Systemic therapy in advanced or metastatic prostate cancer: evaluation of drug efficacy
| ISRCTN | ISRCTN78818544 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN78818544 |
| EudraCT/CTIS number | 2004-000193-31 |
| IRAS number | 243856 |
| ClinicalTrials.gov number | NCT00268476 |
| Secondary identifying numbers | PR08, IRAS 243856 |
- Submission date
- 02/02/2004
- Registration date
- 03/08/2004
- Last edited
- 25/03/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English Summary
Contact information
Ms Claire Amos
Public
Public
MRC Clinical Trials Unit at UCL
2nd Floor
90 High Holborn
London
WC1V 6LJ
United Kingdom
| mrcctu.stampede@ucl.ac.uk |
Study information
| Study design | Randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Patient information can be found at: http://www.stampedetrial.org/participants/ |
| Scientific title | Systemic therapy in advanced or metastatic prostate cancer: evaluation of drug efficacy |
| Study acronym | STAMPEDE |
| Study hypothesis | Current hypothesis as of 15/01/2018: Original Comparisons: Research interventions will improve survival over standard-of-care (SOC) Abiraterone Comparison: Addition of abiraterone to SOC will improve survival over SOC alone M1/RT Comparison: Addition of radiotherapy to SOC will improve survival over SOC alone Enzalutamide and Abiraterone Comparison: Addition of enzalutamide, in combination with abiraterone, to SOC will improve survival over SOC alone Metformin Comparison: Addition of metformin to SOC will improve survival over SOC alone Transdermal Oestradiol Comparison: Transdermal oestrdiol will be non-inferior to standard hormone therapy, while having fewer side-effects and improved quality of life Previous hypothesis: Updated 11/09/2008: Prostate cancer accounts for around one fifth of all cancers among men. In the UK there are around 25,000 new cases of prostate cancer each year, and around 10,000 deaths. Most men are given hormone therapy if their prostate cancer has spread (metastasised), or if the cancer is very likely to spread. This usually stops the tumour from growing for a while. However, in most cases over time the tumour will start to grow again. The trial is testing how well three new drugs work to prevent the tumour from growing again. The drugs are called celecoxib, docetaxel and zoledronic acid and are used with the hormone therapy. Updated 23/01/2013: Recruitment to the celecoxib arms (D and F) is now closed. An additional arm containing abiraterone was added in protocol version 8.0. A further comparison arm involving prostate radiotherapy for patients with metastatic disease is added in the current protocol version 9.0. The trial has multiple arms; the control arm of the trial is androgen deprivation therapy (ADT) only, achieved through the use of luteinising hormone releasing hormone (LHRH) analogues or LHRH antagonists, or bilateral orchidectomy according to local practice. Updated 29/07/2014: Recruitment to the zoledronic acid, docetaxel and abiraterone arms (B, C, E and G) have completed recruitment. Protocol version 12.0 was released on 29/07/2014. This includes the addition of arm J which adds abiraterone and enzalutamide to androgen deprivation therapy (ADT). |
| Ethics approval(s) |
Approved 04/10/2004, West Midlands Edgbaston REC United Kingdom; NA; ), ref: (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, United Kingdom; +44 (0)207 104 8155; edgbaston.rec@hra.nhs.uk), ref: 04/MRE07/35 |
| Condition | Prostate adenocarcinoma |
| Intervention | Interventions as of 14/11/2018: Currently recruiting interventions as of 19/10/2017 Arm A = Standard of Care - control Arm K = ADT + Metformin (included from protocol version 15.0) Arm L = Transdermal Oestradiol therapy (included from protocol version 16.0) Standard-of-Care as of xx/xx/2018: Androgen deprivation therapy (ADT) as per local practice. For some participant groups, this should now be supplemented with SOC Radiotherapy. From protocol v14.0 onwards the SOC permits docetaxel for all suitable participants. From protocol v19.0 onwards, where accessible SOC abiraterone may also be permited as an alternative to docetaxel. In summary, SOC treatment is defined as being one of the following combinations: 1. ADT alone 2. ADT + Prostate Radiotherapy (RT) +/- nodal 3. ADT + Docetaxel 4. ADT + Docetaxel + RT 5. ADT + Abiraterone* 6. ADT + Abiraterone + RT* *Note not all forms of SOC treatment are permitted in all comparisons. SOC abiraterone is only permitted within the metformin comparison. Standard-of-Care: Standard forms of background treatment permitted as part of the STAMPEDE protocol which include licensed androgen deprivation therapy (e.g. LHRH analogues) given in the setting of hormone-naïve prostate cancer and first-line use of docetaxel. Metformin: