STAMPEDE trial: Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (consent)

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Objective for processing

[20 paragraphs unchanged] · • Civil Registration Mortality · • Cancer Registration · • Demographics [2 paragraphs unchanged] · • Identifiable. However, this is only due to the capability to technically re-identify. [40 words unchanged] the majority of the STAMPEDE trial team and methodologists using the data. [1 paragraph unchanged] · • Limited to a study cohort identified by the Controller; 9,037 consented participants (under DARS-NIC-59873-D8C6G) and 1,554 covered by Section 251. 251 (under DARS-NIC-798687-Z0Z8F). [23 paragraphs unchanged]

Expected output

[18 paragraphs unchanged] Clinical work- where outcomes such as fractures and cardiovascular problems are explored [54 words unchanged] help future patients and their clinical teams to better decide between treatment options options.

Benefits reported

The yielded benefits for the data have not yet been achieved. There is yielded benefit in the form of indirect patient benefit through using health systems data (HSD) to provide timely and comprehensive data for primary outcomes. The STAMPEDE trial team demonstrated that HSD can help identify survival outcomes by using the Civil Registrations of Death (CRD) data. Specifically, in the STAMPEDE Metformin Comparison, overall survival data from CRD allowed the trial to report its primary outcome sooner than would have been possible through traditional data derived from case report forms (CRFs) (https://doi.org/10.1016/j.annonc.2024.08.2313). This highlights the ability of HSD to improve trial efficiency and disseminate vital cancer research rapidly.

Changed only in punctuation, spacing or capitalisation: Expected measurable benefits, Processing activities.

