Introduction Current treatments for multiple sclerosis (MS) do not address the pathological processes of neurodegeneration and chronic demyelination. This, coupled with the significant challenges of translating promising phase 2 results to phase 3 trial success, highlights the need for more efficient trial designs, such as platform multi-arm multi-stage (MAMS) trial approaches. MAMS trials have demonstrated success in areas such as oncology and infectious diseases. They are typified by a statistically robust core trial design that allows the addition of further treatment arms and utilisation of interim outcome analyses at pre-defined timepoints, to determine whether to terminate a treatment arm early or proceed to the final outcome analysis. To address the challenges in progressive multiple sclerosis (PMS) treatment discovery, the Optimal Clinical Trials Platform for PMS (OCTOPUS) trial was developed. It currently utilises MRI whole-brain atrophy as its interim outcome measure and the clinically relevant composite Expanded Disability Status Scale Plus (EDSS-Plus) as its final outcome measure. A rigorous and systematic drug selection process that assessed preclinical in vitro and animal model evidence, along with additional human data, led to the prioritisation of R/S-alpha lipoic acid (R/S-ALA) and metformin for testing against placebo, targeting pathobiological mechanisms relevant to PMS. All participants will be eligible to receive the current standard of care, including disease-modifying treatments (DMTs). Method and analysis OCTOPUS will be a multi-centre, randomised, placebo-controlled, double-blind, phase 3, MAMS trial of participants aged 25 to 70 years (inclusive) with PMS and an EDSS score of 4.0 to 8.0 (inclusive). Steady progression must be the major cause of increasing disability rather than relapse in the preceding 2 years. In the trial s first candidate drug cycle, participants will be allocated to R/S-ALA, metformin, or placebo in a 1:1:1 ratio. Cycle 1 active treatments will start as R/S-ALA 600 mg once daily, increased after 4 weeks to 600 mg twice daily, or metformin 1 g once daily, increased after 4 weeks to 1 g twice daily. The trial will be multinational, with participation from 28 hospitals across the UK and 10 hospitals in Australia. Clinician-reported measures will include: the EDSS-Plus and the individual components: EDSS, Timed 25 Foot Walk (T25FW); 9 Hole Peg Test (9HPT); Symbol Digit Modalities Test (SDMT); Sloan Low Contrast Visual Acuity (SLCVA); and Relapse assessment. Patient-reported outcomes include MS specific walking, fatigue, pain, and impact scales. We will include a health economic analysis. Analysis stage 1 will require randomisation of 125 participants per arm and utilise MRI percentage brain volume change (PBVC) with the Structural Image Evaluation using Normalisation of Atrophy (SIENA) technique from baseline to 78 weeks. A positive outcome in analysis stage 1 will detect a 0.15% per year whole brain atrophy difference with a one-sided alpha of 0.35 and power of 95%, ensuring a low probability of erroneously rejecting a treatment arm at this stage. Any arms that show a positive effect will proceed to final analysis stage 2. Analysis stage 2 will require 600 participants per arm. Participants included in stage 1 will also be included in the stage 2. Analysis stage 2 will evaluate time to 6-month confirmed disability progression in the EDSS-Plus, in order to detect a 25% hazard ratio reduction with 90% power and an alpha of 0.05. Assuming one treatment arm proceeds to analysis stage 2, the trial will recruit approximately 1,200 participants and last about 6 years. This is approximately two-thirds the size and half the duration of separately conducted two-arm phase 2 and 3 trials. Ethics and dissemination The protocol was approved by the London Hampstead REC (22/LO/0622). This manuscript is based on protocol version 8.0, 28th August 2025. The findings of this trial will be disseminated through peer-reviewed publications and conference presentations. There will be a close communication strategy developed with the UK MS Society (MSS) and full patient and public involvement and engagement (PPIE). Trial registration ISRCTN: 14048364 EudraCT number: 2021-003034-37 CTA 20363/0445 IRAS number: 1003943 Secondary identifying numbers: ND001, CPMS 54274 Strengths and limitations - The OCTOPUS trial will be the first platform multi-arm multi-stage phase 3 trial in PMS, offering the potential to significantly expedite clinical trial processes with advantages in cost- and time-efficiency, focusing specifically on the poorly treated pathobiological processes of chronic neurodegeneration and demyelination - It will begin by assessing two promising drug candidates, immediate-release metformin and R/S-ALA, and will expand over the duration of the trial to include more drug arms under the same trial master protocol - The flexible and statistically robust trial design means that several components of the design (such as the early analysis stage 1 interim outcome) can be updated in line with evolving scientific knowledge - It will ultimately be the largest ever investigator-initiated phase 3 trial in PMS - It will include a range of national and international trial sites, including neuroscience centres and district