Clinical trials to establish the efficacy of new agents in the adjuvant cancer setting typically take many years to complete. During that time, external factors can impact recruitment and reporting plans. An example is a new standard of care becoming available during the recruitment period.In this paper we describe how we modified the design of the RAMPART trial (NCT03288532) which was set up to investigate immune checkpoint inhibitor therapy in the adjuvant renal cancer setting. The trial had been initiated when no globally accepted adjuvant strategy after nephrectomy existed. A subsequent change in the standard of care for many patients with early renal cancer meant it was no longer feasible to continue to recruit. We needed to find a way to maximise the contribution that RAMPART participants could make to the evidence base for immune checkpoint inhibitor therapy without introducing bias or detriment to the integrity of the trial results. We describe how we agreed and incorporated all design and timeline changes while remaining blinded to accumulating data within the trial, thus protecting the reliability of the future results. We share details of our design modifications to guide others who may have similar experiences, particularly as more agents and combinations of agents are developed and investigated in similar adjuvant settings.

Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomised patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards and flexible parametric models, accounting for baseline stratification factors. One thousand and three patients were contemporaneously randomised (November 2011 to January 2014): median age 67 years; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% unassessable; median PSA 97 ng/mL. At 6.1 years median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95% CI: 0.50-0.71; P = 0.31 x 10(-9)) favoured SOC + AAP, with 5-years survival improved from 41% SOC-alone to 60% SOC + AAP. This was similar in low-risk (HR = 0.55; 95% CI: 0.41-0.76) and high-risk (HR = 0.54; 95% CI: 0.43-0.69) patients. Median and current maximum time on SOC + AAP was 2.4 and 8.1 years. Toxicity at 4 years postrandomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC + abiraterone acetate + prednisolone, irrespective of metastatic disease risk group.

PURPOSE The 2003 Leibovich score guides prognostication and selection to adjuvant clinical trials for patients with locally advanced renal cell carcinoma (RCC) after nephrectomy. We provide a robust external validation of the 2003 Leibovich score using contemporary data from SORCE, an international, randomized trial of sorafenib after excision of primary RCC. METHODS Data used to derive the 2003 Leibovich score were compared with contemporary data from SORCE. Discrimination and calibration of the metastasis-free survival outcome were assessed in data from patients with clear-cell RCC, using Cox proportional hazards regression, Kaplan-Meier curves, and calculation of Harrell's c indexes. Secondary analyses involved three important SORCE groups: patients with any non–clear-cell subtype, papillary, and chromophobe carcinomas. RESULTS Four hundred seven recurrences occurred in 982 patients in the Leibovich cohort and 520 recurrences were recorded in 1,445 patients in the primary SORCE cohort. Clear discrimination between intermediate-risk and high-risk SORCE cohorts was shown; hazard ratio 2.74 (95% CI, 2.29 to 3.28), c-index 0.63 (95% CI, 0.61 to 0.65). A hazard ratio of 0.61 (95% CI, 0.53 to 0.70) confirmed poor calibration of the two cohorts. Discrimination was observed in secondary populations, with c-indexes of 0.64 (95% CI, 0.59 to 0.69) for non–clear-cell RCC, 0.63 (95% CI, 0.56 to 0.69) for papillary RCC, and 0.65 (95% CI, 0.55 to 0.76) for chromophobe RCC. CONCLUSION The 2003 Leibovich score discriminates between intermediate-risk and high-risk clear-cell and non–clear-cell RCC groups in contemporary data, supporting its use for risk stratification in adjuvant clinical trials. Over time, metastasis-free survival for patients with locally advanced RCC has improved. Contemporary data from adjuvant RCC trials should be used to improve prognostication for patients with RCC.