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Objective for processing

Prostate cancer is a major health problem world-wide and accounts for nearly one fifth of all newly-diagnosed male cancers. In the UK, approximately 48,500 men were diagnosed with prostate cancer in 2017 and over 12,000 men died from the disease. The Medical Research Council Clinical Trials Unit at University College London (MRC CTU at UCL) requires access to NHS England data for the purpose of the following research project: The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial STAMPEDE is a randomised controlled trial which is looking looks at adding therapies to standard care for men with high-risk prostate cancer [13 words unchanged] measure is overall survival and intermediate primary outcome measure is failure-free survival. The overall aim of STAMPEDE is to assess novel approaches for the treatment of men with prostate cancer who are starting long-term Androgen Deprivation Therapy (ADT). The Medical Research Council Clinical Trials Unit at University College London (MRC CTU at UCL) is the Data Controller and processes data for this trial. The following is a summary of the aims of the research project provided by the controller UCL: This project plans to use routinely collected health data within STAMPEDE to identify and assess clinical outcomes. The overall aim of STAMPEDE is to assess novel approaches for the treatment of men with prostate cancer who are starting long-term Androgen Deprivation Therapy (ADT). Open since October 2005, this Multi-Arm-Multi-Stage (MAMS) trial is the largest study of treatments for prostate cancer in the world, and is currently recruiting to three arms: “1) Obtain trial outcomes of STAMPEDE participants in England and Wales, overall survival and failure-free survival, through routine data (civil registration mortality data, Demographics, Cancer Registration). This will aid follow-up of participants, especially those who may be lost to follow-up due to relocation, and it will increase the precision of survival estimates. • Standard of Care (SOC, arm A) “2) Longer-term follow-up of participants (10+ years) in the eight closed research arms (B-J and their contemporaneous arm A controls) is required for planned analyses to assess overall survival as described previously, using record-level health data and a longer period of follow-up time. • SOC with Metformin (arm K) “3) Recruitment to STAMPEDE closed at the end of March 2023 with a total of 11,992 participants randomised across the UK. Active follow-up of participants continues for participants in K and L arms and their contemporaneous arm A controls until 2025. Arm K is investigating the addition of metformin to Standard of Care (SOC), to determine if this addition improves survival over SOC alone. Arm L is investigating whether transdermal oestradiol will be non-inferior to standard hormone therapy while having fewer side effects and improved quality of life. Both arms will investigate progression-free survival and overall survival, so it is necessary to use record-level health data for precision in the analyses. The analyses will also help the development of new research arms for STAMPEDE2, the new multi-arm multi-stage trial for prostate cancer. • SOC with Transdermal oestradiol (arm L). “4) The study team also aims to assess the concordance agreement of death data (fact, date, and cause) between trial-specific data collection and death registration data in 10,591 STAMPEDE participants in England and Wales. This assessment will determine whether death registration data can be used in place of trial-specific collection of death information for future trials involving survival analyses. With over 13,000 men recruited, most are from England (85%), with others from Wales (6%), Scotland (7%), N Ireland (2%) and a small number from overseas (1%). To take part in STAMPEDE, patients agree for us to collect information on outcomes such as long-term survival and failure-free survival which can be accessed from routine data sources such as the ONS mortality data and Hospital Episode Statistics (HES). “The trial has assessed the interventions in closed arms B-J, which now require longer-term follow-up, and it continues to actively follow-up participants in two treatment arms (arms K & L) and one control arm (Arm A) for primary analyses planned 2023-2025. These are the arms of the trial: STAMPEDE initially assessed the effects of several medications: bisphosphonate (zoledronic acid), a cytotoxic chemotherapeutic agent (docetaxel) and a cyclooxygenase (Cox-2) inhibitor (celecoxib), as single agents or combinations, in patients commencing long-term ADT for locally advancing or metastatic prostate cancer. Since the start of the trial, a number of new research arms have been added to STAMPEDE over time to evaluate: abiraterone, a steroid synthesis inhibitor; prostate radiotherapy for patients with newly-diagnosed metastatic disease; enzalutamide, an inhibitor of androgen receptor signalling, given with abiraterone; and metformin, an anti-diabetic medication. In Protocol version 16.0, a new research arm was added for transdermal oestradiol, given as an alternative form of ADT. A: Standard of Care (SOC) The multi-stage element of the trial design allows patient recruitment to discontinue in