general hospitals - It will have a high inclusion limit for age (up to 70 years) and disability (up to EDSS 8.0) - Several components (the telephone EDSS and virtual patient-reported outcome measures) will be amenable to remote collection increasing inclusivity and thus addressing public and participant suggestions, while minimising the risk of missing data - The main challenges in this trial design are the statistical and methodological complexity involved in design and implementation, and interpretation of interim trial results. Conclusion The trial launched cycle 1 in January 2023. Analysis stage 1 recruitment of 375 participants was achieved in November 2024, enabling planned interim analysis stage 1 to be conducted by late 2026 (Figure 1). On the 1st of June 2026, in the UK, 24 sites are active with a further 4 in set-up as part of stage 2, and in the Australian extension, Platform Adaptive Trial for Remyelination and Neuroprotection in Multiple Sclerosis (PLATYPUS), 1 site is active, with 9 additional sites in set-up. ### Competing Interest Statement In the last 3 years, JChataway has received support from the Health Technology Assessment (HTA) Programme (National Institute for Health and Care Research, NIHR), the UK MS Society, and the US National MS Society and the Rosetrees Trust. He is supported in part by the National Institute for Health and Care Research, University College London Hospitals (UCLH) Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by MS Canada. A local principal investigator for commercial trials funded by: Ionis and Roche; and has taken part in advisory boards/consultancy for: Biogen, Contineum Therapeutics, FSD Pharma, InnoCare, Pheno Therapeutics and Roche. In the last 5 years ET has received honorarium for consulting work from Biogen, Janssen, Merck, Novartis, and Roche. She has received travel grants to attend or speak at educational meetings from Biogen, Merck, Neuroax, Roche, and Novartis. MP declares institutional educational grant funds or support for medicines from Novartis, Pfizer, Roche, Roche Products, Sanofi, Serum Institute of India, Shionogi, SUMVAX, Synteny Biotechnology, Takeda, Tibotec, Transgene, ViiV Healthcare, Virco Xenothera, CSL Behring, Eli-Lilly, Emergent Biosolutions, Gilead Sciences, GlaxoSmithKline, Grifols, ICON, Janssen Products, Janssen-Cilag, Janssen Pharmaceutica, Johnson & Johnson, Merck Serono, Micronoma, Modus Theraputics, MSD, Mylan, Abcodia, Advanced Accelerator Applications International, Akagera Amgen Aspirin Foundation, Astellas, AstraZeneca, AoA, Baxter, Bayer, Bristol Myers Squibb US, Bri-Bio B&C Group, Cepheid, Cipla, and Clovis JCarpenter reports grants from UK Medical Research Council, personal fees from Wiley, personal fees from Springer, personal fees from University of Bern, personal fees from Statisticians in the Pharmaceutical Industry, and personal fees from Novartis. RH received grants from NIHR DemPRU-QM, NIHR Evidence Synthesis, and NIHR Health Protection Research Unit; received consulting fees from Ministry of Justice, UK Health Security Agency, University of Nottingham, and QuidelOrtho; and leadership role on transforming health and care systems EU funding board as Chair of the Board. AJT receives a fee from being Co-Chair, University College London (UCL)-Eisai Steering Committee drug discovery collaboration; German Aerospace Center, Heath Research (ERA-NET NEURON); consultancy from Sandoz Global Advisory and Novartis. Member, National Multiple Sclerosis Society (USA) Research Programs Advisory Committee; Clinical Trials Committee, Progressive MS Alliance; Board member, European Charcot Foundation; Editor in Chief, Multiple Sclerosis Journal; Editorial Board Member, The Lancet Neurology. AJT has received fees for academic reviews for Jockey Club College at City University of Hong Kong, Health Research Board Ireland, Sant Pau Biomedical Research Institute. AJT has received support from the UCL/ UCLH NIHR Biomedical Research Centre. AJT received travel support from European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), the European Charcot Foundation, Health Research Board Emerging Clinical Scientist Award, Polish Neurological Society, and Armin Curt Farewell Symposium. He receives no fee from being Chair (Scientific Ambassadors), Stop MS Appeal Board, UK MS Society; Research and Academic Counsellor, Fundacio Privada Cemcat; Ambassador, European Brain Council. AJT additionally holds a patent for the MSIS-29 Impact Scale. FB is supported by the NIHR biomedical research centre at UCLH. He has been: on the steering committee or Data Safety Monitoring Board member for Biogen, Merck, Eisai, Prothena and Idorsia; advisory board member for Combinostics, Scottish Brain Sciences, IXICO and Alzheimer Europe; consultant for Roche, Celltrion, Merck, Bracco; research agreements with ADDI, Merck, Biogen, GE Healthcare, Icometrix, Roche; co-founder and shareholder of Queen Square Analytics LTD OC declares being NIHR Research Professor (RP-2017-08- ST2-004); over the past 2 years, member of independent data safety and monitoring board for Novartis; has received consulting fees or speaker honoraria from Lundbeck, Merck or Biogen; contributed to an advisory board for Biogen; she is Deputy Editor of Neurology, for which she receives an honorarium; has