Abstract Background STAMPEDE previously reported adding upfront docetaxel improved overall survival for prostate cancer patients starting long-term androgen deprivation therapy. We report long-term results for non-metastatic patients using, as primary outcome, metastatic progression-free survival (mPFS), an externally demonstrated surrogate for overall survival. Methods Standard of care (SOC) was androgen deprivation therapy with or without radical prostate radiotherapy. A total of 460 SOC and 230 SOC plus docetaxel were randomly assigned 2:1. Standard survival methods and intention to treat were used. Treatment effect estimates were summarized from adjusted Cox regression models, switching to restricted mean survival time if non-proportional hazards. mPFS (new metastases, skeletal-related events, or prostate cancer death) had 70% power (α = 0.05) for a hazard ratio (HR) of 0.70. Secondary outcome measures included overall survival, failure-free survival (FFS), and progression-free survival (PFS: mPFS, locoregional progression). Results Median follow-up was 6.5 years with 142 mPFS events on SOC (3 year and 54% increases over previous report). There was no good evidence of an advantage to SOC plus docetaxel on mPFS (HR = 0.89, 95% confidence interval [CI] = 0.66 to 1.19; P = .43); with 5-year mPFS 82% (95% CI = 78% to 87%) SOC plus docetaxel vs 77% (95% CI = 73% to 81%) SOC. Secondary outcomes showed evidence SOC plus docetaxel improved FFS (HR = 0.70, 95% CI = 0.55 to 0.88; P = .002) and PFS (nonproportional P = .03, restricted mean survival time difference = 5.8 months, 95% CI = 0.5 to 11.2; P = .03) but no good evidence of overall survival benefit (125 SOC deaths; HR = 0.88, 95% CI = 0.64 to 1.21; P = .44). There was no evidence SOC plus docetaxel increased late toxicity: post 1 year, 29% SOC and 30% SOC plus docetaxel grade 3-5 toxicity. Conclusions There is robust evidence that SOC plus docetaxel improved FFS and PFS (previously shown to increase quality-adjusted life-years), without excess late toxicity, which did not translate into benefit for longer-term outcomes. This may influence patient management in individual cases.

Background: 20-60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting. Methods/design: RAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3-11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A active monitoring (no placebo) for one year, Arm B durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART). Trial registration: ISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017-002329-39, CTA #: 20363/0380/001-0001, MREC #: 17/LO/1875, ClinicalTrials.gov Identifier: NCT03288532, RAMPART grant number: MC_UU_12023/25, TransRAMPART grant number: A28690 Cancer Research UK, RAMPART Protocol version 5.0.

The development of therapeutics in oncology is a highly active research area for the pharmaceutical and biotechnology industries, but also has a strong academic base. Many new agents have been developed in recent years, most with specific biological targets. This has mandated the need to look at different ways to streamline the evaluation of new agents. One solution has been the development of adaptive trial designs that allow the evaluation of multiple agents, concentrating on the most promising agents while screening out those which are unlikely to benefit patients. Another way forward has been the growth of partnerships between academia and industry with the shared goal of designing and conducting high quality clinical trials which answer important clinical questions as efficiently as possible. The RAMPART trial (NCT03288532) brings together both of these processes in an attempt to improve out-comes for patients with locally advanced renal cell carcinoma (RCC), where no globally acceptable adjuvant strategy after nephrectomy currently exist. RAMPART is led by the MRC CTU at University College London (UCL), in collaboration with other international academic groups and industry. We aim to facilitate the use of data from RAMPART, (dependent on outcomes), for a future regulatory submission that will extend the license of the agents being investigated. We share our experience in order to lay the foundations for an effective trial design and conduct framework and to guide others who may be considering similar collaborations. Trial Registration: ISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017-002329-39. CTA #: 20363/0380/001-0001. MREC #: 17/LO/1875. ClinicalTrials.gov Identifier: NCT03288532 RAMPART grant number: MC_UU_12023/25. . RAMPART Protocol version 5.0.

BACKGROUND: Little has been published regarding how doctors think and talk about prognosis and the potential benefits of adjuvant therapy. OBJECTIVE: We sought predictions of survival rates and survival times, for patients with and without adjuvant therapy, from the clinicians of patients participating in a randomised trial of adjuvant sorafenib after nephrectomy for renal cell carcinoma. METHODS: A subset of medical oncologists and urologists in the SORCE trial completed questionnaires eliciting their predictions of survival rates and survival times, with and without adjuvant sorafenib, for each of their participating patients. To compare predictions elicited as survival times versus survival rates, we transformed survival times to survival rates. To compare predicted benefits elicited as absolute improvements in rates and times, we transformed them into hazard ratios (HR), a measure of relative benefit.We postulated that a plausible benefit in overall survival (OS) should be smaller than that hypothesized for disease–free survival (DFS) in the trials original sample size justification (i.e. HR for OS should be ≥ 0.75). RESULTS: Sixty–one medical oncologists and 17 urologists completed questionnaires on 216 patients between 2007 and 2013. Predictions of survival without adjuvant sorafenib were similar whether elicited as survival rates or survival times (median 5–year survival rate of 61% vs 60%, p = 0.6). Predicted benefits of sorafenib were larger when elicited as improvements in survival rates than survival times (median HR 0.76 vs 0.83, p < 0.0001). The proportion of HR for predicted OS with sorafenib that reflected a plausible benefit (smaller effect of sorafenib on OS than hypothesized on DFS, i.e. HR ≥ 0.75) was 51% for survival rates, and 65% for survival times. CONCLUSIONS: The predicted benefits of adjuvant sorafenib were larger when elicited as improvements in survival rates than as survival times, and were often larger than the sample size justification for the trial. These potential biases should be considered when thinking and talking about individual patients in clinical practice, and when designing clinical trials.

PURPOSESORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence.PATIENTS AND METHODSWe randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo.RESULTSBetween July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, -0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib.CONCLUSIONSorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.

Background: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone nai ve 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+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. Results: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC+docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). Conclusions: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naive prostate cancer patients regardless of metastatic burden.

Background SORCE is a randomised, double-blind trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) at intermediate or high risk of recurrence (Leibovich classification). Methods We recruited patients from 147 sites in the UK, Australia, France, Belgium, Denmark, The Netherlands and Spain and randomised them (2:3:3) between three years of placebo (A), one year of sorafenib followed by two years of placebo (B) and three years of sorafenib (C). The initial sorafenib dose was 400mg twice per day orally, amended during trial recruitment to a reduced starting dose of 400mg daily. The primary outcome is investigator-reported disease-free survival (DFS). Given the results of the ASSURE and S-TRAC trials, and blinded to SORCE outcomes, we revised the primary analysis to compare three years of sorafenib (arm C) vs placebo (arm A) to focus on the question of longer exposure to sorafenib. Results Between July 2007 and April 2013, we randomised 1711 patients; 430, 642, and 639 to arms A, B, and C respectively. Median age was 58 years; 71% male, 84% clear cell histology, 53% at intermediate risk of recurrence and 47% at high risk of recurrence. We observed no differences in DFS or OS in any of our pre-planned and pre-powered analyses: all randomised patients, high-risk patients only, and patients with clear cell RCC only. Median DFS was not reached for three years sorafenib or for placebo (HR 1.01, 95% CI 0.83 -1.23, p=0.95). We observed non-proportional hazards: restricted mean survival time (RMST) was 6.81 years for three years of sorafenib and 6.82 years for placebo, RMST difference 0.01, 95% CI -0.49 – 0.48, p=0.99. Despite offering treatment adaptations, over half of patients stopped treatment early. Grade 3 hand-foot syndrome was reported in 24% of patients on sorafenib. Conclusions Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence following nephrectomy; it is the appropriate control of our current international adjuvant RCC trial, RAMPART. Clinical trial identification ISRCTN38934710; EudraCT: 2006-006079-19; NCT00492258. Legal entity responsible for the study University College London (UCL). Funding Cancer Research UK, UK Medical Research Council, Educational Grants and Drug Supply from Bayer, Cancer Australia Support for Cancer Clinical Trials Program and University College London. Disclosure T.Q.G. Eisen: Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self), Research grant / Funding (self): Pfizer; Research grant / Funding (self), Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Honoraria (self): Novartis; Honoraria (self): GSK; Honoraria (self): AVEO; Honoraria (self): Astellas; Honoraria (self): Boehringer Ingelheim. I.D. Davis: Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche / Genentech; Research grant / Funding (institution): MSD Oncology; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Janssen Oncology; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Bristol-Myers Squibb. M.R. Stockler: Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Binomics; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Tilray. J.M.G. Larkin: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Achilles Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Nektar Therapeutics; Research grant / Funding (institution): Covance; Research grant / Funding (institution): Immunocore; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution): Aveo; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy: Eisai; Advisory / Consultancy: EUSA Pharma; Advisory / Consultancy: GSK; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Imugene; Advisory / Consultancy: Incyte; Advisory / Consultancy: iOnctura. A. Bex: Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy, Non-remunerated activity/ies: BMS; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eusa; Non-remunerated activity/ies: Roche. S. Joniau: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Astellas ; Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Ferring; Speaker Bureau / Expert testimony: GSK; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Janssen; Research grant / Funding (institution): MDX Health; Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Roche; Speaker Bureau / Expert testimony: Sanofi. J. Bellmunt: Honoraria (self), Advisory / Consultancy: Genentech; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre-Fabre; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Honoraria (institution), Research grant / Funding (self), Research grant / Funding (institution): Takeda; Shareholder / Stockholder / Stock options: Biocline. All other authors have declared no conflicts of interest.

Background: Abiraterone acetate received licencing for use in only "high-risk" metastatic hormone-naive 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. (C) 2019 Published by Elsevier B.V. on behalf of European Association of Urology.