treatment arms that are not showing sufficient activity, based on a series of pre-planned, interim, lack-of-benefit analyses. In general, MAMS is an adaptive design and can be regarded as one type of group sequential design. B: SOC with zoledronic acid There are eight research arms closed to recruitment, five of which have already reported results, and three arms are now in long-term follow-up with further analyses planned: C: SOC with docetaxel • D: SOC with Abiraterone (arm G) celecoxib • SOC with Prostate radiotherapy (arm H) E: SOC with zoledronic acid and docetaxel • F: SOC with Enzalutamide zoledronic acid and abiraterone (arm J) celecoxib Over the next three years (2020 to 2023), five analyses are planned with the following comparisons: G: SOC with abiraterone 1. Arm A vs Arm G: participants with metastatic prostate cancer H: SOC with prostate radiotherapy 2. Arm G vs Arm J: participants with locally advanced prostate cancer J: SOC with enzalutamide and abiraterone 3. Arm A vs Arm J: participants with metastatic prostate cancer K: SOC with metformin 4. Arm A vs Arm H: participants with metastatic prostate cancer L: SOC with transdermal oestradiol” 5. Arm A vs Arm K: all participants. The following NHS England data will be accessed: More than half of men taking part in STAMPEDE will survive for five years or more, but the Medical Research Council (MRC) Clinical Trials Unit (CTU) at University College London (UCL) are concerned that some trial centres find it difficult to maintain full follow-up over this period. Flagging data through NHS Digital’s three data products, Demographics, Civil Registration (Deaths) and Cancer Registration Data will allow the MRC CTU at UCL to ensure that deaths and cancer events are captured promptly. Linked data from NHS Digital will therefore improve the estimates of survival, and may also reduce the burden on NHS sites. For the purposes of survival analysis, the MRC CTU will also be able to assume that patients are alive at a set point in time if not reported dead, thereby increasing reliability of data for this study. · Civil Registration Mortality Furthermore, no man should die from prostate cancer without prior progression, so a reported death will allow MRC CTU to check that events are not missed on the Case Report Forms (CRFs) that clinicians complete for their trial participants. Based on previous discussions with ONS statisticians, the MRC CTU will make assumptions about the survival of patients not reported as dead. · Cancer Registration For the pre-specified primary analysis of time to overall survival or censoring, the MRC CTU uses the date of death to the nearest day (collected on the Death CRF), or time to the day the patient was last known to be alive for individuals who are censored. The aim is to maintain this level of precision in any analyses using information from external sources; using routine data that records time to death or censoring to the nearest day (as opposed to the nearest week or month) enhances the precision with which the MRC CTU will be able to distinguish a difference in survival between two treatment groups. · Demographics Provided that the statistical models are correct, this enables MRC CTU's estimates of the survival difference for patients allocated to one treatment relative to another to reflect as closely as possible the reality of any survival difference attributable to treatment allocation in the study setting; and to obtain a greater degree of confidence in understanding of the true effect on survival of a new treatment based on the data available to us. Access to the above datasets is necessary to allow the MRC CTU at UCL to ensure that mortality and cancer events are captured promptly. The data will therefore improve the estimates of survival, and may also reduce the burden on NHS sites. For the purposes of survival analysis, the MRC CTU will also be able to assume that patients are alive at a set point in time if not reported dead, thereby increasing reliability of data for this study. This can have important implications for the treatment future patients receive: if the evidence collected is strong enough to conclusively suggest a survival advantage gained from a treatment, it is more likely that this treatment will be made available to those patients. Conversely, if the analysis suggests the treatment is effective but the MRC CTU at UCL are not sufficiently confident in the strength of the evidence to support this, the findings are less likely to translate into a real difference for patients. The level of the data will be: For information, there is intention to request access to Hospital Episode Statistics (HES) data linked to this request later, which would allow the MRC CTU at UCL to understand the treatment patterns of the trial cohort. This will be subject to a new application, and thus agreement, with NHS Digital. · Identifiable. However, this is only due to the capability to technically re-identify. The data received from NHS England (pseudonymised) is put into a separate folder of which does not contain identifying details. Identifying details are held in a different folder within the UCL Data Safe Haven (UCL DSH) which is inaccessible to the majority of the STAMPEDE trial team and methodologists using the data. The linkage requested is necessary for the