received research grant support from the UK MS Society, the NIHR UCLH Biomedical Research Centre, and the NIHR; and is vice-president of ECTRIMS (unpaid). EG is Director of Research at the UK MS Society and has no declarations. CR has received research grants from the UK Medical Research Council, Sanofi, Burden Neurological Society, University of Bristol, and Bristol Health Research Charity, and support for clinical research for the OCTOPUS trial (UK MS Society). CR has participated on a data safety monitoring board for the CCMR Two and NEuEoMS trials. Unpaid advisory roles with the UK MS Society, Burden Neurological Institute, Association of British Neurologists, and NICE HTA Assessment Group. HLF has received honoraria for advisory boards or educational activities from Merck, Novartis, and Roche. HLF has research grant support from the NIHR Health Technology Assessment Programme and Efficacy and Mechanisms Evaluation, UK MS Society, and the Horne Family Charitable Trust. She has been a local PI for multiple sclerosis clinical trials of an investigational medicinal product funded by Novartis, Roche, and Biogen Idec. LF has received honoraria for speaking or as an advisory board member from Biogen, Novartis, Merck, Sanofi Genzyme, and Roche and received support for attending educational meetings from Biogen, Novartis, Merck, Sanofi Genzyme, and Teva. MM has received travel support, speaker honoraria, or consultation fees from Merck-Sereno, Novartis, and Roche. RN receives support from UK MS Society to Imperial College and Swansea university; is a trustee of the Multiple Sclerosis Trials Collaboration charity; and attended paid advisory boards for Novartis and Roche. IG received the following funding in the last 36 months: research grants from Medical Research Council UK, National Institute for Health and Care Research, MS Society UK, Wessex Medical Research, Independent Research Fund Denmark, Rosetrees Trust, Guarantors of Brain, Kedrion, The Binding Site (Part of Thermo Fisher Scientific), and Evgen; speaker honoraria and travel funding from Novartis. D.G. and V.I. are employed by Binding Site (Part of Thermo Fisher Scientific). MBurnell has been funded by grants from the Medical Research Council (MRC), Cancer Research UK, the National Institute for Health Research (NIHR), and The Eve Appeal. RAF has participated on advisory boards, received travel grants and attended educational programmes sponsored by Roche and Novartis. SAB has been awarded funding by the Medical Research Future Fund, MS Australia and the Trish Foundation. He is a principal investigator for a clinical trials sponsored by Novartis and Sanofi, and has received speakers fees from Novartis for chairing scientific meetings. SB has been a principal investigator in clinical trials sponsored by Biogen Idec, Novartis, Genzyme and ATARA Biotherapeutics. ORP has received honoraria and travel expenses from Biogen, Bayer, Genzyme, Merck, Novartis, Roche, Sanofi and Teva and served on advisory boards/acted as a speaker for Biogen, Celgene, Janssen, Merck, Neuraxpharm, Novartis, Roche and Sanofi. SPl is founder, chief scientific officer, and shareholder (>5%) of Cambridge Innovation Technologies Consulting and is a consultant for Aspen Therapeutics, Secretome Therapeutics, Macomics, Solute Guard Therapeutics, and Astex Pharmaceutical. SPa has been funded by grants from the National Institute for Health and Care Research (NIHR) and is a hub lead for the NIHR Leeds Clinical Research Facility. In the last 3 years DF has received research support from the UK MS Society, Higher Education Authority (Rep. of Ireland), Wellcome, Research Ireland and Sangamo Inc. She received consultancy fees for participation in an advisory board for Sangamo Inc. TA has received honoraria or consulting fees for participating in advisory boards related to trial steering committees and data and safety monitoring committees, speaker fees & research grants Janssen, Merck, Novartis, Roche and Sanofi-Genzyme. She is partially funded by the NIHR SCPRA fellowship. All other authors declare no competing interests. ### Clinical Trial ISRCTN: 14048364; EudraCT: 2021-003034-37; CTA: 20363/0445; IRAS: 1003943 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The National Research Ethics Service Committee (London, Hampstead) reviewed the trial protocol and materials to be given to participants (approved 14th October 2022, REC ref 22/LO/0622). The trial protocol and materials to be given to Australian participants has also been reviewed and approved by the Gold Coast Hospital and Health Service, Human Research Ethics Committee (approved 16th December 2024, HREC/2024/QGC/97381). This article refers to the current protocol (Version: 8.0, Date: 28th August 2025). The findings of this trial will be disseminated through peer-reviewed publications and conference presentations. There will be a close communication strategy developed with the United Kingdom Multiple Sclerosis Society and full Patient and Public Involvement Engagement. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes N/A - no data is presented in the current work as it is a protocol paper Multiple Sclerosis Society, https://ror.org/043fwdk81, 135 National Institute for Health and Care Research (NIHR) Research Delivery Network (RDN) MS Australia

