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Background The optimal timing of RT after RP for prostate cancer (PCa) is uncertain. RADICALS-RT compared the efficacy and safety of adjuvant RT (aRT) versus an observation policy with salvage RT for PSA failure (Obs+sRT). Methods Patients with post-op PSA≤0.2ng/ml and ≥1 risk factor (pT3/4, Gleason 7-10, positive margins or pre-op PSA≥10ng/ml) were randomised ≤22wk after surgery to aRT or Obs+sRT for PSA failure (PSA≥0.1ng/ml or 3 consecutive rises). Stratification factors were Gleason score, margin status, RT schedule (52.5Gy/20f, 66Gy/33f) and centre. The primary outcome measure (OM) was freedom-from-distant metastases (FFDM) with >1200 pts needed for 80% power to detect an improvement from 90% to 95% at 10yr with aRT. It is too early to present results on the primary OM, but we present secondary OMs: bPFS (any of PSA≥0.4ng/ml post-RT, PSA≥2.0ng/ml at any time, local/distant progression, deferred HT, PCa death), freedom-from-non-protocol hormone therapy (HT), safety (RTOG scale), and patient reported OMs (ICSmaleSF). Standard survival analysis methods were used. Results 1396 pts were randomised (697 aRT, 699 Obs+sRT) from Oct-2007 to Dec-2016 (82% UK, 13% Denmark, 4% Canada, 1% Ireland). Median follow-up is 5yr. 93% (649/697) aRT started RT within 5mo; 33% (228/699) Obs+sRT started RT by 8yr after randomisation; 26% (166/649) aRT and 31% (71/228) Obs+sRT reported HT with their RT. With 169 events, bPFS at 5yr was 85% v 88% for aRT and Obs+sRT, respectively: HR = 1.10 (95%CI 0.81-1.49, p = 0.56). Freedom-from-non-protocol HT at 5yr was 92% v 94% (HR = 1.24, 95%CI 0.76-2.01, p = 0.39). Self-reported urinary incontinence was worse at 1yr in 5.3% vs 2.7% (p = 0.008), and RTOG Grade 3/4 urethral stricture was reported at any time in 8% vs 5% (p = 0.03), for aRT & Obs+sRT, respectively. Conclusions First results from RADICALS-RT do not show a benefit for aRT after RP in this patient group. Further follow-up is needed to report on long-term OMs, including FFDM. Adjuvant RT after RP increases risk of urinary morbidity. An observation policy with sRT for PSA failure should be the current standard after RP. Clinical trial identification ISRCTN 40814031. Legal entity responsible for the study University College London. Funding Cancer Research UK, MRC Clinical Trials Unit at UCL, Canadian Cancer Trials Group. Disclosure C. Parker: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research Funding, Speaker Fees and Advisory Board Honoraria: Bayer; Advisory / Consultancy, Advisory Board Honoraria: AAA; Speaker Bureau / Expert testimony, Speaker Fees: Janssen. N.W. Clarke: Advisory / Consultancy, Consultation and advisory fees: Janssen. C. Catton: Advisory / Consultancy, Consulting fees: Bayer; Advisory / Consultancy, Research grant / Funding (self), Consulting fees and research support: AbbVie; Advisory / Consultancy, Consulting fees: Sanofi; Research grant / Funding (institution), Peer reviewed trial funding: Canadian Cancer Trials Group. H. Payne: Advisory / Consultancy, Speaker Bureau / Expert testimony, Paid lectures and advisory boards : Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Paid lectures and advisory boards: Astellas; Advisory / Consultancy, Paid advisory boards: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Paid lectures and advisory boards: Ferring; Advisory / Consultancy, Paid advisory boards: Ipsen. F. Saad: Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Astellas; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Amgen; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Janssen; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Bayer; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Sanofi; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Pfizer; Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca. H. Lindberg: Research grant / Funding (self), Non-remunerated activity/ies: Astellas Pharma; Research grant / Funding (self), Non-remunerated activity/ies: Bayer; Research grant / Funding (self), Non-remunerated activity/ies: Janssen; Research grant / Funding (self), Non-remunerated activity/ies: Sanofi Aventis; Research grant / Funding (self): Roche. A. Zarkar: Travel / Accommodation / Expenses, Support for attendance of a conference: Bayer; Speaker Bureau / Expert testimony, Educational meeting presentation: Pfizer; Speaker Bureau / Expert testimony, Chairing an educational meeting presentation: Janssen; Speaker Bureau / Expert testimony, Educational meeting presentation: Astellas; Research grant / Funding (self), IST: Sanofi. M.K.B. Parmar: Research grant / Funding (institution), Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Astellas; Research grant / Funding (institution), Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Clovis Oncology; Research grant / Funding (institution), Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Novartis; Research grant / Funding (institution), Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Pfizer; Research grant / Funding (institution), Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Sanofi. M.R. Sydes: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research Funding, Speaker Fees and Advisory Board Honoraria: Bayer; Honoraria (self), Advisory / Consultancy, Advisory Board Honoraria: AAA; Speaker Bureau / Expert testimony, Speaker Fees: Janssen. All other authors have declared no conflicts of interest.