performance of a task carried out in the public interest; improving the treatment offered to men with prostate cancer (GDPR section 6:1(e)). Processing is also necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with section 9:2(j) of GDPR. The data will be minimised as follows: STAMPEDE is currently funded by Cancer Research UK’s Clinical Research Committee (formerly the Clinical · Limited to a study cohort identified by the Controller; 9,037 consented participants and 1,554 covered by Section 251. Trials Advisory Awards Committee; CTAAC; ref C547/A3804 - STAMPEDE). UCL is the trial’s Sponsor and delegates sponsorship responsibilities to MRC CTU at UCL. UCL is the sponsor and controller as the organisation responsible for ensuring that the data will only be processed for the purpose described above. The lawful basis for processing personal data under the UK GDPR is: Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller. The lawful basis for processing special category data under the UK GDPR is: Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. The funding is provided by Cancer Research UK. The funding is specifically for the STAMPEDE Trial described. The funder will have no ability to suppress or otherwise limit the publication of findings. Amazon Web Services (AWS) is a processor acting under the instructions of UCL. AWS’ role is limited to secure back-up of data stored in UCL’s Data Safe Haven. UCL uses offsite data centre services provided by VIRTUS data centre. VIRTUS does not have access to the data. Data provided by NHS England will only be accessed and processed by substantive employees of UCL, or Master’s or PhD students affiliated with UCL. Any student working with the data held under this Data Sharing Agreement must have completed relevant data protection and confidentiality training and are subject to UCL policies on data protection and confidentiality. Any students accessing the data will do so under the supervision of a substantive employee of UCL. UCL would be responsible and liable for any work carried out by students. These students would only work on the data for the purposes described in this Agreement. Patient and Public Involvement and Engagement (PPIE) was sought to discuss the use of routine data of trial participants recruited before 2013, where it was unknown if they also consented to data linkage (optional participation). Two focus groups of twelve and seven people met in July and September 2021 respectively. They were recruited by Prostate Cancer UK and Cancer Research UK. All who attended have been affected by cancer in some capacity, either a patient or a family member. Overall, the groups expressed agreement that it was acceptable to access routine data of trial participants without consent provided there was transparency, i.e. information stating that this was being done in line with the reasons given on the trial website. As only a few trial participants (estimated to be up to 12) did not agree to linkage of their routine data before 2013 and it was not known why, the groups felt it was acceptable to use the routine data as most of the trial cohort would have agreed, and it was not practical to go back to them to ask for retrospective consent. Some felt involvement in the clinical trial should automatically allow for the use of routine data, so participants would have to opt-out or withdraw from the trial if they didn’t agree. Consequently, the privacy notice was revised on the trial website to clearly explain the use of routine data without explicit consent to linkage. Members discussed how the patient information sheet and consent form should clearly state that routine data will be accessed and that participation in the trial would permit access to the records held by NHS Digital (who have since become NHS England) and other data providers. Both documents have provided this information about data linkage since 2013 when all patient-facing documentation was updated The aim of the study is to assess new treatment approaches for people affected by high-risk prostate cancer, through a multi-centre randomised controlled clinical trial. Manufacturers of study drugs have contributed discounted or free drugs for use in the STAMPEDE and funding of Educational grants in return for accessing the final primary outcomes report and record-level trial-relate data (NOT NHS England data). There is a potential commercial benefit where the outcome of the study favours a drug which might lead to a change to clinical guidelines and influence the choice of treatment by the treating physician. The results of the study will be helpful for drug manufacturers as they will aid theirs, as well as the public’s and healthcare professional’s understanding, on the most effective treatment for prostate cancer. This will be achieved through an increased evidence base to underpin the understanding and education for the commercial funders. The following commercial organisation are involved in this study: 1. Sanofi Aventis 2. Novartis 3. Pfizer 4. Janssen 5. Astellas 6. CLOVIS None of the commercial organisations above have had, or will have, any role in study design, data collection or analysis, writing or presentation of the findings of the research, or decision to submit for publication, nor suppress any of the findings of the research.

