Local cytoreductive treatments for men with newly diagnosed metastatic prostate cancer in addition to standard of care treatment

ISRCTN	ISRCTN58401737
DOI	https://doi.org/10.1186/ISRCTN58401737
ClinicalTrials.gov number	NCT03763253
Secondary identifying numbers	18HH4804

Submission date: 09/11/2018
Registration date: 21/11/2018
Last edited: 23/08/2023

Recruitment status: No longer recruiting
Overall study status: Ongoing
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-comparing-different-treatments-for-prostate-cancer-that-has-spread-ip2-alanta

Study website

Contact information

Prof Hashim U. Ahmed
Scientific

Imperial College London
Charing Cross Hospital
Fulham Palace Road
London
W6 8RF
United Kingdom

ORCID ID	0000-0003-1674-6723
Phone	+44 (0)2033115473
Email	atlanta@imperial.ac.uk

Mr Taimur Shah
Scientific

Imperial College London
Charing Cross Hospital
Fulham Palace Road
London
W6 8RF
United Kingdom

Mr Martin J. Connor
Scientific

Imperial College London
Charing Cross Hospital
Fulham Palace Road
London
W6 8RF
United Kingdom

Ms Kasia Smigielska
Public

Imperial College London
Charing Cross Hospital
Fulham Palace Road
London
W6 8RF
United Kingdom

