STAMPEDE trial: Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (s251)

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

STAMPEDE is a randomised controlled trial which looks at adding therapies to standard care for men with high-risk prostate cancer starting long-term hormone therapy for the first time. The trial's definitive primary outcome 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 following is a summary of the aims of the research project provided by the controller UCL:

“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.

“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.

“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.

“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.

“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:

A: Standard of Care (SOC)

B: SOC with zoledronic acid

C: SOC with docetaxel

D: SOC with celecoxib

E: SOC with zoledronic acid and docetaxel

F: SOC with zoledronic acid and celecoxib

G: SOC with abiraterone

H: SOC with prostate radiotherapy

J: SOC with enzalutamide and abiraterone

K: SOC with metformin

L: SOC with transdermal oestradiol”

The following NHS England data will be accessed:

• Civil Registration Mortality

• Cancer Registration

• Demographics

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.

The level of the data will be:

• 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 data will be minimised as follows:

• 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 (under DARS-NIC-798687-Z0Z8F).

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.

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.

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.

The data will:

- 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 data will not be transferred to any other location, it will remain in the UCL Data Safe Haven.

The data will be stored on servers at UCL.

The Data will be accessed by authorised personnel via remote access.

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.

For remote access:

- 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;

- Access controls granting users the minimum level of access required are in place;

- Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data;

- Multifactor authentication (MFA) is required for remote access;

- Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access;

- 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.

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).

The data will not leave England and Wales at any time.

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.

All personnel accessing the data have been appropriately trained in data protection and confidentiality

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.

There will be no requirement and no attempt to reidentify individuals when using the data.

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.

Amazon Web Services provides cloud hosting services to UCL and will store the data as contracted by UCL.

The expected outputs of the processing will be:

• 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.

• Presentations at major international and national scientific conferences

• Publication in high-impact peer-reviewed journals

• A written summary of results distributed to participants.

• News articles on the STAMPEDE website

• Tweets on the @MRCCTU Twitter account

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.

The outputs will be communicated to relevant recipients through the following dissemination channels:

• 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

• Articles on the Tackle Prostate Newsletter and Prostate Matters

• Films

• 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.

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.

The use of the data could:

• 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.

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.