This anti-diabetic medication is proposed to have both anti-cancer effects and may help prevent the adverse metabolic effects of long-term ADT. Transdermal Oestradiol: This form of hormone treatment which can suppress testosterone as effectively as standard ADT and has been shown to avoid some of the side-effects. For example, treatment with transdermal oestradiol does not appear to cause the bone to thin which is a common problem with standard forms of ADT. It may also help to avoid some of the side effects and therefore improve overall quality of life compared with standard forms of ADT. Interventions closed to recruitment as of 19/10/2017 Arm B = ADT + zoledronic acid Arm C = ADT + docetaxel Arm D = ADT + celecoxib Arm E = ADT + zoledronic acid + docetaxel Arm F = ADT + zoledronic acid + celecoxib Arm G = ADT + abiraterone Arm H = ADT + radiotherapy to the prostate Arm J = ADT + abiraterone + enzalutamide Zoledronic acid: Prostate cancer cells can spread to bones and weaken them. Zoledronic acid is a drug that reduces bone destruction and hardens bones. This may make them more resistant to attack by cancer cells. Docetaxel & Prednisolone: A drug that stops cells replicating that is currently being used to treat a range of cancers including lung, breast and ovarian cancer as well as prostate cancer. Docetaxel prolongs survival in men with relapsed metastatic prostate cancer. Celecoxib: An aspirin-like drug that is used to treat arthritis. It slows down the growth of cancer cells in the laboratory. We wished to see if it had the same effect on cancer cells in patients. Recruitment to new patients for the evaluation of this drug is finished as a planned interim analysis failed to demonstrate sufficient activity. Abiraterone Acetate & Prednisolone: An inhibitor of steroid hormone synthesis that blocks prostate cancer cells from generating their own male hormones. This is thought to be a major way in which prostate cancer cells resume growth following castration based therapies. The agent prolongs survival when given to men following failure of docetaxel chemotherapy. Prostate radiotherapy: A treatment with high-energy x-rays targeted to the prostate gland. This treatment is now mandatory for patients with cancer that is confined to the prostate gland as large trials have shown it improves survival times. We are not certain whether we should give radiotherapy to the prostate if the cancer has already spread. Enzalutamide: An androgen receptor signaling inhibitor and has gained recent approval for use on its own in the treatment of advanced CRPC, and there is evidence of activity for hormone-naïve prostate cancer. Interventions as of 15/01/2018: Currently recruiting interventions as of 19/10/2017 Arm A = Standard of Care - control Arm K = ADT + Metformin (included from protocol version 15.0) Arm L = Transdermal Oestradiol therapy (included from protocol version 16.0) Standard-of-Care: Standard forms of background treatment permitted as part of the STAMPEDE protocol which include licensed androgen deprivation therapy (e.g. LHRH analogues) given in the setting of hormone-naïve prostate cancer and first-line use of docetaxel. Metformin: This anti-diabetic medication is proposed to have both anti-cancer effects and may help prevent the adverse metabolic effects of long-term ADT. Transdermal Oestradiol: This form of hormone treatment which can suppress testosterone as effectively as standard ADT and has been shown to avoid some of the side-effects. For example, treatment with transdermal oestradiol does not appear to cause the bone to thin which is a common problem with standard forms of ADT. It may also help to avoid some of the side effects and therefore improve overall quality of life compared with standard forms of ADT. Interventions closed to recruitment as of 19/10/2017 Arm B = ADT + zoledronic acid Arm C = ADT + docetaxel Arm D = ADT + celecoxib Arm E = ADT + zoledronic acid + docetaxel Arm F = ADT + zoledronic acid + celecoxib Arm G = ADT + abiraterone Arm H = ADT + radiotherapy to the prostate Arm J = ADT + abiraterone + enzalutamide Zoledronic acid: Prostate cancer cells can spread to bones and weaken them. Zoledronic acid is a drug that reduces bone destruction and hardens bones. This may make them more resistant to attack by cancer cells. Docetaxel & Prednisolone: A drug that stops cells replicating that is currently being used to treat a range of cancers including lung, breast and ovarian cancer as well as prostate cancer. Docetaxel prolongs survival in men with relapsed metastatic prostate cancer. Celecoxib: An aspirin-like drug that is used to treat arthritis. It slows down the growth of cancer cells in the laboratory. We wished to see if it had the same effect on cancer cells in patients. Recruitment