Study information

Study design	Three-arm unblinded randomized controlled trial using a positive control
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use contact details to request a Participant Information Sheet
Scientific title	Additional Treatments to the Local tumour for metastatic prostate cancer: Assessment of Novel Treatment Algorithms
Study acronym	IP2 - ATLANTA
Study objectives	The trialists hypothesise that men with metastatic disease who undergo treatment of the local tumour in the form of either radical therapy (prostatectomy or radiotherapy) or minimally invasive ablative therapy (MIAT), combined with metastases directly therapy, will have improved survival compared to those who receive standard of treatment alone. They will be investigating this newly evolving treatment paradigm in a formal randomised control trial (RCT).
Ethics approval(s)	Approved 22/01/2019, Wales Research Ethics Committee 5 Bangor (Health and Care Research Wales Castlebridge 4, 15-19 Cowbridge Road East, Cardiff, CF11 9AB; +44(0)2920 785736; WalesREC5@wales.nhs.uk), ref: 19/WA/0005
Health condition(s) or problem(s) studied	Prostate cancer; metastatic disease (Any T, Any N, M1+) of any grade, stage or Prostate Specific Antigen (PSA) level
Intervention	Current interventions as of 23/08/2023: Stratified randomisation via the electronic platform REDCap database. Intervention Arm 1: Minimally Invasive Ablative Therapy (MIAT) to prostate in addition to SOC systemic treatment. The exact treatment protocol and modality used (cryotherapy or high intensity focused ultrasound, HIFU) will be set within the MIAT SOP. For those patients who are undergoing MIAT no local prostate radiotherapy will be given as part of the intervention. Radiotherapy can be given subsequently for palliative reasons. MIAT can be provided by a site other than the recruiting site with follow-up visits at recruiting site. Intervention Arm 2: Radical therapy (prostatectomy or external beam radiotherapy [Prostate radiotherapy using a dose of external beam radiotherapy of 60Gy/20Fr over 27 days OR 74-78Gy in 2Gy per fraction with or without simultaneous nodal radiotherapy, as defined in Local Radiotherapy SOP]) in addition to SOC systemic treatment. Modality based on physician and patient preference and patient co-morbidities. Radiotherapy or surgery can be provided by a site other than the recruiting site with follow-up visits at the recruiting site. The surgical technique is at the discretion and expertise of the surgical team but will be laid down in the Prostatectomy SOP. For those patients who are undergoing radical prostatectomy no local prostate radiotherapy will be given as part of the intervention. Radiotherapy can be given subsequently for palliative reasons. The radiotherapy doses and protocol in this arm will be higher defined in the Radiotherapy Intervention Arm 2 SOP. Metastases Directed Therapy (Intervention Arm 1 and 2): In both intervention arms 1 and 2, metastases directed therapy (MDT) may be used but intent to use MDT to be declared prior to randomisation. In the case of a metastatic recurrence after MDT, a re-treatment with MDT would be allowed if there were new metastatic areas/locations. The imaging reporting of metastases as well as doses and protocol for MDT as defined in and determined by an Imaging Reporting SOP and a Metastases-Directed Therapy SOP. Treatment duration of trial therapies: Prostatectomy 1 day; Radiotherapy 4 to 7.5 weeks; Minimally invasive therapy (MIAT) 1 day [68Ga]PSMA-11 PET-CT Sub study--Now completed: The trialists will also ask men in the pilot part of ATLANTA if they are willing to undergo a PSMA PET scan. They want to see if this scan might be as accurate in detecting residual disease as prostate biopsies and standard body scans, like MRI, CT or bone scans. This however is optional and participants will be told that they do not have to agree to take part in this optional research, but can still take part in the ATLANTA study. The tests required for this exploratory research will be explained to patients prior to consent in the Patient Information Sheet and verbally by clinician. The target recruitment for this study is 25 patients. Previous interventions from 08/07/2021 to 23/08/2023: Stratified randomisation via the electronic platform known as the InForm database. Intervention Arm 1: Minimally Invasive Ablative Therapy (MIAT) to prostate in addition to standard of care systemic treatment. The exact treatment protocol and modality used (cryotherapy or high intensity focused ultrasound, HIFU) will be set within the MIAT SOP. For those patients who are undergoing MIAT no local prostate radiotherapy will be given as part of the intervention. Radiotherapy can be given subsequently for palliative reasons. Intervention Arm 2: Radical therapy with either prostatectomy or external beam radiotherapy (high radical dose set out in Radiotherapy Intervention Arm 2 SOP) in addition to standard of care systemic treatment. Modality based on physician and patient preference and patient co-morbidities. The surgical technique is at the discretion and expertise of the surgical team but will be laid down in the Prostatectomy SOP. For those patients who are undergoing radical prostatectomy no local prostate radiotherapy will be given as part of the intervention. Radiotherapy can be given subsequently for palliative reasons. Metastases Directed Therapy (Intervention Arm 1 and 2): In both intervention arms 1 and 2, metastases directed therapy (MDT) may be used but intent to use MDT to be declared prior to randomisation. In the case of a metastatic recurrence after MDT, a re-treatment with MDT would be allowed if there were new metastatic areas/locations. The imaging reporting of metastases as well as doses and protocol for MDT will be defined and determined by an Imaging Reporting SOP and a Metastases-Directed Therapy SOP. In total, 80 men will be approached in 10 UK centre to estimate recruitment rate, acceptability of the trial randomisation, reported toxicities and adherence to trial interventions in a pilot phase- this phase has now been successfully completed. They will also be included into the main phase where 918 will be recruited over 30 UK centres- current phase. Participants will remain in the study for a maximum of 4 years. The aims are to see whether men will participate in this trial (pilot) before a larger trial (main) is run, and the impact of these treatments on quality of