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 STAMPEDE has previously reported that upfront docetaxel (Doc) improved overall survival (OS) for patients (pts) starting long-term androgen deprivation therapy (ADT). We report the long-term outcomes for M1 pts using OS as the primary outcome measure. We also assessed if benefit of Doc depended on metastatic burden, as suggested by previous trials, using the CHAARTED definition of high burden (HB) and low burden (LB) baseline disease. Methods 724 SOC and 362 SOC+Doc pts were recruited with a 2:1 randomised stratified allocation. Analysis used Cox regression models, adjusted for all stratification factors, with emphasis on restricted mean survival time if hazards were non-proportional. Retrospectively-collected imaging data, blinded to trial arm, was used to categorise pts as having LB or HB disease. Results Median follow-up was ∼6.5yr, compared to ∼3.5yr when last reported. There were 494 deaths on SOC (41% increase in deaths compared to previous report), with median OS=43.1 months (m). There was good evidence of benefit of SOC+Doc on OS (median = 59.1m, HR=0.81, 95% CI 0.69-0.95, P=0.009). Metastatic burden was assessable for 830/1086 (76%) pts; subgroups were representative of the full M1 cohort in terms of stratification factors. There was no evidence of heterogeneity of Doc effect between the LB and HB subgroups (interaction P=0.827; LB HR=0.76, 95%CI 0.54-1.07, P=0.107; HB HR=0.81, 95%CI 0.64-1.02, P=0.064). Analysis of other outcomes also found evidence of benefit of SOC+Doc over SOC in failure-free survival (FFS; HR=0.66, 95% CI 0.57-0.76, P Conclusions The clinically significant benefit in survival for upfront Doc persists after longer follow-up, with no evidence that the benefit differed dependent on disease burden. We advocate that upfront Doc is considered for both LB and HB M1 pts. 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.W. Clarke: Advisory / Consultancy: Janssen. G. Attard: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Medivation; Advisory / Consultancy: Novartis; Advisory / Consultancy: Millennium Pharmaceuticals; Advisory / Consultancy, Travel / Accommodation / Expenses: Abbott Laboratories; Advisory / Consultancy, Travel / Accommodation / Expenses: Essa Pharmaceuticals; Advisory / Consultancy, Travel / Accommodation / Expenses: 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 (institution), I was an employee of the ICR, where abiraterone acetate was developed, up to 8 January 2018. The Institute of Cancer Research (ICR). S. Chowdhury: Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen Pharmaceutical. 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), My employer, The Institute of Cancer Research, receives a royalty income from abiraterone. I receive a share of this income through the ICR's Rewards to Discoverer's Scheme: The Institute of Cancer Research (ICR); Research grant / Funding (self): Cancer Research UK; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Sandoz; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen. S. Gillessen: Honoraria (institution): Bayer; Honoraria (institution): Curevac; Honoraria (institution), Advisory / Consultancy: Janssen; Honoraria (institution): Astellas; Honoraria (institution), Advisory / Consultancy: Orion; Advisory / Consultancy: MaxiVax SA; Honoraria (institution), Advisory / Consultancy: AAA; Honoraria (institution): Ferring; Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution): Innocrin Pharmaceuticals; Honoraria (institution), Advisory / Consultancy: Sanofi; Honoraria (institution): Novartis; Non-remunerated activity/ies: Nectar Therapeutics; Non-remunerated activity/ies: ProteoMedix; Honoraria (institution): Cell Search; Honoraria (institution): Clovis; Honoraria (institution): Bristol-Myers Squibb. R. Jones: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: 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. Z. Malik: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Travel / Accommodation / Expenses: Bayer. M.D. Mason: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer. C. Parker: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer; Honoraria (self), Advisory / Consultancy: AAA; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen. A.G. Omlin: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Molecular Partners; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Research grant / Funding (institution): Teva. 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. M.K.B. Parmar: Research grant / Funding (self), Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Astellas; Research grant / Funding (self), Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Clovis Oncology; Research grant / Funding (self), Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Novartis; Research grant / Funding (self), Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Pfizer; Research grant / Funding (self), Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Sanofi. 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. All other authors have declared no conflicts of interest.

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.