to new patients for the evaluation of this drug is finished as a planned interim analysis failed to demonstrate sufficient activity. Abiraterone Acetate & Prednisolone: An inhibitor of steroid hormone synthesis that blocks prostate cancer cells from generating their own male hormones. This is thought to be a major way in which prostate cancer cells resume growth following castration based therapies. The agent prolongs survival when given to men following failure of docetaxel chemotherapy. Prostate radiotherapy: A treatment with high-energy x-rays targeted to the prostate gland. This treatment is now mandatory for patients with cancer that is confined to the prostate gland as large trials have shown it improves survival times. We are not certain whether we should give radiotherapy to the prostate if the cancer has already spread. Enzalutamide: An androgen receptor signaling inhibitor and has gained recent approval for use on its own in the treatment of advanced CRPC, and there is evidence of activity for hormone-naïve prostate cancer. Current interventions as of 29/07/2014: Arm A = Androgen deprivation therapy (ADT) - control Arm H = ADT + radiotherapy to the prostate (included from protocol version 9.0) Arm J = ADT + abiraterone + enzalutamide (included from protocol version 12.0) 1. Prostate radiotherapy (included from protocol version 9.0): treatment with high-energy x-rays targeted to the prostate gland. This treatment is now mandatory for patients with cancer that is confined to the prostate gland as large trials have shown it improves survival times. We are not certain whether we should give radiotherapy to the prostate if the cancer has already spread. 2. Abiraterone (included from protocol version 8.0): An inhibitor of steroid hormone synthesis that blocks prostate cancer cells from generating their own male hormones. This is thought to be a major way in which prostate cancer cells resume growth following castration based therapies. The agent prolongs survival when given to men following failure of docetaxel chemotherapy. 3. Enzalutamide is a androgen receptor signalling inhibitor and has gained recent approval for use on its own in the treatment of advanced CRPC,(50) and there is evidence of activity for hormone-naïve prostate cancer. Previous interventions from 23/01/2013 to 29/07/2014: Arm A = Androgen deprivation therapy (ADT) - control Arm B = ADT + zoledronic acid Arm C = ADT + docetaxel Arm D = ADT + celecoxib Arm E = ADT + zoledronic acid + docetaxel (NOW CLOSED) Arm F = ADT + zoledronic acid + celecoxib (NOW CLOSED) Arm G = ADT + abiraterone (included from protocol version 8.0): Arm H = ADT + radiotherapy to the prostate (included from protocol version 9.0) 1. Zoledronic acid: Prostate cancer cells can spread to bones and weaken them. Zoledronic acid is a drug that reduces bone destruction and hardens bones. This may make them more resistant to attack by cancer cells. 2. Docetaxel: A drug that stops cells replicating that is currently being used to treat a range of cancers including lung, breast and ovarian cancer as well as prostate cancer. Docetaxel prolongs survival in men with relapsed metastatic prostate cancer. 3. Celecoxib: An aspirin-like drug that is used to treat arthritis. It slows down the growth of cancer cells in the laboratory. We wished to see if it had the same effect on cancer cells in patients. Recruitment to new patients for the evaluation of this drug is finished as a planned interim analysis failed to demonstrate sufficient activity. 4. Abiraterone (included from protocol version 8.0): An inhibitor of steroid hormone synthesis that blocks prostate cancer cells from generating their own male hormones. This is thought to be a major way in which prostate cancer cells resume growth following castration based therapies. The agent prolongs survival when given to men following failure of docetaxel chemotherapy. 5. Prostate radiotherapy (included from protocol version 9.0): treatment with high-energy x-rays targeted to the prostate gland. This treatment is now mandatory for patients with cancer that is confined to the prostate gland as large trials have shown it improves survival times. We are not certain whether we should give radiotherapy to the prostate if the cancer has already spread. Previous interventions until 23/01/2013: Patients will be randomised to the control arm (Arm A) or one of the five investigational arms. All patients will receive androgen suppression (AS) to castration level. The method of AS is a local choice but must be specified for each patient prior to randomisation. All trial treatments should commence as soon as practically possible after randomisation. Patients having a bilateral orchidectomy should commence any additional treatment within four weeks of the operation unless there is a strong clinical reason not to do so. Arm A = Androgen suppression (AS) - control Arm B = AS + zoledronic acid Arm C = AS + docetaxel Arm D = AS + celecoxib Arm E = AS + zoledronic acid + docetaxel Arm F = AS + zoledronic acid + celecoxib |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Pharmacodynamic |