life. [68Ga]PSMA-11 PET-CT substudy: The trialists will also ask men in the pilot part of ATLANTA if they are willing to undergo a PSMA PET scan. They want to see if this scan might be as accurate in detecting residual disease as prostate biopsies and standard body scans, like MRI, CT or bone-scans. This however is optional and participants will be told that they do not have to agree to take part in this optional research, but can still take part in the ATLANTA study. The tests required for this exploratory research will be explained to patients prior to consent in the Patient Information Sheet and verbally by clinician. Target recruitment for this study is 25 patients. This substudy has now successfully been completed and we are not recruiting into this as we are now in the main phase of the trial. Previous interventions: Stratified randomisation via the electronic platform known as the InForm database. Intervention Arm 1: Minimally Invasive Ablative Therapy (MIAT) to prostate in addition to standard of care systemic treatment. The exact treatment protocol and modality used (cryotherapy or high intensity focused ultrasound, HIFU) will be set within the MIAT SOP. For those patients who are undergoing MIAT no local prostate radiotherapy will be given as part of the intervention. Radiotherapy can be given subsequently for palliative reasons. Intervention Arm 2: Radical therapy with either prostatectomy or external beam radiotherapy (high radical dose set out in Radiotherapy Intervention Arm 2 SOP) in addition to standard of care systemic treatment. Modality based on physician and patient preference and patient co-morbidities. The surgical technique is at the discretion and expertise of the surgical team but will be laid down in the Prostatectomy SOP. For those patients who are undergoing radical prostatectomy no local prostate radiotherapy will be given as part of the intervention. Radiotherapy can be given subsequently for palliative reasons. Metastases Directed Therapy (Intervention Arm 1 and 2): In both intervention arms 1 and 2, metastases directed therapy (MDT) may be used but intent to use MDT to be declared prior to randomisation. In the case of a metastatic recurrence after MDT, a re-treatment with MDT would be allowed if there were new metastatic areas/locations. The imaging reporting of metastases as well as doses and protocol for MDT will be defined and determined by an Imaging Reporting SOP and a Metastases-Directed Therapy SOP. In total, 80 men will be approached in 10 UK centre to estimate recruitment rate, acceptability of the trial randomisation, reported toxicities and adherence to trial interventions in a pilot phase. They will also be included into the main phase where 918 will be recruited over 30 UK centres. Participants will remain in the study for a maximum of 4 years. The aims are to see whether men will participate in this trial (pilot) before a larger trial (main) is run, and the impact of these treatments on quality of life. [68Ga]PSMA-11 PET-CT substudy: The trialists will also ask men in the pilot part of ATLANTA if they are willing to undergo a PSMA PET scan. They want to see if this scan might be as accurate in detecting residual disease as prostate biopsies and standard body scans, like MRI, CT or bone-scans. This however is optional and participants will be told that they do not have to agree to take part in this optional research, but can still take part in the ATLANTA study. The tests required for this exploratory research will be explained to patients prior to consent in the Patient Information Sheet and verbally by clinician. Target recruitment for this study is 25 patients.
Intervention type	Mixed
Primary outcome measure	Internal Pilot: 1. Compliance to randomised arm, measured using the electronic Case Report Form on a monthly basis. 2. Recruitment and randomisation rate, measured using the electronic Case Report Form on a monthly basis. 3. Safety (adverse events), measured using the electronic Case Report Form at baseline, week 12, week 26, week 28, week 32, week 34 then every 12 weeks for first year and every 24 weeks for remaining years 2 to 4 for all patients. 4. Proportion of patients with complete pathological response, measured on post SOC systemic therapy prostate biopsies at 6-9 months. Phase II: 1. Progression-free survival (PFS), with progression defined as a composite outcome of biochemical failure (PSA progression value) or local progression or lymph node progression or bone metastases progression (new sites) or progression or development of new distant metastases, defined as lymph nodes outside the pelvis, bone or organ involvement or skeletal-related events confirmed as progression as in the Systemic Therapy in Advancing Or Metastatic Prostate Cancer: Evaluation Of Drug Efficacy (STAMPEDE) RCT. PFS will be assessed from the time of enrollment to the end of the study. Depending on when the patient is recruited, the follow-up duration will be 2-4 years.
Secondary outcome measures	1. Urinary, sexual and rectal side effects, measured using the IPSS, IIEF15 and EPIC questionnaires at baseline, week 26, week 28, week 34, then every 12 weeks for first year and every 24 weeks for remaining years 2 to 4 2. Patient-reported outcomes, measured using the IPSS, IIEF15, EPIC Bowel and Bladder, EQ-5D-5L, EORTC QLQ-FA12 (Fatigue), EORTC QLQ-ELD14 (Elderly), EORTC QLQ-C30 (General), EORTC QLQ PR25 (Prostate), EORTC QLQ-BM22 (Bone Metastases) questionnaires at baseline, week 26, week 28, week 34, then every 12 weeks for first year and every 24 weeks for remaining years 2 to 4 3. Progression on PSA and imaging and impact of clinical features on progression, measured using PSA blood tests at baseline, week 12, 26, 34 then every 12 weeks for first year and every 24 weeks for remaining years 2 to 4 and Imaging tests at baseline and if progression is suspected by a clinician 4. Health-related quality-of-life, measured using the IPSS, IIEF15, EPIC Bowel and Bladder, EQ-5D-5L, EORTC QLQ-FA12 (Fatigue), EORTC QLQ-ELD14 (Elderly), EORTC QLQ-C30 (General), EORTC QLQ PR25 (Prostate), EORTC QLQ-BM22 (Bone Metastases) questionnaires at baseline, week 26, week 28, week 34, then every 12 weeks for first year and every 24 weeks for remaining years 2 to 4 5. Data on costs and resource utilisation for future cost-effectiveness analysis, measured as defined in the statistical analysis plan at trial completion
Overall study start date	23/02/2017
Completion date	31/08/2026