Background Docetaxel (Doc) was initially licenced for CRPC (TAX327) but more recently trials showed Doc at HSPC diagnosis improved survival, shifting patterns of use. Higher neutropenic toxicity rates were reported in the HSPC trials, but it is unclear if this was due to the Doc timing or differences in case-mix. We compared sepsis rates for Doc at HSPC and CRPC using routine NHS data for men randomised in STAMPEDE in England. Methods STAMPEDE patient data were linked to routine NHS data (Hospital Episode Statistics: HES; Systemic Anti-Cancer Therapy: SACT). Patient note review (ref) linked to NHS data assessed admission rates by HSPC & CRPC Doc at 1 site (N = 44) and were used to develop and validate algorithms for detecting sepsis events across the entire data set. Algorithms were restricted to sepsis-only & sepsis + neutropenia (S+N) (N = 3645). Missing HES CRPC Doc regimens were imputed with HES (N = 3645) or enhanced with SACT (N = 1573). Odds ratios (OR) were calculated for risk of sepsis (OR Results Sepsis rates varied by method; for most, rates at CRPC were higher than in TAX327 but similar to or higher than reported STAMPEDE HSPC data. Table . 862P HSPC Sepsis/Pts CRPC Sepsis/Pts % diff OR, 95% CI N % N % Ref 2/15 13 6/22 27 -14 0.4 (0.1 - 2.1) HES Sepsis 69/834 8 114/1183 10 -2 0.9 (0.6 - 1.2) S+N 134/834 16 148/1183 13 3 1.3 (1.0 - 1.6) Imputed 134/834 16 489/1351 36 -20 0.4 (0.4 - 0.6) + SACT 41/200 21 60/297 20 1 1.0 (0.7 - 1.6) Conclusions This analysis does not support the hypothesis that HSPC Doc has a higher sepsis risk than Doc use in CRPC. Sepsis rates found using routine data were higher than in the TAX327 trial but similar to reported “real world” CRPC data. Rates varied by data-identification method used; for most, CRPC sepsis rates were higher or similar to HSPC rates & overall a little higher than the reported STAMPEDE HSPC rate. These data suggest CRPC Doc has a similar or higher sepsis rate than use in HSPC & this should be factored into discussions for men with newly-diagnosed metastatic HSPC and supports Doc use in this setting. Legal entity responsible for the study The STAMPEDE Trial Group. Funding University of Warwick, Warwick Medical School (HM PhD studentship). Disclosure M.K.B. Parmar: Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Clovis oncology; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution), The Unit I am Director of also receives educational grants and other non- financial support from a large number of different companies: Other. P. Patel: Advisory / Consultancy: Roche/Genentech. M.R. Sydes: Honoraria (self): Lilly; Honoraria (self), Research grant / Funding (self): Sanofi; Honoraria (self): Janssen; Research grant / Funding (self): Astellas Pharma; Research grant / Funding (self): Janssen-Cilag; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Novartis; Research grant / Funding (self): Clovis Oncology. N.D. James: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy: Bayer; Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Astellas Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Janssen; Honoraria (self), Speaker Bureau / Expert testimony: Pierre Fabre; Speaker Bureau / Expert testimony: Ferring; Honoraria (self): Oncogenex; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis. All other authors have declared no conflicts of interest.

Background Prostate radiotherapy (PRT) with androgen deprivation therapy (ADT) is now recommended as a first line option for de-novo low burden metastatic prostate cancer. In the STAMPEDE “M1|RT comparison” metastatic burden was a determinant of benefit, based on pre-specified prognostic criteria. We have now performed exploratory analyses of metastases as defined by site and number to improve prediction of treatment benefit from PRT. Methods Patients (pts) randomized to the ADT (± docetaxel) vs PRT + ADT (± docetaxel) were studied. Metastatic site, distribution and number were evaluated based on conventional imaging and used to explore treatment effects to refine the metastatic burden definition. Results focused on the trial’s key outcome measures: overall (OS) & failure-free survival (FFS), analysed using standard survival analysis methods. HR Results Following exclusions (imaging unavailable for central review, n = 122), 1939 pts randomized in “M1|RT comparison” were included. Of these, 181 pts had only lymph node (LN) mets, 1587 had bone (±LN) mets and 171 had other visceral mets (±bone/LN). Baseline characteristics such as age (median 68 years), PSA (median 98 ng/ml) were balanced between the arms. In LN only pts, PRT improved OS (HR = 0.62, 95%CI 0.35-1.09) & FFS (HR = 0.64, 95%CI 0.43-0.96). In bone (±LN) pts with 0.1) for baseline factors such as age, N stage, Gleason score, RT schedule or docetaxel use. Conclusions Prostate RT + ADT (± docetaxel) improved OS & FFS in pts with only LN or Clinical trial identification NCT00268476. Legal entity responsible for the study Medical Research Council-Clinical Trials Unit and University of Manchester. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Purpose: The use of prophylactic agents after primary resection can decrease the incidence of tumor recurrence in patients with stage TaT1 bladder cancer. However, the long-term impact on progression to muscle invasive disease as well as on duration of survival is unknown. A combined analysis of individual patient data from previously performed European Organization for Research and Treatment of Cancer (EORTC) and Medical Research Council (MRC) randomized clinical trials was done in an attempt to answer these crucial questions. We compared immediate versus no adjuvant prophylactic treatment after transurethral resection with respect to disease-free interval, time to progression to muscle invasive disease, time to appearance of distant metastases, duration of survival and progression-free survival.Materials and Methods: All EORTC and MRC prophylactic, randomized phase III trials with primary or recurrent, stage TaT1 transitional cell bladder cancer that compared transurethral resection alone or wit...