| Phase | Phase II/III |
| Drug / device / biological / vaccine name(s) | Current drug name(s) as of 29/09/2021: Abiraterone acetate, prednisolone, enzalutamide, metformin, transdermal oestradiol Previous drug name(s) as of 15/01/2018: Zoledronic acid, docetaxel, celecoxib, abiraterone acetate, prednisolone, enzalutamide, metformin, transdermal oestradiol Previous drug name(s): Celecoxib, docetaxel, zoledronic acid, abiraterone, enzalutamide |
| Primary outcome measure | Current primary outcome measures as of 15/01/2018: Pilot phase: Safety Efficacy Stage I-III: Failure-free survival (FFS) Efficacy Stage IV: Overall survival Previous as of 11/09/2008: Pilot phase: Safety Efficacy Stage I-III: Failure-free survival (FFS) Efficacy Stage IV: Overall survival |
| Secondary outcome measures | Current secondary outcome measures as of 15/01/2018: Pilot phase: Feasibility Efficacy Stage I-III: 1. Overall survival (OS) 2. Toxicity 3. Skeletal related events Efficacy Stage IV: 1. Quality of life 2. Cost effectiveness 3. Failure-free survival 4. Toxicity 5. Skeletal related events Previous as of 11/09/2008: Pilot phase: 1. Feasibility Efficacy Stage I-III: 2. Overall survival (OS) 3. Toxicity 4. Skeletal related events Efficacy Stage IV: 1. Quality of life 2. Cost effectiveness 3. Failure-free survival 4. Toxicity 5. Skeletal related events |
| Overall study start date | 17/10/2005 |
| Overall study end date | 31/08/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Male |
| Target number of participants | 12,420 |
| Total final enrolment | 11992 |
| Participant inclusion criteria | Participant inclusion criteria as of 14/11/2018: Participants must fulfil all the criteria in one of the following three categories: 1. HIGH-RISK NEWLY DIAGNOSED NON-METASTATIC NODE-NEGATIVE DISEASE - Both: 1.1. At least two of: Stage T3/4, PSA ≥ 40 ng/ml or Gleason sum score 8-10 1.2. Intention to treat with radical radiotherapy (unless there is a contra-indication; exemption can sought in advance of consent, after discussion with MRC CTU) OR 2. NEWLY DIAGNOSED METASTATIC OR NODE-POSITIVE DISEASE - At least one of: 2.1. Stage Tany N+ M0 2.2. Stage Tany Nany M+ OR 3. PREVIOUSLY TREATED WITH RADICAL SURGERY AND/OR RADIOTHERAPY, NOW RELAPSING - At least one of: 3.1. PSA ≥ 4 ng/ml and rising with doubling time less than 6 months 3.2. PSA ≥ 20 ng/ml 3.3. N+ 3.4. M+ AND 4. FOR ALL PATIENTS 4.1. Histologically confirmed prostate adenocarcinoma 4.2. Intention to treat with long-term androgen deprivation therapy 4.3. Treating clinician and participant should have decided if additional systemic therapy with docetaxel or abiraterone is to be used as part of the standard-of-care prior to randomisation 4.4 Fit for all protocol treatment2 and follow-up, WHO performance status 0-23 4.5 Have completed the appropriate investigations prior to randomisation 4.6. Adequate haematological function: neutrophil count >1.5x109/l and platelets >100x109/l 4.7. Estimated creatinine clearance >30ml/min 4.8. Written informed consent 4.9. Willing and expected to comply with follow-up schedule 4.10. Using effective contraceptive method if applicable Participant inclusion criteria as of 23/01/2013: Patients must fulfil both of the criteria in Section 1 or one criterion in Section 2 or at least one criteria in Section 3. Additionally, all patients must fulfil the criteria in Section 4. 1. HIGH-RISK NEWLY DIAGNOSED NON-METASTATIC NODE-NEGATIVE DISEASE - Both: 1.1. At least two of: Stage T3/4, PSA ≥ 40 ng/ml or Gleason sum score 8-10 1.2. Intention to treat with radical radiotherapy (unless there is a contra-indication; exemption can sought in advance of consent, after discussion with MRC CTU) OR 2. NEWLY DIAGNOSED METASTATIC OR NODE-POSITIVE DISEASE - At least one of: 2.1. Stage Tany N+ M0 2.2. Stage Tany Nany M+ OR 3. PREVIOUSLY TREATED WITH RADICAL SURGERY AND/OR RADIOTHERAPY, NOW RELAPSING - At least one of: 3.1. PSA ≥ 4 ng/ml and rising with doubling time less than 6 months 3.2. PSA ≥ 20 ng/ml 3.3. N+ 3.4. M+ AND 4. FOR ALL PATIENTS 4.1. Histologically confirmed prostate adenocarcinoma 4.2. Intention to treat with long-term androgen deprivation therapy 4.3. Fit for all protocol treatment2 and follow-up, WHO performance status 0-23 4.4 Have completed the appropriate investigations prior to randomisation 4.5. Adequate haematological function: neutrophil count >1.5x109/l and platelets >100x109/l 4.6. Estimated creatinine clearance >30ml/min 4.7. Serum potassium ≥3.5mmol/L 4.8. Written informed consent 4.9. Willing and expected to comply with follow-up schedule 4.10. Using effective contraceptive method if applicable Previous inclusion criteria until 23/01/2013: Patients must fulfil one of the inclusion criteria in section one or one of the inclusion criteria in section two. Additionally, all patients must fulfil the inclusion criteria in section three: Section one - high risk newly diagnosed patients must fulfil one of the following criteria: 1. Stage T3/4 N0 M0 histologically confirmed prostate adenocarcinoma with Prostate Specific Antigen (PSA) = 40 ng/ml or Gleason sum score eight to ten 2. Stage Tany N + M0 or Tany Nany M + histologically confirmed prostate adenocarcinoma 3. Multiple sclerotic bone metastases with a PSA = 100 ng/ml Section two - patients with histologically confirmed prostate adenocarcinoma previously treated with radical surgery or radiotherapy that are now relapsing. (Please note that prior hormone therapy for localised disease must have been completed 12 months previously, have been no longer than 12 months in duration and given as adjuvant or neoadjuvant therap: 1. PSA = 4 ng/ml and rising with doubling time less than six months 2. PSA = 20 ng/ml Section three - for all patients: 1. Intention to treat with long-term androgen suppression 2. Fit for all protocol treatment and follow-up, World Health Organisation (WHO) performance status zero to two 3. Have completed the appropriate investigations prior to randomisation 4. Adequate haematological function: neutrophil count more than 1.5 x 10^9 l and platelets more than 100 x 10^9 l 5. Adequate renal function: Serum creatinine less than 1.5 Upper Limit of Normal (ULN) 6. Adequate liver function: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) less than 1.5 ULN, bilirubin less than ULN 7. Normal testosterone level prior to treatment 8. Written informed consent 9. Willing and expected to comply with follow-up schedule |
| Participant exclusion criteria | Participant exclusion criteria as of 14/11/2018: 1. Prior systemic therapy for locally-advanced or metastatic prostate cancer 2. Metastatic brain disease or leptomeningeal disease 3. Abnormal liver functions consisting of any of the following: 3.1. Serum bilirubin ≥1.5 x ULN (except for participants with Gilbert’s disease, for whom the upper limit of serum bilirubin is 51.3μmol/l or 3mg/dl) 3.2. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 x ULN 4. Any other previous or current malignant disease which, in the judgement of the responsible clinician, is likely to interfere with STAMPEDE treatment or assessment 5. Any surgery (e.g. TURP) performed within the past 4 weeks 6. Participants with significant cardiovascular disease, including: 6.1. Severe/unstable angina 6.2. Myocardial infarction less than 6 months prior to randomisation 6.3. Arterial thrombotic events less than 6 months prior to randomisation 6.4. Clinically significant cardiac failure requiring treatment, defined as New York Heart Association (NYHA) class II or above1 6.5. Cerebrovascular disease (e.g. stroke or transient ischaemic episode) less than 6 months prior to randomisation 6.6. Or any other significant cardiovascular disease that in the investigator's opinion means the participant is unfit for any of the study treatments. 7. Prior chemotherapy for prostate cancer2 8. Prior exposure to long-term hormone therapy before randomisation 9. Prior exposure to systemic treatment for prostate cancer (excluding ADT or participants receiving abiraterone as part of SOC) Comparison-Specific Selection Criteria In addition to the general inclusion and exclusion criteria, the following comparison-specific eligibility criteria apply. Metformin Comparison In addition to the general inclusion and general exclusion criteria the following comparison-specific inclusion criteria must be met to be eligible for randomisation to the "metformin comparison": 1. Hb A1c <48mmol/mol (equivalent to <6.5%)1 2. Adequate renal function, defined as GFR ≥45ml/min/1.73m2 (except for Switzerland 2) 3. No history of lactic acidosis or predisposing conditions 4. No current or previous treatment with metformin 5. No contraindications to metformin The method used to determine glomerular filtration rate may vary according to local practice. Equations that either estimate glomerular filtration rate (eGFR) or creatinine clearance (CrCl) may be used and the same threshold value applies. Where possible, HbA1c should be performed prior to commencing SOC docetaxel to reduce the likelihood of corticosteroid-related hyperglycaemia impacting on eligibility. All participants with abnormal baseline HbA1c (i.e. 6.5% or higher) should be informed and referred to their GP for further