Background STAMPEDE previously reported that adding upfront docetaxel (Doc) improved overall survival (OS) for locally advanced and metastatic patients (pts) starting long-term androgen deprivation therapy (ADT). We report the long-term outcomes for M0 pts using metastatic progression-free survival (mPFS) as primary outcome, previously shown to be a surrogate for OS in M0 pts. Methods Standard-of-care (SOC) was ADT +/- radical radiotherapy (RT) to the prostate. 460 SOC and 230 SOC+Doc pts were recruited with 2:1 randomised stratified allocation. Standard survival intention-to-treatment analysis methods used Cox regression models adjusted for all stratification factors, with emphasis on restricted mean survival time (RMST) for non-proportional (non-PH) hazards. There was 70% power (2-sided α = 0.05) to detect HR = 0.70 for mPFS (= new metastases, skeletal related events or PCa death). Secondary outcome measures included failure free survival (FFS) and progression free survival (PFS = mPFS or locoregional progression). Results Median follow-up was ∼6.5yr compared to ∼3.5yr when last reported, with 142 mPFS events (a 54% increase) on SOC. There was no good evidence of an advantage of SOC+Doc over SOC on mPFS (HR = 0.89, 95% CI 0.66-1.19, P = 0.425); with 5yr mPFS 82% in SOC+Doc vs. 77% SOC. Secondary outcomes showed evidence that SOC+Doc improved FFS (HR = 0.70, 95% CI 0.55-0.88, P = 0.002) and PFS (non-PH P = 0.033, RMST difference=5.8 months, 95% CI 0.5-11.2, P = 0.031). There was no good evidence of a benefit of SOC+Doc on OS (125 SOC deaths; HR = 0.88, 95% CI 0.64-1.21, P = 0.442). There was no evidence that SOC+Doc increased late toxicity compared to SOC: after 1yr, G3-5 toxicity reported for 29% SOC and 30% SOC+Doc. The impact of SOC RT (nominated prior to randomisation) with and without SOC+Doc will also be detailed by subgroup. Conclusions There is robust evidence SOC+Doc improves FFS and PFS (which we have previously shown increases Quality Adjusted Life Years). There is however no good evidence that this translates into benefit for longer-term outcomes (OS or mPFS). The benefits of upfront SOC+Doc for improved FFS and PFS with no excess late toxicity may contribute to treatment discussions. Clinical trial identification NCT00268476. Legal entity responsible for the study University College London. Funding Cancer Research UK; Sanofi; MRC; Astellas; Clovis; Janssen; Novartis; Pfizer. Disclosure N.D. James: Advisory / Consultancy: Sanofi; Advisory / Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Janssen. N.W. Clarke: Advisory / Consultancy: Janssen. G. Attard: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Medivation; Advisory / Consultancy: Novartis; Advisory / Consultancy: Millennium Pharmaceuticals; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Abbott Laboratories; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Essa Pharmaceuticals; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Bayer Healthcare Pharmaceuticals; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Sanofi-Aventis; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Arno Therapeutics; Research grant / Funding (self): Innocrin Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Janssen; Advisory / Consultancy: Veridex; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Roche/Ventana; Advisory / Consultancy, Non-remunerated activity/ies: Pfizer; Research grant / Funding (self), I was an employee of the ICR, where abiraterone acetate was developed, up to 8 January 2018. : The Institute of Cancer Research (ICR). W. Cross: Speaker Bureau / Expert testimony: Janssen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer. D. Dearnaley: Research grant / Funding (institution), Financial Support for Trial Recruitment: UK National Institute for Health Research Clinical Research Network (NIHR CRN); Research grant / Funding (institution): The Institute of Cancer Research (ICR); Research grant / Funding (self), C46/A3976, C46/A10588 and C33589/A19727. : Cancer Research UK; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Sandoz; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen. R. Jones: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Astellas; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis. M.D. Mason: Honoraria (self), Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Bayer. C. Parker: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer; Honoraria (self): AAA; Speaker Bureau / Expert testimony: Janssen. M.K.B. Parmar: Research grant / Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Astellas; Research grant / Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Clovis Oncology; Research grant / Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Novartis; Research grant / Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Pfizer; Research grant / Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Sanofi. M.R. Sydes: Research grant / Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Astellas; Research grant / Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Clovis Oncology; Research grant / Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Novartis; Research grant / Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Pfizer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eli Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Janssen; Research grant / Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Sanofi. All other authors have declared no conflicts of interest.