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	Male
Target number of participants	399
Key inclusion criteria	1. Diagnosed with prostate cancer within 6 months of screening visit 2. Metastatic disease (Any T, Any N, M1+) of any grade, stage or Prostate Specific Antigen (PSA) level 3. Fit to undergo standard of care treatment for metastatic disease and both minimally invasive therapy and prostate radiotherapy/prostatectomy 4. Performance status 0-2 5. Histologically proven local tumour
Key exclusion criteria	Added 23/08/2023: Current exclusion criteria as of 06/10/2021: 1. Patient did not undergo and/or is unable to undergo standard of care baseline imaging tests for confirmation of metastatic status (CT abdomen/pelvis AND chest X-ray (or CT chest) AND radioisotope bone scan (or whole body imaging such as MRI or PET imaging as alternative to all preceding scans mentioned here) AND prostate MRI. 2. Prior exposure to long-term androgen deprivation therapy or hormonal therapy for the treatment of prostate cancer unless started within 6 months of screening visit. 3. Prior chemotherapy or local or systemic therapy for treatment of prostate cancer (apart from ADT or hormonal therapy as outlined above) Previous exclusion criteria from 08/02/2021 to 06/10/2021: 1. Patient did not undergo and/or is unable to undergo standard of care baseline imaging tests for confirmation of metastatic status (CT abdomen/pelvis AND chest X-Ray (or CT chest) AND radioisotope bone scan (or whole body imaging such as MRI or PET imaging as alternative to all preceding scans mentioned here) AND prostate MRI 2. Prior exposure to long-term androgen deprivation therapy or hormonal therapy for the treatment of prostate cancer unless started within 4 months of screening visit 3. Prior chemotherapy or local or systemic therapy for treatment of prostate cancer (apart from ADT or hormonal therapy as outlined above in Exclusion Criteria 2) Previous exclusion criteria: 1. Patient did not undergo and/or is unable to undergo standard of care baseline imaging tests for confirmation of metastatic status (CT abdomen/pelvis AND chest X-Ray (or CT chest) AND radioisotope bone scan (or whole body imaging such as MRI or PET imaging as alternative to all preceding scans mentioned here) AND prostate MRI 2. Prior exposure to long-term androgen deprivation therapy or hormonal therapy for the treatment of prostate cancer unless started within 3 months of randomisation 3. Prior chemotherapy or local or systemic therapy for treatment of prostate cancer (apart from ADT or hormonal therapy as outlined above in Exclusion Criteria 2)
Date of first enrolment	10/04/2019
Date of final enrolment	31/08/2024