management. Transdermal Oestradiol Comparison In addition to the general inclusion and exclusion criteria, participants fulfilling all of the following are eligible for the “transdermal oestradiol comparison”: 1. ≤8 weeks of anti-androgen (AR-antagonists) use 2. ≤1 dose of monthly or 4-weekly LHRH agonist/antagonist 3. No prior LHRH agonist injection with a stated duration of effect greater than 1 month 4. ≤12 weeks since first dose of any hormone therapy 5. Not had a bilateral orchidectomy 6. No use of cyproterone acetate (77) prior to randomisation 7. No known porphyria 8. No known history of deep vein thrombosis or pulmonary embolism confirmed radiologically 9. No known thrombophilic disorder (e.g. Protein C, Protein S, antithrombin deficiency) 10. Not planned to receive SOC abiraterone Participant exclusion criteria as of 16/01/2018: Patients must not fulfil any of the criteria, below. 1. Prior systemic therapy for locally-advanced or metastatic prostate cancer except as listed in 1.3 2. Metastatic brain disease or leptomeningeal disease 3. Abnormal liver functions consisting of any of the following: 3.1. Serum bilirubin ≥1.5 x ULN (except for patients with Gilbert’s disease, for whom the upper limit of serum bilirubin is 51.3µmol/l or 3mg/dl 3.2. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 x ULN 4. Any other previous or current malignant disease which, in the judgement of the responsible clinician, is likely to interfere with STAMPEDE treatment or assessment 5. Any surgery (e.g. TURP) performed within the past 4 weeks 6. Patients with significant cardiovascular disease, including: 6.1. Severe/unstable angina 6.2. Myocardial infarction less than 6 months prior to randomisation 6.3. Arterial thrombotic events less than 6 months prior to randomisation 6.4. Clinically significant cardiac failure requiring treatment (NYHA II-IV)³ 6.5. Cerebrovascular disease (e.g. stroke or transient ischemic episode) less than 6 months prior to randomisation 6.6. Patients with uncontrolled hypertension defined as systolic BP greater or equal than 160mmHg or diastolic BP greater or equal than 95mmHg⁴ 6.7. Or any other significant cardiovascular disease that in the investigator’s opinion means the patient is unfit for any of the study treatments 7. Prior chemotherapy for prostate cancer (excluding patients receiving docetaxel as part of the new SOC) 8. Prior exposure to long-term hormone therapy before randomisation 9. Prior exposure to systemic treatment for prostate cancer (excluding hormone therapy) e.g. abiraterone and enzalutamide Comparison-Specific Selection Criteria Metformin Comparison 1. Patients with known diabetes mellitus are not eligible for randomisation. All non-diabetic patients require an HbA1c to be performed prior to randomisation (ideal timeline: within 8 weeks prior to randomisation), to confirm their non-diabetic status. 2. HbA1c <48mmol/mol (equivalent to <6.5%) 3. Adequate renal function, defined as GFR ≥45ml/min/1.73m² 4. No history of lactic acidosis or pre-disposing conditions 5. Not current or previous treatment with metformin 6. No contra-indications to metformin Transdermal Oestradiol Comparison Patients who have any of the following are not eligible for the transdermal oestradiol comparison 1. >8 weeks of anti-androgen use 2. >1 dose of monthly or 4 weekly LHRH agonist/antagonist 3. Prior LHRH agonist injection with a stated duration of effect greater than 1 month 4. >12 weeks since first dose of any hormone therapy 5. Bilateral orchidectomy 6. Cyproterone acetate started prior to randomisation 7. Known porphyria 8. Any history of deep vein thrombosis or pulmonary embolism confirmed radiologically Known thrombophilic disorder (e.g. Protein C, Protein S, antithrombin deficiency) Current exclusion criteria as of 29/07/2014: 1. Prior systemic therapy for locally advanced or metastatic prostate cancer except as listed in Section 4.1.3 2. Metastatic brain disease or leptomeningeal disease 3. Abnormal liver functions consisting of any of the following: 3.1. Serum bilirubin ≥1.5 x ULN (except for patients with Gilberts disease, for whom the upper limit of serum bilirubin is 51.3μmol/l or 3mg/dl) 3.2. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 x ULN 4. Any other previous or current malignant disease which, in the judgement of the responsible physician, is likely to interfere with STAMPEDE treatment or assessment 5. Patients with contra-indications to prednisolone, including active peptic ulceration or a history of gastrointestinal bleeding 6. Patients with active inflammatory bowel disease 7. Symptomatic peripheral neuropathy grade 2 (NCI CTC)5 8. Any surgery (e.g. TURP) performed within the past 4 weeks 9. Patients with significant cardiovascular disease such that, in the investigator's opinion, the patient is unfit for any of the study treatments. This might include: 9.1. Severe/unstable angina 9.2. Myocardial infarction less than 6 months prior to randomisation 9.3. Arterial thrombotic events less than 6 months prior to randomisation 9.4. Clinically significant cardiac failure requiring treatment (NYHA II-IV)6 9.5. Cerebrovascular disease (e.g. stroke or transient ischaemic episode) less than 2 years prior to randomisation 9.6. Patients with uncontrolled hypertension defined as systolic BP greater or equal than 160 mmHg or diastolic BP greater or equal than 95 mmHg 10. Patients receiving treatment with drugs known to induce CYP3A4 (including phenytoin, carbamazepine, Phenobarbital)7 11. Prior exposure to abiraterone 12. Prior exposure to enzalutamide 13. Prior chemotherapy for prostate cancer 14. Prior therapy with zoledronic acid or other bisphosphonates other than treatment for hypercalcaemia or low bone density 15. Prior exposure to policy of long-term hormone therapy before randomisation (unless as described in Section 4.4.2) 16. History of seizure including any febrile seizure, loss of consciousness, or transient ischaemic attack within 12 months of randomisation or any condition that may pre-dispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization) 17. Unexplained history of loss of consciousness within 12 months of randomisation 18. Operation of heavy machinery during treatment SELECTION CRITERIA FOR COMPARISON OF RESEARCH (M1) RT FOR METASTATIC DISEASE All patients meeting criteria the above criteria are eligible for the trial, but not all can be allocated to the research (M1) radiotherapy arm. The selection criteria for this 'RT to the prostate' comparison are: 1. Newly-diagnosed prostate cancer 2. Demonstrable M1 disease 3. No contraindication to radiotherapy e.g. no previous pelvic radiotherapy and no history of inflammatory bowel disease 4. No previous radical prostatectomy Any patients meeting these criteria will have a chance to be allocated to Arm H. Previous exclusion criteria from 23/01/2013 to 29/07/2014: 1. Prior systemic therapy for locally advanced or metastatic prostate cancer except as listed in Section 4.1.3. 2. Metastatic brain disease or leptomeningeal disease 3. Abnormal liver functions consisting of any of the following: 3.1. Serum bilirubin ≥1.5 x ULN (except for patients with Gilberts disease, for whom the upper limit of serum bilirubin is 51.3μmol/l or 3mg/dl) 3.2. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 x ULN 4. Any other previous or current malignant disease which, in the judgement of the responsible physician, is likely to interfere with STAMPEDE treatment or assessment 5. Patients with active peptic ulceration, gastrointestinal bleeding, inflammatory bowel disease 6. Symptomatic peripheral neuropathy grade 2 (NCI CTC)5 7. Any surgery (e.g. TURP) performed within the past 4 weeks 8. Patients with significant cardiovascular disease such that, in the investigator's opinion, the patient is unfit for any of the study treatments. This might include: 8.1. Severe/unstable angina 8.2. Myocardial infarction less than 6 months prior to randomisation 8.3. Arterial thrombotic events less than 6 months prior to randomisation 8.4. Clinically significant cardiac failure requiring treatment (NYHA II-IV)6 8.5. Cerebrovascular disease (e.g. stroke or transient ischaemic episode) less than 2 years prior to randomisation 8.6. Patients with uncontrolled hypertension defined as systolic BP greater or equal than 160 mmHg or diastolic BP greater or equal than 95 mmHg 9. Patients who have been scheduled to have major dental extractions within the next 2 years 10. Patients receiving treatment with drugs known to induce CYP3A4 (including phenytoin, carbamazepine, Phenobarbital)7 11. Prior exposure to abiraterone 12. Prior chemotherapy for prostate cancer 13. Prior therapy with zoledronic acid other than short-term treatment for hypercalcaemia 14. Prior exposure to policy of long-term hormone therapy before randomisation (unless as described in Section 4.4.2 of the protocol) SELECTION CRITERIA FOR COMPARISON OF RESEARCH (M1) RT FOR METASTATIC DISEASE All patients meeting criteria above are eligible for the trial, but not all can be allocated to the research (M1) radiotherapy arm. The selection criteria for this RT to the prostate comparison are: 1. Newly diagnosed prostate cancer 2. Demonstrable M1 disease 3. No contraindication to radiotherapy e.g. no previous pelvic radiotherapy, 4. No previous radical prostatectomy Patients meeting these criteria will have a chance to be allocated to Arms A and H. Previous exclusion criteria until 23/01/2013: 1. Prior systemic therapy for locally advanced or metastatic prostate cancer except as listed in section two 2. Metastatic brain disease or leptomeningeal disease 3. Any other previous or current malignant disease which, in the judgement of the responsible physician, is likely to interfere with STAMPEDE treatment or assessment 4. Symptomatic peripheral neuropathy grade two (National Cancer Institute Common Toxicity Criteria [NCI CTC]) 5. Any surgery (e.g. transurethral resection of the prostate [TURP]) performed within the past four weeks |
