Background: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients.Methods: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC þ docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional.
BackgroundAdding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP.MethodRecruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP.ResultsA total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8–10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82–1.65); failure-free survival HR = 0.51 (95% CI 0.39–0.67); progression-free survival HR = 0.65 (95% CI 0.48–0.88); metastasis-free survival HR = 0.77 (95% CI 0.57–1.03); prostate cancer-specific survival HR = 1.02 (0.70–1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55–1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm.ConclusionsThis direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs.Trial registrationClinicaltrials.gov: NCT00268476.
Research in Context Panel:Evidence before this study: Preclinical data, epidemiological studies, and meta-analyses of randomised data from cardiovascular trials support the hypothesis that aspirin could be an effective adjuvant cancer therapy (Langley R, et al. Br J Cancer 2011;105(8):1107-13; Algra AM et al. Lancet Oncol 2012;13(5):518-27 ). Globally, several phase III studies are ongoing to assess this, though debate continues about the safety profile of aspirin particularly after radical therapy for gastrointestinal malignancies.Added value of this study: The Add-Aspirin trial (encompassing 4 individually powered phase III studies in gastro-oesophageal, colorectal, prostate and breast cancer) is the largest of the ongoing trials and includes a pre-defined feasibility analysis to assess the acceptability of randomisation, tolerability and toxicity based on an open label run-in phase prior to double-blind randomisation. The data show that aspirin is well tolerated after radical cancer therapy, acceptable to patients, and there is no evidence to suggest there is increased toxicity in the gastro-oesophageal cohort over other tumour-specific cohorts.Implications of all the available evidence: Aspirin is a low cost generic drug with the potential to have a large impact on cancer outcomes globally. Outcomes from gastro-oesophageal cancer remain poor and there is an imperative to complete recruitment to the ongoing trials as quickly as possible. The rationale and supporting evidence for evaluating aspirin as a potential anti-cancer therapy remains strong. More generally, a run-in approach may be useful in adjuvant (or prevention) studies for reducing the risk of non-adherence and participant attrition at a later date. ABSTRACT Background: Pre-clinical, epidemiological and randomised data indicate aspirin prevents tumour development and metastases leading to reduced cancer mortality, particularly for gastro-oesophageal and colorectal cancer. Randomised trials evaluating aspirin use after primary radical therapy are ongoing. To address concerns about toxicity particularly bleeding after radical treatment for gastro-oesophageal cancer, a pre-planned feasibility analysis was incorporated into the ongoing Add-Aspirin trial. Method: The Add-Aspirin protocol includes 4 phase III randomised-controlled trials evaluating the effect of aspirin on recurrence/survival after radical therapy in 4 tumour cohorts: gastro-oesophageal (GO), colorectal (CRC), breast and prostate. An open-label run-in phase (aspirin 100mg daily for 8 weeks) precedes double-blind randomisation (1:1:1 aspirin 300mg: aspirin 100mg: matched placebo). A preplanned analysis of feasibility, including recruitment, adherence, and toxicity was performed. The trial is registered with the International Standard Randomised Controlled Trials Number registry (ISRCTN74358648), and remains open to recruitment. Findings: After two years of recruitment (October 2015-October 2017), 3494 participants were registered on the trial (gastro-oesophageal 115, colorectal 950, breast...
Background STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL). Methods and findings Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively. Conclusions Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC. Trial registration ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544.
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