162 Background: Results from large randomised controlled trials have shown that adding docetaxel to standard of care (SOC) in men initiating hormone therapy for prostate cancer prolongs survival for those with metastatic disease and prolongs time to treatment failure for those without metastatic disease. We report on the impact of docetaxel on health related quality of life (HRQoL), resource use and cost-effectiveness for men treated in the STAMPEDE trial. Methods: Health outcomes and costs in the UK NHS were modelled using EuroQol (EQ-5D)and resource use data collected within the STAMPEDE trial (STAMPEDE enrolled men advanced prostate cancer starting first line hormone therapy. SOC was hormone therapy for ≥2 years and radiotherapy in some patients. Docetaxel (75 mg/m2) was administered alongside SOC for six 3-weekly cycles with prednisolone 10 mg daily. Lifetime predictions of costs, changes in predicted survival duration, quality adjusted life years (QALYs), and incremental cost effectiveness ratios (ICERs) were calculated. Results: Compared to patients allocated SOC, docetaxel was estimated to extend predicted survival by an average of 0.89 years for M1 patients and 0.78 years for M0 patients. Docetaxel was estimated to extend discounted QALYs by 0.51 years in M1 patients and 0.39 years in M0 patients. QALY gains in M0 patients were driven by the beneficial effect of delayed and reduced relapse. Docetaxel was cost-effective both in M1 patients (ICER = £5,514/QALY vs. SOC) and M0 patients (higher QALYs, lower costs vs. SOC). The probabilistic sensitivity analysis indicated a very high probability ( > 99%) that docetaxel is cost-effective in both M0 and M1 patients. Docetaxel remained cost effective in M0 patients even when no survival advantage was assumed due to reductions and delays in relapse. Conclusions: Docetaxel improves overall HRQoL, delays time to, and reduces the need for, subsequent therapy, and is cost-effective, amongst patients with both non-metastatic and metastatic disease. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in non-metastatic patients. Clinical trial information: ISRCTN78818544.