| Recruitment start date | 17/10/2005 |
| Recruitment end date | 31/03/2023 |
Locations
Countries of recruitment
- England
- Northern Ireland
- Scotland
- Switzerland
- United Kingdom
- Wales
Study participating centre
CRUK Institute for Cancer Studies
Birmingham
B15 2TT
United Kingdom
B15 2TT
United Kingdom
Sponsor information
University College London
Research organisation
Research organisation
MRC Clinical Trials Unit at UCL
90 High Holborn
London
WC1V 6LJ
United Kingdom
| Phone | +44 (0)20 7670 4831 |
|---|---|
| mrcctu.stampede@ucl.ac.uk | |
| Website | http://www.ucl.ac.uk/ |
"ROR" |
https://ror.org/02jx3x895 |
Funders
Funder type
Research organisation
Cancer Research UK (UK)
Private sector organisation / Other non-profit organizations
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- CR_UK, Cancer Research UK - London, CRUK
- Location
- United Kingdom
Results and Publications
| Intention to publish date | |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not provided at time of registration |
| Publication and dissemination plan | Not provided at time of registration |
| IPD sharing plan | Not provided at time of registration |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 03/09/2008 | Yes | No | |
| Results article | results | 11/06/2009 | Yes | No | |
| Results article | results | 01/05/2012 | Yes | No | |
| Results article | results | 15/09/2012 | Yes | No | |
| Results article | results | 01/05/2013 | Yes | No | |
| Results article | results | 01/11/2014 | Yes | No | |
| Results article | results | 01/06/2015 | Yes | No | |
| Results article | results | 01/02/2016 | Yes | No | |
| Results article | results | 01/03/2016 | Yes | No | |
| Results article | results | 19/03/2016 | Yes | No | |
| Results article | results | 01/12/2016 | Yes | No | |
| Results article | results | 10/05/2017 | Yes | No | |
| Results article | results | 27/07/2017 | Yes | No | |
| Plain English results | 31/01/2019 | 08/11/2021 | No | Yes | |
| Plain English results | 13/01/2022 | 13/01/2022 | No | Yes | |
| Results article | 07/06/2022 | 08/06/2022 | Yes | No |
Editorial Notes
25/03/2025: The overall study end date was changed from 31/03/2025 to 31/08/2025.
20/06/2024: The following changes were made:
1. IRAS number added.
2. Protocol number added.
3. Full ethics approval information added.
4. The overall study end date was changed from 01/12/2024 to 31/03/2025.
5. Pharmacodynamic was added as a pharmaceutical study type.
6. Northern Ireland, Scotland and Wales were added as countries of recruitment.
10/05/2023: Sponsor details updated.
04/04/2023: The recruitment end date was changed from 01/12/2022 to 31/03/2023. Total final enrolment added.
08/06/2022: Publication reference added.
08/11/2021: The CRUK summary link has been updated in the plain English summary and the outputs table.
29/09/2021: The following changes have been made:
1. The recruitment end date has been changed from 01/12/2020 to 01/12/2022.
2. The drug name(s) have been updated.
3. The total target enrolment number and target number of participants have been changed from 8100 to 12420.
4. The sponsor has been updated.
20/09/2021: Internal review.
10/06/2020: The scientific contact has been deleted and a public contact added.
14/11/2018: The following changes were made:
1. The interventions were updated.
2. The participant inclusion criteria was updated.
3. The participant exclusion criteria was updated.
16/01/2018: The exclusion criteria has been updated.
15/01/2018: The following changes have been made:
1. The phase has changed from phase III to phase II/III
2. The interventions have been updated
3. The hypothesis has been updated.
4. The overall trial end date has been updated from 01/12/2017 to 01/12/2024
5. The primary and secondary outcomes have been updated.
6. The recruitment end date has been updated from 01/12/2017 to 01/12/2020
7. The sponsor website has been added.
8. Publication references have been added.
28/07/2016: Publication reference added.
29/07/2014: The following changes were made to the trial record:
1. The overall trial end date was changed from 01/12/2015 to 01/12/2017.
2. The target number of participants was changed from 3,300 to 8,100.
23/01/2013: The overall trial end date was changed from 01/12/2013 to 01/12/2015.
11/09/2008: The overall trial end date was changed from 01/10/2012 to 01/12/2013.