Processing activities

All organisations party to this agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract). There will not be any access to the data by any third parties. MRC CTU at UCL will transfer data to NHS England. The data will consist of identifying details (specifically NHS Number, Date of Birth, Postcode and a unique person ID) for the cohort to be linked with NHS England data. The requested data will be used for the long-term assessment of men in both the many comparisons of the STAMPEDE trial protocol. The primary outcome measure is survival, but cause of death, which can be difficult to ascertain in men with prostate cancer, is an important secondary outcome measure. The data from NHS Digital will allow the MRC CTU at UCL to ensure that deaths are captured and included promptly by all centres and clinics involved in the trial, and to verify that all information is correct and recorded. The number of participants and the rationale for their inclusion will always be included in all presented results. NHS England data will provide the relevant records from the Demographics, Civil Registrations of Deaths, and Cancer Registration datasets to the STAMPEDE Trial team at MRC CTU at UCL. MRC CTU at UCL is not permitted to re-identify individuals under this agreement. The data will: The data will be held on UCL’s Data Safe Haven using UCL approved computers. The Data Safe Haven is UCL’s technical solution for transferring and storing research information that is highly confidential. It meets the requirements of the NHS Digital DSP Toolkit and ISO 27001 Information Security standard. Access is controlled by the Information Asset Owner, and all UCL staff complete training in confidentiality and data protection, which is renewed annually. - contain no direct identifying data items but will contain a unique person ID. MRC CTU at UCL will not identify individuals through the linkage of other data in their possession. The processing activities are as follows: The data will not be transferred to any other location, it will remain in the UCL Data Safe Haven. 1. The STAMPEDE Trial team will identify the trial participants for linkage to NHS Digital data, and inform the UCL MRC CTU Head of Data Management Systems (DMS; acting as the Cohort Contributor and the Data Recipient). The team will provide Study ID, date of birth and date of last visit to the Head of DMS. The data will be stored on servers at UCL. 2. The UCL MRC CTU Head of DMS has a secure database of Patient Identifiable Data (PID) in UCL’s Data Safe Haven; and will extract the PID and merge this with a list of Study IDs. The Data will be accessed by authorised personnel via remote access. 3. The Study ID list will be sent by the UCL MRC CTU Head of DMS to NHS Digital with the following identifiers for linkage to the requested NHS Digital data products (Demographics, Cancer Registration, Civil Registration (Deaths): The Controller must confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract. • Study ID (STAMPEDE trial participant identifier) For remote access: • NHS Number - Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA; • Date of birth - Access controls granting users the minimum level of access required are in place; • Postcode - Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data; There is no linkage field for gender as the entire trial cohort is male. - Multifactor authentication (MFA) is required for remote access; Patients have consented for data to be shared with researchers in an anonymised or linked anonymised form (this is where the 'Linked anonymised data' are anonymous to the people who receive and hold it (e.g. a research team) but contain information or codes that would allow the suppliers of the data to identify people from it). They have also consented that personal details can be used to obtain long term follow up information from national registries. - Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access; A privacy notice detailing the linkage of trial participant information to electronic health records held by NHS Digital and other similar bodies was published on the STAMPEDE website in 2018. At the same time, two letters about 1) Ongoing participation and trial updates for participants in Arms A (joined after 15 Nov 2011), G, H, J, K and L, and 2) End of participation for participants in Arms B, C, D, E, F and Arm A (who joined before 15 Nov 2011) were sent by trial centres. These letters provided updated information to trial participants about the use of their personal data (name, postcode, NHS number) to obtain health data from NHS Digital, Public Health England and the National Cancer Registration and Analysis Service. All participants have the opportunity to withdraw from the trial if they have any objections to the use of their data in this way. - All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this DSA) and complies with the organisation’s remote access policy. 4. NHS Digital will use the supplied information to extract linked data from the requested data products, including the full date and cause of death. These pseudonymised datasets with the Study ID will be sent to the MRC CTU at UCL using the specified transfer method. The data will reside in UCL’s Data Safe Haven and will be identified by Study ID only, thus there will be no identifying personal data attached to a study number. Only defined members of the STAMPEDE trial team and MRC CTU’s methodology team will have access to Data Safe Haven for data analysis - all are substantive employees of UCL. All UCL substantive employees have completed training in data protection and confidentiality, and users of Data Safe Haven receive appropriate training before granted access. The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose). 5. NHS Digital records will be uploaded to UCL’s Data Safe Haven, an output file for trial statisticians with the study-specific trial number will be prepared, and checked to ensure there is no PID within the file. . The data will not leave England and Wales at any time. 6. This output file is placed in a secure directory with limited access only to certain members of STAMPEDE trial team. Access is restricted to individuals within the MRC CTU of UCL who have authorisation from the trial’s management group. All such individuals are substantive employees or students (masters/doctoral) supervised by substantive employees of UCL. 7. Trial statisticians undertake data cleaning/validation activities for the processing of the data for the STAMPEDE trial. All personnel accessing the data have been appropriately trained in data protection and confidentiality 8. The data will be used as a prompt to follow-up with site to get them to complete STAMPEDE Case Report Forms. The data will be linked at person record level with pseudonymised trial datasets obtained from the STAMPEDE Trial team and stored in the UCL’s Data Safe Haven. Data provided by NHS Digital will only be accessed and processed by substantive employees of UCL. There will be no requirement and no attempt to reidentify individuals when using the data. There will be no access to data by other third parties not listed in this agreement. Trial statisticians undertake data cleaning/validation activities for the processing of the data for the STAMPEDE trial. Methodologists will also undertake data cleaning and validation activities for the concordance studies. All outputs produced with data provided by NHS Digital will be aggregated with small numbers suppressed and in line with the HES Analysis Guide. Amazon Web Services provides cloud hosting services to UCL and will store the data as contracted by UCL.