Background Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy. Methods We did a randomised controlled phase 3 trial at 117 hospitals in Switzerland and the UK. Eligible patients had newly diagnosed metastatic prostate cancer. We randomly allocated patients open-label in a 1: 1 ratio to standard of care (control group) or standard of care and radiotherapy (radiotherapy group). Randomisation was stratified by hospital, age at randomisation, nodal involvement, WHO performance status, planned androgen deprivation therapy, planned docetaxel use (from December, 2015), and regular aspirin or non-steroidal anti-inflammatory drug use. Standard of care was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December, 2015. Men allocated radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomisation. The primary outcome was overall survival, measured as the number of deaths; this analysis had 90% power with a one-sided a of 2.5% for a hazard ratio (HR) of 0.75. Secondary outcomes were failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. The primary outcome analysis was by intention to treat. Two prespecified subgroup analyses tested the effects of prostate radiotherapy by baseline metastatic burden and radiotherapy schedule. This trial is registered with ClinicalTrials.gov, number NCT00268476. Findings Between Jan 22, 2013, and Sept 2, 2016, 2061 men underwent randomisation, 1029 were allocated the control and 1032 radiotherapy. Allocated groups were balanced, with a median age of 68 years (IQR 63-73) and median amount of prostate-specific antigen of 97 ng/mL (33-315). 367 (18%) patients received early docetaxel. 1082 (52%) participants nominated the daily radiotherapy schedule before randomisation and 979 (48%) the weekly schedule. 819 (40%) men had a low metastatic burden, 1120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0.76, 95% CI 0.68-0.84; p<0.0001) but not overall survival (0.92, 0.80-1.06; p=0266). Radiotherapy was well tolerated, with 48 (5%) adverse events (Radiation Therapy Oncology Group grade 3-4) reported during radiotherapy and 37 (4%) after radiotherapy. The proportion reporting at least one severe adverse event (Common Terminology Criteria for Adverse Events grade 3 or worse) was similar by treatment group in the safety population (398 [38%] with control and 380 [39%] with radiotherapy). Interpretation Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer. Copyright (c) 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Background: Abiraterone acetate plus prednisone/prednisolone (AAP) is licenced in the EU for use in "high risk" newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) based on results of the LATITUDE trial. However, the STAMPEDE "AAP comparison" did not suggest a differential effect, with similar benefits in M0 & M1 patients (pts). We evaluate heterogeneity of AAP effect on overall (OS) & failure-free-survival (FFS) in pts with LATITUDE defined high & low risk M1 disease treated with androgen deprivation therapy (ADT) or ADT + AAP, randomised within the STAMPEDE trial. Methods: Staging scans were evaluated centrally for M1 pts randomized to ADT (Arm A) or AAP (Arm G) within trial. Following review, pts were classified as low or high risk according to the LATITUDE criteria. The primary study endpoint was overall survival (OS) & the secondary endpoint was failure-free survival (FFS). Further exploratory analysis evaluated skeletal related events (SRE), progression free survival (PFS) & prostate cancer specific survival (PCSS). Secondary differential analysis by tumor volume (high/low) was done using the criteria defined in CHAARTED. Results: 901 of 990 eligible M1 pts were evaluable. Median age 67yr, median PSA 96ng/ml, median follow up 42mth. 473 pts were high risk & 428 low risk according to LATITUDE criteria. AAP treated pts had clinically & statistically significant OS improvements in both high (HR: 0.54, 95% CI [0.41-0.70]; p < 0.001) & low (HR: 0.66, 95% CI [0.44-0.98]; p = 0.041) risk groups. Pts receiving AAP also benefited from prolonged FFS within both high (HR: 0.31, 95% CI [0.25-0.39]; p < 0.001) & low risk groups (HR: 0.238, 95% CI [0.17-0.33]; p < 0.001). No evidence of heterogeneity between risk groups was found in OS or FFS (interaction p-value, p = 0.385 & p = 0.294 respectively). Further analyses incorporating the alternative CHAARTED volume definition was done with similar outcomes. Conclusions: Men with primary mHSPC treated with AAP plus ADT had a significant increase in OS & FFS compared to those receiving ADT alone, irrespective of risk/volume sub-classification. These results show AAP treatment benefit across all mHSPC pts, irrespective of M1 risk/volume sub-stratification using conventional imaging. Clinical trial identification: NCT00268476. Legal entity responsible for the study: Medical Research Council Clinical Trials Unit at UCL. Funding: This comparison was financially supported by Janssen and by Cancer Research UK (CRUK_A12459) with core funding from the Medical Research Council (MRC_MC_UU_12023/25). The protocol platform is also supported by Astellas, Clovis Oncology, Novartis, Pfizer and Sanofi Aventis. Disclosure: N.D. James: Sanofi and Novartis advisory board; Janssen grant and personal fees, advisory board, speaker fees and assistance with travel. C.C. Parker: Bayer grant and personal fees for research funding, speaker fees and advisory board honoraria; Advanced Accelerator Applications (AAA) advisory board honoraria; Janssen speaker fees. G. Attard: Veridex consulting fees; Roche/Ventana consulting fees, speakers' bureaus, travel and accommodation. S. Chowdhury: Janssen honoraria, speakers fees and travel grant. D.P. Dearnaley: UK NIHR CRN financial support for trial recruitment. J.S. de Bono: Janssen advisory board honoraria. C.E. Gilson, M.K. Parmar: Educational grant plus drug from Astellas, Janssen, Novartis, Pfizer, Sanofi-Aventis for STAMPEDE. Educational grant from Clovis Oncology for STAMPEDE. S. Gillessen: Compensated consultancy and advisory roles (including IDMC): AAA International, Active Biotech, Astellas Pharma, Bayer, Bristol-Myers Squibb, CellSearch (Menarini Silicon Biosystems), Clovis, Curevac, Dendreon, Ferring, Innocrin, Janssen, MaxiVAX SA, Millennium, Novartis, Orion, Pfizer, Roche, Sanofi Aventis; Speakers bureaus (compensated): Janssen, Novartis; Patent application for a biomarker method (WO 2009138392 A1). M.D. Mason: Sanofi speaker fees and honoraria; Janssen and Bayer speaker fees. M.R. Sydes: Educational grant plus drug from Astellas, Janssen, Novartis, Pfizer, Sanofi-Aventis for STAMPEDE. Educational grant from Clovis Oncology for STAMPEDE. Speaker fee for educational meetings: Eli Lilly, Janssen. N.W. Clarke: Janssen consultation and advisory fees All other authors have declared no conflicts of interest.

Background: Adding 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. Method: Recruitment 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/m(2) 3-weekly x 6 + prednisolone 10mg daily; or SOC + abiraterone acetate 1000mg = prednisolone 5mg 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. Results: A 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. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naive 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.

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; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). CONCLUSIONS: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 .).