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophinreleasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided alpha of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 072). Standard time-toevent analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 89 years (70-100), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the longcourse ADT group; HR 0773 [95% CI 0612-0975]; p=0029). 10-year metastasis-free survival was 719% (95% CI 676-757) in the short-course ADT group and 781% (742-815) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy.

Background:Although often overlooked, patient and public involvement (PPI) is vital when considering the design and delivery of complex and adaptive clinical trial designs for chronic health conditions such as multiple sclerosis (MS). Methods:We conducted a rapid review to assess current status of PPI in the design and conduct of clinical trials in MS over the last 5 years. We provide a case study describing PPI in the development of a platform clinical trial in progressive MS. Results:We identified only eight unique clinical trials that described PPI as part of articles or protocols; nearly, all were linked with funders who encourage or mandate PPI in health research. The OCTOPUS trial was co-designed with people affected by MS. They were central to every aspect from forming part of a governance group shaping the direction and strategy, to the working groups for treatment selection, trial design and delivery. They led the PPI strategy which enabled a more accessible, acceptable and inclusive design. Conclusion:Active, meaningful PPI in clinical trial design increases the quality and relevance of studies and the likelihood of impact for the patient community. We offer recommendations for enhancing PPI in future MS clinical trials.

Background Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. Methods We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0-2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m(2) intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). Findings Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86-107) in the abiraterone trial and 72 months (61-74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76.6 months (95% CI 67.8-86.9) in the abiraterone group versus 45.7 months (41.6-52.0) in the standard of care group (hazard ratio [HR] 0.62 [95% CI 0.53-0.73]; p<0.0001). In the abiraterone and enzalutamide trial, median overall survival was 73.1 months (61.9-81.3) in the abiraterone and enzalutamide group versus 51.8 months (45.3-59.0) in the standard of care group (HR 0.65 [0.55-0.77]; p<0.0001). We found no difference in the treatment effect between these two trials (interaction HR 1.05 [0.83-1.32]; p interaction=0.71) or between-trial heterogeneity (I-2 p=0.70). In the first 5 years of treatment, grade 3-5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial). Interpretation Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting longterm androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. Copyright (c) 2023 The Author(s). Published by Elsevier Ltd.

Background To improve trial efficiency (time and cost) the Optimal Clinical Trials Platform for Progressive Multiple Sclerosis (OCTOPUS) trial [ISRCTN 14048364] will test a number of treatments, to slow disability in Progressive MS (PMS) in a multi-arm multi-stage fashion: a MAMS Platform. Timely recruitment is important and the UK MS Register (UKMSR) has designed and is operating the registration of interest (ROI) portal. Aim: To examine the initial wave of potential participants for OCTOPUS. Method We built a dual-element recruitment platform comprising, UKMSR and non-UKMSR (similar, but without previously collected data). All registered were emailed to complete follow-up survey with specific eligibility criteria. Aggregated data were made available to the study team for further clinical assessment. Results Registrants: 569 non-UKMSR-ROI, 1637 UKMSR. As of: 11/1/2023 follow up data were provided by: Non-UKMSR: 413;153(37%) meeting eligibility. 30(7%) currently ineligible. UKMSR: 860; 659(40%) meeting eligibility. 311(19%) currently ineligible Participants were ineligible for reasons including: age (25-70 inclusive allowable), no evidence of pro- gression, unable to tolerate MRI (required for stage 1), contraindicated medication. 812 participants are eligible with 82% having UKMSR patient-reported outcome data. Conclusion Trial recruitment can be challenging. UK MS Register eligibility screening methods will be valuable in ensuring the trial recruits participants quickly, ensuring efficiency and cost effectiveness.

PURPOSE:Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices. METHODS:A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints. RESULTS:Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2; P = .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5; P < .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0; P = .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6; P < .001). CONCLUSION:Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment.