Expected output

The MRC CTU at UCL will create intermediate trial reports for review by the Independent Data Monitoring Committee (IDMC), who are an independent group of experts who monitor patient safety and treatment efficacy data. The IDMC usually meets a minimum of once a year per "comparison". Reports to the committee are confidential, and they are the only people to see data by randomised group while the trial is in progress. The IDMC will only see NHS Digital data that has been aggregated with small numbers suppressed. They may recommend changes to the trial, for action by the trial steering committee. Results for each comparison are triggered by a certain number of deaths in the contemporaneously randomised control arm patients for each comparison. Peer reviewed publications and high impact medical journals - either cancer-specific journal (like JCO or Lancet Oncology) or a general medical journal (like Lancet, The Journal of the American Medical Association, The New England Journal of Medicine) will be produced. MRC CTU at UCL will look to general journals first but will review the results and whether they might or might not appear to a general audience. The expected outputs of the processing will be: MRC CTU will communicate the STAMPEDE results using at least: • MRC CTU at UCL will create intermediate trial reports for review by the Independent Data Monitoring Committee (IDMC), who are an independent group of experts who monitor patient safety and treatment efficacy data. • Presentation Presentations at major international and national scientific conferences [1 paragraph unchanged] • A written summary of results distributed to participants participants. [2 paragraphs unchanged] MRC CTU at UCL will communicate the results to the wider patient population via articles in the Tackle Prostate newsletter, Prostate Matters. The outputs will not contain NHS England data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived. MRC CTU at UCL will also inform Prostate Cancer UK of the results, building on the relationship MRC CTU at UCL have with them for other trials in MRC CTU's prostate cancer portfolio. If appropriate, MRC CTU at UCL will work with the MRC and UCL press offices to develop press release(s) about the results. Depending on what the results show, MRC CTU at UCL may also look at other methods of communication. For previous prostate cancer trials MRC CTU at UCL have used films, briefing papers and events to communicate the results to health-workers and patients. The outputs will be communicated to relevant recipients through the following dissemination channels: MRC CTU will communicate the results to the trial participants via a lay summary which will be distributed by STAMPEDE site staff. The summary is prepared at the MRC CTU by the STAMPEDE trial team and the MRC CTU PPI Group (includes patient representatives and our Policy, Communications and Research Impact Coordinator); this is the same way that previous STAMPEDE findings were disseminated to participants, and examples of the correspondence to STAMPEDE site staff and the participant summary from earlier comparisons have been saved as supporting documents. • Journals either cancer-specific journals (like JCO or Lancet Oncology) or a general medical journal (like Lancet, The Journal of the American Medical Association, The New England Journal of Medicine MRC CTU at UCL will communicate the results to the wider patient population via articles in the Tackle Prostate newsletter, Prostate Matters. MRC CTU at UCL will also inform Prostate Cancer UK of the results, building on the relationship MRC CTU at UCL have with them for other trials in MRC CTU's prostate cancer portfolio. If appropriate, MRC CTU at UCL will work with the MRC and UCL press offices to develop press release(s) about the results. Depending on what the results show, MRC CTU at UCL may also look at other methods of communication. For previous prostate cancer trials MRC CTU at UCL have used films, briefing papers and events to communicate the results to health-workers and patients. • Articles on the Tackle Prostate Newsletter and Prostate Matters All outputs will be aggregated with small numbers suppressed and in line with the HES Analysis Guide. • Films The next indicative date for data output is Summer 2020 for the Abiraterone long-term comparison (Arms A vs G) in metastatic prostate cancer patients. All outputs will be aggregated with data already held on the consenting patients. No data published will lead to individuals being identified. • Events to communicate results to health workers and patients. • Briefing papers • Participant Information leaflets The next indicative date for data output is Autumn 2023 for long-term comparisons. A pilot methodological study was conducted to assess the concordance of the date and causes of death recorded in STAMPEDE with that in the corresponding Civil Registration of Deaths dataset, for comparison A-H (SOC + radiotherapy to the prostate) of over 2000 men with newly diagnosed metastatic prostate cancer. The results were reported at the International Clinical Trials Methodology Conference in Oct 2022 as a poster presentation (Ahmed et al, 2022; abstract P-145). The study found excellent agreement between trial-collected dates of death and that of the Civil Registration data. This showed that Civil Registration data can be used to accurately estimate overall survival of trial participants, and can be used for longer-term follow-up of participants in the other trial arms Reference: Ahmed S, Coong H, Brawley CD, et al. Assessing the suitability of death records from routine sources: a study within a trial. International Clinical Trials Methodology Conference (P-145). 3-6 October 2022: Harrogate, UK.https://hscic365.crm11.dynamics.com/main.aspx?appid=098cef58-b638-42aa-8417-a614049ff93b&forceUCI=1&pagetype=entityrecord&etn=cps_applicationholderdsa&id=aa40a114-916e-41d5-b084-0bb3ceb6cfc8 Methodological work- the STAMPEDE team is primarily focused on whether data that had been collected on trial-specific data collection forms could have been collected from NHSD source. A series of these “data utility comparisons” looking at outcomes, treatments and adverse events in trial participants will deliver and the findings should be available in Q3/4-2023. The findings will have implications for future trials and how they may be conducted, although the findings would need to be contextualised by many other such comparisons. A manuscript setting out the need for such comparisons will be submitted shortly. Clinical work- where outcomes such as fractures and cardiovascular problems are explored according to comparative treatment allocation. These are important in this setting in the long-term but had either not been collected in the trial or had not been easy for trial teams to collect and report. Papers are in development and abstracts have been submitted to clinical conferences for the Autumn 2023. These findings will help future patients and their clinical teams to better decide between treatment options