Locations

Countries of recruitment

England
United Kingdom
Wales

Study participating centres

Charing Cross Hospital, Imperial College Healthcare NHS Trust

Fulham Palace Road, Hammersmith
London
W6 8RF
United Kingdom

Southampton General Hospital

Tremona Road
Southampton
SO16 6YD
United Kingdom

Sunderland Royal Hospital

Kayll Road
Sunderland
SR4 7TP
United Kingdom

Cambridge Queen Elizabeth Hospital, Kings Lynn

Gayton Road, King's Lynn
King's Lynn
PE30 4ET
United Kingdom

Northwick Park, London North West Healthcare NHS Trust

Watford Rd
Harrow
HA1 3UJ
United Kingdom

Freeman Hospital

Newcastle upon Tyne Hospitals NHS Foundation Trust
Freeman Rd
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom

Wirral University Teaching Hospital

Wirral University Teaching Hospital NHS Foundation Trust
Arrowe Park Rd
Birkenhead
CH49 5PE
United Kingdom

Royal Devon and Exeter NHS Trust

Barrack Road
Exeter
EX2 5DW
United Kingdom

Croydon University Hospital

530 London Road
Thornton Heath
London
CR7 7YE
United Kingdom

Royal Marsden Hospital

203 Fulham Road
Chelsea
London
SW3 6JJ
United Kingdom

Glan Clwyd Hospital

North Wales Clinical Research Centre NWCRC
Unit 5 Gwenfro
Wrexham
LL13 7YP
United Kingdom

Chelsea and Westminister

369 Fulham Road
London
SW10 9NH
United Kingdom

West Middlesex University Hospital

Twickenham Road
Isleworth
TW7 6A
United Kingdom

Kings College Hospital

Denmark Hill
London
SE5 9RS
United Kingdom

The Clatterbridge Cancer Centre NHS Foundation Trust

Clatterbridge Hospital
Clatterbridge Road
Bebington
Wirral
CH63 4JY
United Kingdom

Darent Valley Hospital

Darenth Wood Road
Dartford
DA2 8DA
United Kingdom

Wycombe Hospital

Queen Alexandra Road
High Wycombe
HP11 2TT
United Kingdom

Oxford University Hospitals NHS Foundation Trust

Churchill Hospital
Old Road
Headington
Oxford
OX3 7LE
United Kingdom

University College London Hospitals NHS Foundation Trust

250 Euston Road
London
NW1 2PG
United Kingdom

North Middlesex University Hospital Trust

North Middlesex Hospital
Sterling Way
London
N18 1QX
United Kingdom

Sponsor information

Imperial College London and Imperial College Healthcare NHS Trust
University/education

Joint Research Compliance Office
Room 215, Level 2, Medical School Building, Norfolk Place
London
W2 1PG
England
United Kingdom

Phone	+44 (0)2075949459
Email	becky.ward@imperial.ac.uk
Website	https://www.imperial.ac.uk/joint-research-compliance-office/
"ROR"	https://ror.org/041kmwe10

Funders

Funder type

Research organisation

Wellcome Trust
Private sector organisation / International organizations

Location: United Kingdom

Results and Publications

Intention to publish date	31/01/2027
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	Main study: When the study is completed the results will be analysed and presented at international meetings before being published in a medical journal. Large studies such as this take many years to complete and for the final results to appear. When the study results are concluded, they will be presented by clinicians and patient groups, and posted on our website for patients to access. The trial website is available via a link on this page. A newsletter presenting the salient findings in an easy-to-read style will be written in conjunction with the patient representative at study end. This will be circulated to all consenting participants by email or letter depending on their preferences. Findings will be presented through the websites and newsletter of a number of supporting organisations of which our team members have links including Prostate Cancer UK, Maggie’s support group, Pelican Cancer Foundation and CRUK. The social media presence of organisations involved will be used to highlight news about the trial. Sub-study results: After completion of the study the results may be presented at national/international scientific meetings or published in a leading medical journal. The patient will not be identified in any report/publication, and the patient is made aware that the results of some of the tests done as a part of this research may not be available to them individually. Data and images obtained from the scans may be used in an anonymous form for future research, including that carried out by commercial healthcare companies. The participants will not be contacted by any companies carrying out such research and they will not be given access to the participants medical records. It is also made clear in the sub-study PIS that if any inventions resulting in commercial gain emerge from any of this research the participant will not be eligible to benefit financially from these discoveries.
IPD sharing plan	The datasets generated during and/or analysed during the current study are/will be available upon request from Prof. Hashim U Ahmed (hashim.ahmed@imperial.ac.uk).