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.

BackgroundMen with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population.MethodsThese open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8–10, and prostate-specific antigen [PSA] concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0–2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial with no overlapping controls, the combination-therapy group also received enzalutamide (160 mg daily orally). ADT was given for 3 years and combination therapy for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression. In this primary analysis, we used meta-analysis methods to pool events from both trials. The primary endpoint of this meta-analysis was metastasis-free survival. Secondary endpoints were overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity and adverse events. For 90% power and a one-sided type 1 error rate set to 1·25% to detect a target hazard ratio for improvement in metastasis-free survival of 0·75, approximately 315 metastasis-free survival events in the control groups was required. Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation. STAMPEDE is registered with ClinicalTrials.gov, NCT00268476, and with the ISRCTN registry, ISRCTN78818544.FindingsBetween Nov 15, 2011, and March 31, 2016, 1974 patients were randomly assigned to treatment. The first trial allocated 455 to the control group and 459 to combination therapy, and the second trial, which included enzalutamide, allocated 533 to the control group and 527 to combination therapy. Median age across all groups was 68 years (IQR 63–73) and median PSA 34 ng/ml (14·7–47); 774 (39%) of 1974 patients were node positive, and 1684 (85%) were planned to receive radiotherapy. With median follow-up of 72 months (60–84), there were 180 metastasis-free survival events in the combination-therapy groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR not evaluable [NE]–NE) than in the control groups (not reached, 97–NE; hazard ratio [HR] 0·53, 95% CI 0·44–0·64, p<0·0001). 6-year metastasis-free survival was 82% (95% CI 79–85) in the combination-therapy group and 69% (66–72) in the control group. There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1·02, 0·70–1·50, p=0·91) and no evidence of between-trial heterogeneity (I2 p=0·90). Overall survival (median not reached [IQR NE–NE] in the combination-therapy groups vs not reached [103–NE] in the control groups; HR 0·60, 95% CI 0·48–0·73, p<0·0001), prostate cancer-specific survival (not reached [NE–NE] vs not reached [NE–NE]; 0·49, 0·37–0·65, p<0·0001), biochemical failure-free-survival (not reached [NE–NE] vs 86 months [83–NE]; 0·39, 0·33–0·47, p<0·0001), and progression-free-survival (not reached [NE–NE] vs not reached [103–NE]; 0·44, 0·36–0·54, p<0·0001) were also significantly longer in the combination-therapy groups than in the control groups. Adverse events grade 3 or higher during the first 24 months were, respectively, reported in 169 (37%) of 451 patients and 130 (29%) of 455 patients in the combination-therapy and control groups of the abiraterone trial, respectively, and 298 (58%) of 513 patients and 172 (32%) of 533 patients of the combination-therapy and control groups of the abiraterone and enzalutamide trial, respectively. The two most common events more frequent in the combination-therapy groups were hypertension (abiraterone trial: 23 (5%) in the combination-therapy group and six (1%) in control group; abiraterone and enzalutamide trial: 73 (14%) and eight (2%), respectively) and alanine transaminitis (abiraterone trial: 25 (6%) in the combination-therapy group and one (<1%) in control group; abiraterone and enzalutamide trial: 69 (13%) and four (1%), respectively). Seven grade 5 adverse events were reported: none in the control groups, three in the abiraterone acetate and prednisolone group (one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder), and four in the abiraterone acetate and prednisolone with enzalutamide group (two events each of septic shock and sudden death).InterpretationAmong men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Abiraterone acetate with prednisolone should be considered a new standard treatment for this population.FundingCancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.

Background There are limited research and literature on the trial management challenges encountered in running adaptive platform trials. This trial design allows both (1) the seamless addition of new research comparisons when compelling clinical and scientific research questions emerge, and (2) early stopping of accrual to individual comparisons that do not show sufficient activity without affecting other active comparisons. Adaptive platform design trials also offer many potential benefits over traditional trials, from faster time to accrual to contemporaneously recruiting multiple research comparisons, added flexibility to focus on more promising research comparisons via pre-planned interim analyses and potentially shorter time to primary results. We share here our experiences from a trial management perspective, highlighting the challenges and successes. Methods We evaluated the operational aspects of making changes to these adaptive platform trials and identified both common and trial-specific challenges. The operational steps and challenges linked to both the addition of new research comparisons and stopping recruitment following pre-planned interim analysis were considered in our evaluation. Results Specific operational challenges in these adaptive platform protocols, additional to those in traditional two-arm trials, were identified. Key lessons are presented describing some of the solutions and considerations over conducting these trials. Careful consideration on the practicality of the protocol structure (modular versus single protocol), the longevity and continuity of trial oversight committees, and having clear clinical and scientific criteria for the addition of new research comparisons were identified as some of the most common challenges. Conclusions Understanding the operational complexities associated with running adaptive platform protocols is paramount for their conduct, adaptive platform trials offer an efficient model to run randomised controlled trials and we are continuing to work to reduce further the effort required from an operational perspective. Trial registration FOCUS4: ISRCTN Registry, ISRCTN90061546 . Registered on 16 October 2013. STAMPEDE: ISRCTN Registry, ISRCTN78818544 . Registered on 2 February 2004.