Background: Adding abiraterone acetate + prednisone (AAP) & adding docetaxel + prednisone (DocP) to standard of care (SOC) each improved survival vs SOC in STAMPEDE: a multi-arm multi-stage platform randomised controlled protocol recruiting pts with high risk locally advanced or metastatic PCa starting long-term ADT. We share the first direct, randomised data of SOC+AAP or SOC+DocP using a STAMPEDE subset. Methods: Recruitment to the "DocP comparison" & "AAP comparison" overlapped Nov2011 - Jan2014. SOC was long term ADT or 2+yr ADT with RT (for some M0). Stratified randomisation allocated pts 2:1:2 to SOC: or SOC + Doc 75mg/m2 3-weekly x6 + P 5mg twice daily: or SOC + AA 1000mg + P 5mg daily. AAP duration depended on stage & intent for radical RT. Primary outcome measure was death from any cause. Analyses used Cox proportional hazards & flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison; power is limited, but is indicative of the likely magnitude of difference: HR < 1 favours SOC+AAP, HR > 1 favours SOC+DocP. All confidence intervals (CI) are 95%. Results: 566 pts were contemporaneously randomised: 189 SOC+DocP (the last of 592 SOC+DocP pts) & 377 SOC+AAP (the first of 960 SOC+AAP pts). Groups were well balanced with 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO PS 0; median age 66yr & PSA 56ng/ml. At median follow up 4 yr, there were 149 deaths (45 SOC+Doc, 111 SOC+AAP): survival HR 1.16 (0.82-1.65); failure free survival HR = 0.51 (0.39-0.67); progression free survival HR 0.65 (0.48-0.88); metastases free survival HR 0.77 (0.57-1.03); & SRE HR 0.83 (0.55-1.25). There was no heterogeneity by baseline M0/M1. Grade 3, 4, 5 toxicity was 36%, 13%, 1% SOC+DocP, & 40%, 7%, 1% SOC+AAP. Subsequent treatments varied by arm, with much crossing after progression. Conclusions: In this direct, randomised, comparative analysis of 2 new standards for HNPC, FFS & PFS clearly favoured SOC+AAP &, with less certainty, MFS & SRE favoured SOC+AAP & survival SOC+Doc. Worst toxicity grade was similar. Drug availability may drive treatment choice. Published STAMPEDE data also contribute to a network MA (#2871). Clinical trial identification: NCT00268476 Legal entity responsible for the study: Medical Research Council Funding: Cancer Research UK, Medical Research Council, Janssen; Astellas, Clovis Oncology, Novartis, Pfizer, Sanofi-Aventis Disclosure: M.R. Sydes: Grants and non-financial support from Janssen, Astellas, Clovis Oncology, Novartis, Pfizer, Sanofi-Aventis M.D. Mason: Personal fees and other from Sanofi, personal fees from Bayer, other from Janssen, outside the submitted work N.W. Clarke: Personal fees from Janssen Pharmaceuticals, during the conduct of the study; personal fees from Janssen Pharmaceuticals, outside the submitted work; . D. Dearnaley: Financial Support for Trial Recruitment M. Russell: Dr. Russell reports from Jannsen-Cilag, outside the submitted work. R. Jones: Personal fees and non-financial support from Janssen, grants, personal fees and other from Astellas, outside the submitted work. J. de Bono: Employee of the ICR which has a commercial interest in abiraterone. Has served on Janssen Advisory Board as a consultant. S. Gillessen: Bayer, CureVac, Janssen Cilag, Dendreon Corp, Astellas, Millennium Pharmaceuticals, Orion, Sanofi, MaxiVax SA, AAA, Bristol-Myers Squibb, Ferring, Roche, Innocrin Pharmaceuticals, Nektar Therapeutics, ProteoMedix. S. Chowdhury: Personal fees from Janssen Paharmaceutical, outside the submitted work; . J. Lester: Personal fees, non-financial support and other from Janssen, personal fees, non-financial support and other from Astellas, outside the submitted work. M.K. Parmar: Jansenn: Unrestricted grant to contribute to this comparison of STAMPEDE which supports the protocol overall, plus abiraterone and distribution. N.D. James: Grants, personal fees and non-financial support from Janssen, Astellas, Sanofi, Novartis during the conduct of the study; grants and non-financial support from Clovis Oncology, Pfizer All other authors have declared no conflicts of interest.

