international randomised controlled trial ( NCT00268476 ) using novel multi-arm, multi-stage methods to assess adding 1 or 2 of three agents (docetaxel, zoledronic acid (ZA), celecoxib) in 5 research arms in men with PCa starting long-term HT for the first time. Methods: HT was given as per standard care. Celecoxib was planned as 400mg bid until the sooner of 1 year or disease (including PSA) progression. The trial has 3 intermediate activity stages (I-III) where the outcome measure (OM) is failure-free survival (FFS) and 1 final efficacy stage (IV) with overall survival as primary OM. At the end of each stage, research arms are compared pairwise to the control arm. Accrual of further patients is discontinued early for any research arm either showing (a) safety concerns or (b) insufficient evidence of activity (lack-of-benefit) where the treatment effect on FFS is compared against a pre-defined stopping guideline. The interim activity “hurdle” becomes increasingly stringent stage-by-stage. Results: From Oct-2008 to Feb-2011, 2114 patients were consented and randomised, including 875 in this comparison. With 205 control FFS events, there was evidence of insufficient activity for HT+celecoxib over HT-alone: HR 0.98 (95%CI 0.90-1.06). The Independent Data Monitoring Committee recommended stopping accrual to this arm; stopping celecoxib was also recommended for patients currently on treatment. (Accrual was also stopped to HT+celecoxib+ZA but data are not disclosed.) There was no evidence of differences in toxicity: 25% and 23% of patients reporting grade ≥3 toxicities or adverse events with or without celecoxib. Control arm FFS was 51% at 2 years, in line with expectations. Conclusions: Celecoxib shows no evidence of activity in this setting. Accrual continues seamlessly to the other research arms. Follow-up of all arms is ongoing. Support: MRC, Cancer Research UK, Novartis, Sanofi-Aventis, Pfizer.

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/m(2)) 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.

BACKGROUND: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design.METHODS: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer).RESULTS: A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; PCONCLUSIONS: Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544 .).