Objectives To assess whether neoadjuvant or concurrent platinum-based chemotherapy improves the survival of patients with locally advanced bladder cancer, and to determine whether there is any evidence that chemotherapy is more or less effective within well-defined subgroups of patients. Patients and methods A formal meta-analysis (overview) was carried out using updated individual data from 479 patients (301 deaths) from four randomized trials comparing local definitive treatment alone with neoadjuvant or concurrent single-agent cisplatin followed by local definitive treatment. Further summary data were available from a similar randomized trial of cisplatin and doxorubicin in 325 patients (127 deaths). Results Combined analysis of the individual patient data gave an overall hazard ratio of 1.02 in favour of local therapy alone (P= 0.845, 95% confidence interval = 0.81–1.26), representing a 2% increase in the relative risk of death with the use of chemotherapy. When this analysis was supplemented by data from the only trial for which individual patient information was not available, the hazard ratio was 0.91 in favour of chemotherapy (P= 0.328, 95% confidence interval = 0.75–1.10), representing a 9% reduction in the relative risk of death. The only prognostic factor for which the evidence suggested a differential treatment effect (interaction) across groups was age (chi-square test for trend = 3.833, P= 0.05), with younger age groups (

The use of meta-analyses or overviews to combine formally the results of related randomised clinical trials is becoming increasingly common. However the distinction between analyses based on information extracted from the published literature and those based on collecting and reanalysing updated individual patient data is not clear. We have investigated the difference between meta-analysis of the literature (MAL) and meta-analysis of individual patient data (MAP) by comparing the two approaches using randomised trials of cisplatin-based therapy in ovarian cancer. The MAL was based on 788 patients and the MAP on 1329 and estimated median follow-ups were 3.5 and 6.5 years, respectively. The MAL gave a result of greater statistical significance (p = 0.027 vs p = 0.30) and an estimate of absolute treatment effect three times as large as the MAP (7.5% vs 2.5%). Publication bias, patient exclusion, length of follow-up, and method of analysis all contributed to this observed difference. The results of a meta-analysis of the literature alone may be misleading. Whenever possible, a meta-analysis of updated individual patient data should be done because this provides the least biased and most reliable means of addressing questions that have not been satisfactorily resolved by individual clinical trials.

Background: During an international workshop held in September 1998, a group of specialists in the field of ovarian cancer reached consensus on a number of issues with implications for standard practice and for research of advanced epithelial ovarian cancer. Methods: Five groups of experts considered several issues which included: biologic factors, prognostic factors, surgery, initial chemotherapy, second-line treatment, the use of CA 125, investigational drugs, intra-peritoneal treatment and high-dose chemotherapy. The group attempted to arrive at answers to questions such as: Are there prognostic factors, which help to identify patients who will not do well with current therapy? What is the current best therapy for advanced ovarian carcinoma? What directions should research take in advanced ovarian cancer? These issues were discussed in a plenary meeting. Results: One of the major conclusions drawn by the consensus committee was that in previously untreated advanced ovarian cancer, cisplatin plus paclitaxel has been shown to be superior to previous standard therapy with cisplatin plus cyclophosphamide (level I evidence). However, for many patients, carboplatin plus paclitaxel is a reasonable alternative because of toxicity and convenience considerations. Most participants felt that the benefits in terms of toxicity for the paclitaxel-carboplatin are such that its widespread adoption at this stage is justified. Until mature survival data are available a minority of investigators would recommend continued use of cisplatin plus paclitaxel, specifically for those patients with advanced disease with the best prognostic characteristics. For future clinical research in this area, new end points for randomised clinical trials, together with a new Trials Network, are proposed.