Background Whole brain radiotherapy (WBRT) and dexamethasone are widely used to treat brain metastases from non-small cell lung cancer (NSCLC), although there have been no randomised clinical trials showing that WBRT improves either quality of life or overall survival. Even after treatment with WBRT, the prognosis of this patient group is poor. We aimed to establish whether WBRT could be omitted without a significant effect on survival or quality of life.Methods The Quality of Life after Treatment for Brain Metastases (QUARTZ) study is a non-inferiority, phase 3 randomised trial done at 69 UK and three Australian centres. NSCLC patients with brain metastases unsuitable for surgical resection or stereotactic radiotherapy were randomly assigned (1: 1) to optimal supportive care (OSC) including dexamethasone plus WBRT (20 Gy in five daily fractions) or OSC alone (including dexamethasone). The dose of dexamethasone was determined by the patients' symptoms and titrated downwards if symptoms improved. Allocation to treatment group was done by a phone call from the hospital to the Medical Research Council Clinical Trials Unit at University College London using a minimisation programme with a random element and stratification by centre, Karnofsky Performance Status (KPS), gender, status of brain metastases, and the status of primary lung cancer. The primary outcome measure was quality-adjusted life-years (QALYs). QALYs were generated from overall survival and patients' weekly completion of the EQ-5D questionnaire. Treatment with OSC alone was considered noninferior if it was no more than 7 QALY days worse than treatment with WBRT plus OSC, which required 534 patients (80% power, 5% [one-sided] significance level). Analysis was done by intention to treat for all randomly assigned patients. The trial is registered with ISRCTN, number ISRCTN3826061.Findings Between March 2, 2007, and Aug 29, 2014, 538 patients were recruited from 69 UK and three Australian centres, and were randomly assigned to receive either OSC plus WBRT (269) or OSC alone (269). Baseline characteristics were balanced between groups, and the median age of participants was 66 years (range 38-85). Significantly more episodes of drowsiness, hair loss, nausea, and dry or itchy scalp were reported while patients were receiving WBRT, although there was no evidence of a difference in the rate of serious adverse events between the two groups. There was no evidence of a difference in overall survival (hazard ratio 1.06, 95% CI 0.90-1.26), overall quality of life, or dexamethasone use between the two groups. The difference between the mean QALYs was 4.7 days (46.4 QALY days for the OSC plus WBRT group vs 41.7 QALY days for the OSC group), with two-sided 90% CI of -12.7 to 3.3.Interpretation Although the primary outcome measure result includes the prespecified non-inferiority margin, the combination of the small difference in QALYs and the absence of a difference in survival and quality of life between the two groups suggests that WBRT provides little additional clinically significant benefit for this patient group.Funding Cancer Research UK, Medical Research Council Clinical Trials Unit at University College London, and the National Health and Medical Research Council in Australia. Copyright (C) The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license.

8005 Background: Brain metastases affect up to 40% of patients with non-small cell lung cancer (NSCLC), and for inoperable cases whole brain radiotherapy (WBRT) and dexamethasone is standard treatment. However there are no randomised clinical trials to show whether WBRT improves either QoL or survival. Methods: A phase III randomised non-inferiority trial with a primary outcome measure of quality adjusted life years (QALYs). Patients with brain metastases from NSCLC (not suitable for resection or stereotactic radiotherapy) were randomly allocated to either optimal supportive care, including dexamethasone, plus WBRT 20 Gy/5f (OSC+WBRT) or OSC alone. QALYs were generated from OS and patients' weekly completion of the EQ-5D questionnaire. OSC alone was considered non-inferior to OSC+WBRT if not greater than 7 QALY days worse (80% power and a 1-sided 5% significance level required 534 patients.) Secondary outcome measures include sub-group analyses to identify/validate predictive classifications. Results: From 2007-2014 538 patients were recruited from 69 UK and 3 Australian centres. Baseline characteristics were balanced between arms and reflect everyday clinical practice: male 58%, median age 66 years (range 38 – 85), Karnofsky performance status < 70 38%, 54% had extracranial metastases, 30% had a solitary brain metastasis and 59% diagnosed with brain metastases within 28 days of randomisation. By January 2015 522/538 patients had died. There was no significant difference in OS from randomisation (hazard ratio 1.05 (95% CI 0.89 – 1.26) median survival OSC+WBRT v OSC (65 v 57 days)), overall QoL or steroid use between the 2 groups. The difference between the mean QALYs was -1.9 days (OSC+WBRT 43.3 v OSC 41.4 QALY days), two-sided 90% confidence interval for difference -9.1 to +6.6 QALY days. Conclusions: This is the only large randomised trial evaluating the utility of WBRT in this disease. Although the results include the pre-specified non-inferiority margin, the estimate of the difference in QALYs suggests WBRT provides no additional clinically significant benefit for this group of patients. Clinical trial information: 3826061.