Expected measurable benefits

In the UK there are 48,500 new cases of prostate cancer each year and 12,000 deaths. STAMPEDE aims to provide evidence as to what is the best way of treating men with newly diagnosed advanced prostate cancer, and the trial has already led to improvements in standard care. It involves many different comparisons, and as an ongoing trial is expected to provide further important results over coming years. The findings of this research study are expected to contribute to evidence-based decision-making for policy-makers, local decision-makers such as doctors, and patients to inform best practice to improve the care, treatment and experience of health care users relevant to the subject matter of the study. Since opening in 2005 over 13 000 participants have joined the trial. MRC CTU at UCL has already reported practice-changing results that show adding docetaxel or abiraterone improve disease control and life-expectancy. Several other strategies have been tested with more results expected soon, including the results of abiraterone and enzalutamide combination and radiotherapy to the prostate in men with newly-diagnosed metastatic disease. The use of the data could: The benefits of utilising routine data from NHS Digital will be improvement in the timely collection of survival data, with improved accuracy, thereby gaining robust evidence contributing to the impact on healthcare of men with prostate cancer. It will also alleviate some of the reporting burden on trial centre staff. • Provide evidence as to what is the best way of treating men with newly diagnosed advanced prostate cancer. • help healthcare systems to better understand the health and care needs of men with prostate cancer. • lead to the identification or improvement of treatments or interventions, or health and care system design to improve health and care outcomes or experience. It is anticipated that the findings will provide new evidence to health professionals and patients about the efficacy of using transdermal oestrodial and metformin to treat prostate cancer, specifically to increase survival time. Analyses of the older closed comparisons (A vs B-J) will also enable patients to know which treatments have longer-term benefits. It is hoped that through publication of findings in appropriate media, the findings of this research will add to the body of evidence that is considered by the bodies, organisations and individual care practitioners charged with making policy decisions for or within the NHS or treatment decisions in relation to specific patients The trial has long established connections with prostate cancer charities and patient support groups, so these will be used to advertise findings from the trial. In particular, articles in the Tackle Prostate Newsletter and Prostate Matters will be published. Films will be made, and events to communicate results to health workers and patients will be held. A patient information booklet of STAMPEDE findings will also be produced to send to trial participants.

Benefits reported

Yielded Benefits is not a requirement for new applications. The yielded benefits for the data have not yet been achieved.