Background: Abiraterone acetate and prednisolone (AAP) improved survival in men with castration-refractory PCa; we assessed it earlier in the disease. STAMPEDE is a randomised controlled trial using a multi-arm multi-stage platform design, recruiting pts starting long-term ADT with high-risk locally advanced or metastatic PCa. The overall survival advantage of HR = 0.63 was dominated by deaths in M1 pts. We focus on outcomes in the "AAP comparison" pt subgroup with M0 disease at randomisation. Methods: Standard-of-care (SOC) was ADT for 2+yr; radiotherapy (RT) was mandated for N0M0 disease (unless contraindicated) & encouraged for N+M0. Stratified randomisation allocated pts 1:1 to SOC or SOC+abiraterone acetate 1000mg + prednisolone 5mg daily (SOC+AAP). AAP continued to PSA, radiological & clinical progression, capped at 2 years in pts having radical RT. The definitive primary outcome measure (OM) was death from any cause; Failure-Free Survival (FFS) was the intermediate primary OM. Secondary OMs included Metastasis-Free Survival (MFS). Analyses used Cox proportional hazards, adjusted for stratification factors. Results: 915 M0 pts were randomised to SOC or SOC+AAP from Nov 2011 to Jan 2014: median age 67 yr (IQR 44-84); 81% WHO PS 1; 42% N+M0; 82% planned to receive SOC RT; median follow-up 38m. N0M0 pts not planned for RT (previously treated or contraindication) are not excluded from subgroup estimates. FFS was improved in SOC+AAP in N0M0: HR = 0.14 (95%CI 0.07-0.30) with 3yr FFS 80% SOC vs 98% SOC+AAP. In N+M0, FFS was improved on SOC+AAP HR = 0.26 (95%CI 0.17-0.40), translating into an effect on survival consistent with the overall trial estimate, HR = 0.67 (95%CI 0.39- 1.17). Estimates of MFS are favourable for SOC+AAP within both subgroups; N0M0 HR=0.62 (95%CI CI 0.33-1.14), N+M0 HR=0.47 (95%CI 0.29-0.78). Survival estimates in N0M0 pts are immature, with only 26 deaths. Conclusions: Early clinical outcomes for all M0 pts who had AAP are excellent, particularly in N0M0 pts also planned for RT. The models from the ICECaP project suggest that MFS improvements of this magnitude in M0 pts should translate into a survival advantage. Clinical trial identification: NCT00268476 Legal entity responsible for the study: UK Medical Research Council Funding: MRC, CRUK, Janssen; Astellas, Clovis Oncology, Novartis, Pfizer, Sanofi Aventis Disclosure: N. James: Grants, personal fees and non-financial support from Janssen, Astellas, Sanofi, Novartis during the conduct of the study; grants and non-financial support from Clovis Oncology, Pfizer. J. de Bono: Other from AstraZeneca, Glaxosmithkline, Pfizer, Taiho, Daiichi, Novartis, Genmab, Merck Serano, Merck, Genentech/Roche. Has a patent null pending. N.W. Clarke: Personal fees from Janssen Pharmaceuticals, during the conduct of the study. Personal fees from Janssen Pharmaceuticals, outside the submitted work. M.D. Mason: Personal fees and other from Sanofi, personal fees from Bayer, other from Janssen, outside the submitted work. D. Dearnaley: UK National Institute for Health Research Clinical Research Network, Janssen Pharma, Sandoz Pharmaceuticals, Cadence Research, Janssen-Cilag, ISSECAM, other from Clovis. Royalties from a patent GB9305269 – 17. M. Russell: Janssen-Cilag, outside the submitted work. C. Gilson: Grants from Clovis Oncology, outside the submitted work. R. Jones: Personal fees and non-financial support from Janssen and Astellas, outside the submitted work. S. Gillessen: Bayer, CureVac, Janssen Cilag, Dendreon Corp, Astellas, Millennium Pharmaceuticals, Orion, Sanofi, MaxiVax SA, AAA, Bristol-Myers Squibb, Ferring, Roche, Innocrin Pharmaceuticals, Nektar Therapeutics, ProteoMedix. A. Birtle: Advisory boards to disclose with Astellas, Janssen, Sanofi and outside of relevant work with AstraZeneca and Bayer. S. Chowdhury: Personal fees from Janssen Paharmaceutical, outside the submitted work. Z. Malik: Consultancy and advisory boards Janssen, Sanofi and Astellas Sponsorship to attend medical conferences Astellas, Bayer and Janssen. J. O'Sullivan: Personal fees from Janssen, outside the submitted work. M.K. Parmar: Grants and non-financial support from Janssen, Astellas, Clovis Oncology, Novartis, Pfizer, Sanofi-Aventis, outside the submitted work. M.R. Sydes: Grants and non-financial support from Janssen, Astellas, Clovis Oncology, Novartis, Pfizer, Sanofi-Aventis. All other authors have declared no conflicts of interest.