Introduction Molecular characterisation of tumours is increasing personalisation of cancer therapy, tailored to an individual and their cancer. FOCUS4 is a molecularly stratified clinical trial for patients with advanced colorectal cancer. During an initial 16-week period of standard first-line chemotherapy, tumour tissue will undergo several molecular assays, with the results used for cohort allocation, then randomisation. Laboratories in Leeds and Cardiff will perform the molecular testing. The results of a rigorous pre-trial inter-laboratory analytical validation are presented and discussed.Methods Wales Cancer Bank supplied FFPE tumour blocks from 97 mCRC patients with consent for use in further research. Both laboratories processed each sample according to an agreed definitive FOCUS4 laboratory protocol, reporting results directly to the MRC Trial Management Group for independent cross-referencing.Results Pyrosequencing analysis of mutation status at KRAS codons 12/13/61/146, NRAS codons 12/13/61, BRAF codon600 and PIK3CA codons542/545/546/1047, generated highly concordant results. Two samples gave discrepant results; in one a PIK3CA mutation was detected only in Leeds, and in the other, a PIK3CA mutation was only detected in Cardiff. pTEN and mismatch repair (MMR) protein expression was assessed by immunohistochemistry (IHC) resulting in 6/97 discordant results for pTEN and 5/388 for MMR, resolved upon joint review. Tumour heterogeneity was likely responsible for pyrosequencing discrepancies. The presence of signet-ring cells, necrosis, mucin, edge-effects and over-counterstaining influenced IHC discrepancies.Conclusions Pre-trial assay analytical validation is essential to ensure appropriate selection of patients for targeted therapies. This is feasible for both mutation testing and immunohistochemical assays and must be built into the workup of such trials.Trial registration number ISRCTN90061564.

BACKGROUND:Advanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy. METHODS:COIN-B was an open-label, multicentre, randomised, exploratory phase 2 trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with advanced colorectal cancer who had received no previous chemotherapy for metastases. Randomisation was done centrally (by telephone) by the Medical Research Council Clinical Trials Unit using minimisation with a random element. Treatment allocation was not masked. Patients were assigned (1:1) to intermittent chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil). Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption (those taking intermittent cetuximab) or planned maintenance by continuing on weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance cetuximab, respectively. The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. We tested BRAF and NRAS status retrospectively. The trial was registered, ISRCTN38375681. FINDINGS:We registered 401 patients, 226 of whom were enrolled. Results for 169 with KRAS wild-type are reported here, 78 (46%) assigned to intermittent cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to intermittent cetuximab and 66 of those assigned to continuous cetuximab were included in the primary analysis. 10-month failure-free survival was 50% (lower bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI 41) in the continuous group; median failure-free survival was 12.2 months (95% CI 8.8-15.6) and 14.3 months (10.7-20.4), respectively. The most common grade 3-4 adverse events were skin rash (21 [27%] of 77 patients vs 20 [22%] of 92 patients), neutropenia (22 [29%] vs 30 [33%]), diarrhoea (14 [18%] vs 23 [25%]), and lethargy (20 [26%] vs 19 [21%]). INTERPRETATION:Cetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials.