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			26/07/2023	No	No

Editorial Notes

23/08/2023: The following changes have been made:
1. The interventions and exclusion criteria were updated.
2. The target number of participants was changed from 918 to 399.
3. The Clatterbridge Cancer Centre NHS Foundation Trust, Darent Valley Hospital, Wycombe Hospital, Oxford University Hospitals NHS Foundation Trust, University College London Hospitals NHS Foundation Trust, and North Middlesex University Hospital Trust were added to the study participating centres.
05/04/2022: The following changes have been made:
1. The recruitment end date has been changed from 30/04/2022 to 31/08/2024.
2. The overall trial end date has been changed from 01/03/2024 to 31/08/2026.
3. The intention to publish date has been changed from 01/03/2025 to 31/01/2027.
08/07/2021: The following changes have been made:
1. The scientific title has been changed from "Adjuvant Treatments to the Local tumour for metastatic prostate cancer: Assessment of Novel
Treatment Algorithms" to "Additional Treatments to the Local tumour for metastatic prostate cancer: Assessment of Novel Treatment Algorithms".
2. The trial participating centre "Kings College Hospital" has been added.
3. The interventions have been updated.
4. The EudraCT number has been added.
08/02/2021: The following changes were made to the trial record:
1. The scientific title was changed from "Adjuvant Treatments to the Local tumour for metastatic prostate cancer: Assessment of Novel Treatment Algorithms" to "Adjuvant Treatments to the Local tumour for metastatic prostate cancer: Assessment of Novel Treatment Algorithms".
2. The recruitment end date was changed from 01/01/2021 to 30/04/2022.
3. The exclusion criteria were changed.
4. The following trial participating centres were removed: Guys and St Thomas Hospital, The Royal United Hospital, Worcestershire Acute Hospitals NHS Trust, University Hospital Coventry, Wexham Park Hospital, Norfolk and Norwich University Hospital, The Royal Marsden NHS Foundation Trust/
5. The following trial participating centres were added: West Middlesex University Hospital, Chelsea and Westminister, Glan Clwyd Hospital, Royal Marsden Hospital, Croydon University Hospital.
15/04/2020: The public contact has been updated.
06/08/2019: Cancer Research UK lay summary link added to plain English summary field.
05/08/2019: Internal review.
22/07/2019: The trial participating centre was added: The Royal Marsden NHS Foundation Trust.
19/07/2019: The following changes were made to the trial record:
1. The following trial participating centres were removed: St George's Hospital, St George's Healthcare NHS Trust, Ashford and St Peters, Broomfield Hospital, Princess Alexandra Hospital, Lister Hospital, Glan Clwyd Hospital (Betsi Cadwaladr University Health Board), Wrexham Maelor Hospital (Betsi Cadwaladr University Health Board).
2. The following trial participating centres were added: Northwick Park, London North West Healthcare NHS Trust, The Royal United Hospital, Royal United Hospitals Bath NHS Foundation Trust, Freeman Hospital, Newcastle, Newcastle upon Tyne Hospitals NHS Foundation Trust, Wirral University Teaching Hospital, Wirral University Teaching Hospital NHS Foundation Trust, Worcestershire Acute Hospitals NHS Trust, University Hospital Coventry, University Hospitals Coventry & Warwickshire NHS Trust (UHCW), Royal Devon and Exeter NHS Trust, Wexham Park Hospital, Frimley Health NHS Foundation Trust, Norfolk and Norwich University Hospital, Norfolk & Norwich University Hospital NHS Foundation Trust.
17/07/2019: The following changes were made to the trial record:
1. The ethics approval was added.
2. The recruitment start date was changed from 01/01/2019 to 10/04/2019.
21/06/2019: Internal review.
23/05/2019: ClinicalTrials.gov number added.
05/04/2019: Internal review.
05/03/2019: Internal review.