TPS3645 Background: Targeted therapies based on somatic gene mutations or activated pathways have inhibited progression of some cancers. However, although various targets are identifiable in CRC, KRAS mutation is currently the only validated predictive biomarker for selection of a targeted therapy. FOCUS4 is a rolling phase II-III trial for testing in a staged way both the utility of molecular stratification and the efficacy of novel agents in subpopulations of mCRC patients. It is also a trial of a new strategy for testing stratified approaches to therapy in any biologically complex tumour type using a Multi-Arm, Multi-Stage design. Methods: The study population consists of subjects with newly diagnosed inoperable mCRC. Subjects receive first-line chemotherapy for 16 weeks. During this time the tumour is tested for BRAF/PIK3CA/KRAS/NRAS mutations and PTEN loss. Subjects with responding or stable disease on CT, who would normally be candidates for a treatment break, are then randomised to four coherent biomarker-based subgroups: FOCUS4-A: BRAF mutant, FOCUS4-B: PIK3CA mutant or complete loss of PTEN on IHC, FOCUS4-C: KRAS or NRAS mutant, FOCUS4-D: All wild type (no mutations of BRAF, PIK3CA, KRAS or NRAS). For each subgroup, a relevant novel agent or combination is to be tested in an adaptive double-blind placebo controlled randomised trial design with multiple interim analyses for early termination if there is no strong evidence of worthwhile activity. There will also be a 5thsubgroup FOCUS4-N testing maintenance capecitabine for unclassifiable tumours or for patients whose marker defined cohort is temporarily suspended. The primary endpoint is progression free survival. Promising results in any biomarker defined cohort will then be tested for response in cohorts without the biomarker. Within the overall trial, biomarker developments can be accommodated with changes in the distribution of the cohorts or testing of new targeted agents. Enrolment will commence in May 2013. Upto 3400 patients will be registered over a 4-5 year period depending on which cohorts pass their staged interim analyses and proceed to later stages, including an overall survival endpoint. Clinical trial information: 2012-005111-12.

QUARTZ is the first phase III randomised clinical trial of whole brain radiotherapy (WBRT) for patients with inoperable brain metastases from non-small cell lung cancer. It is designed as a non-inferiority trial to assess whether WBRT may be omitted without detriment to the patient’s survival while improving quality of life. QUARTZ opened to recruitment in March 2007 and currently has 76 UK and Australian centres open. Despite universal support of the importance of the question and a number of major initiatives aimed at improving recruitment, by mid-2010 recruitment was slower than targeted and the trial was under threat of closure. It was suggested that one of the reasons for investigators not offering the trial to large numbers of their patients and for patients rejecting randomisation, was the lack of good quality preliminary randomised data to support the trial question. Therefore it was proposed to make the unusual step to release interim results from the trial in order to provide investigators with further information upon which to base trial decisions and discussions.

536^ Background: COIN-B is a trial of intermittent chemotherapy (ICT) plus intermittent cetuximab (C) vs ICT plus continuous C in the first-line treatment of aCRC. It complements the COIN trial by investigating how C might safely and effectively be added to an ICT strategy. Methods: Patients (pts) had measurable aCRC; no prior CT for metastases; WHO PS 0-2 and good organ function. Randomisation was: Arm D - continuous OxFU + weekly C for 12 wks then a planned break from all therapy; Arm E - OxFU + weekly C for 12 wks then weekly C. Upon RECIST progression on either arm, OxFU (or FU) plus C was restarted and continued until progression on maximal tolerated therapy. Prospective KRAS testing was introduced in May 2008. Primary outcome measure is Failure-Free Survival (FFS) at 10 months (mo) in KRAS-wt pts who had not progressed, died or failed the treatment strategy within 3 mo of randomisation. The trial was powered to differentiate between a desired 10-mo FFS rate of 50% and a minimum of 35%, in 136 pts (168 allowing for drop-outs). Secondary outcome measures included safety, overall survival (OS) and toxicity. Results: 169 KRAS-wt pts were randomised 07/07 to 06/10, 77 arm D / 92 arm E. Median age 64 years (IQR 55-70); 92% PS 0-1. In Arms D and E respectively, 65 (84%) and 67 (73%) pts were eligible for the primary analysis; 10-mo FFS rates were 48% vs 54% (one-sided 95% confidence limit 37% and 43% respectively). Median FFS was 12.0 vs 13.7 mo respectively (IQR 6.1-20.3 and 8.6-23.2). Median OS was 20.1 vs 18.4 mo. First CFI length was 3.7 mo vs 5.1 mo (IQR 2.5-6.2 and 2.5-8.9). In pre-planned exploratory analysis, median time to progression/death after chemo break was 3.1 mo (IQR 2.1-8.1) in Arm D and 6.0 mo (IQR 2.9-10.9) in Arm E. Toxicity was similar and only 1 arm D pt had G 3 hypersensitivity following C reintroduction. Analyses by BRAF & NRAS (tested retrospectively) will be presented. Conclusions: C was safely incorporated in 2 ICT strategies. Continuous C as maintenance was associated with a longer CFI and longer time to progression/death. This encouraging strategy of incorporating biological maintenance therapy needs validation in phase III trials.