Please select the eligibility criteria that correspond to the clinical trial below.
Title: STAMPEDE: Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial
Brief Summary: The overall aim of this trial, which is called STAMPEDE, is to assess novel approaches for the treatment of men with prostate cancer who are starting long-term ADT for the first time, termed hormone-naïve prostate cancer. This trial aims to see if we can improve the way in which prostate cancer is currently managed, either by adding new treatments to the standard approach or by modifying the type of hormone therapy aiming to improve quality-of-life by reducing the side effects of treatment. Each new treatment approach is compared against a control arm receiving the current standard treatments. We aim to identify treatment strategies that enable men to live longer, or as long but with an improved quality-of-life, as well as offering value for money for the health service.

Since opening to accrual in Oct-2005, the trial has tested many ways of treating prostate cancer and some results are now already known. More than 10,000 men will join the trial with answers becoming available throughout the trial. New patients joining the trial from Protocol version 17.0 onwards (activated in December 2018) may be eligible to join one of two treatment comparisons, metformin (treatment group K; the "metformin comparison") and transdermal oestradiol (treatment group L; the "transdermal oestradiol comparison"). A computer program will be used to allocate which treatment each participant receives, using a chance process.

Summary of the research arms in STAMPEDE trial platform Summary of research treatment groups currently open to recruitment (June 2017)

1. Metformin (Arm K): This anti-diabetic medication is proposed to have both anti-cancer effects and may help prevent the adverse metabolic effects of long-term ADT. STAMPEDE will investigate whether adding metformin to the current standard-of-care for non-diabetic men can improve all-cause survival.
2. Transdermal oestradiol (Arm L): This is an alternative form of hormone treatment which has been shown to suppress testosterone as effectively as standard ADT and avoid some of the side-effects. It may also help to avoid the adverse metabolic effects and fatigue and therefore improve overall quality of life compared with standard forms of ADT. STAMPEDE will investigate whether transdermal oestradiol can treat the cancer as well as current standard forms of ADT.
3. Control group (Arm A): Patients allocated to this group receive the current standard-of-care ADT +/- RT +/- docetaxel.


Options:
A: DISEASE CHARACTERISTICS:

* Histologically confirmed prostate adenocarcinoma

  * Metastatic disease
* Measurable or evaluable disease
* No brain metastases

PATIENT CHARACTERISTICS:

Age

* 18 and over

Performance status

* ECOG 0-2

Life expectancy

* At least 3 months

Hematopoietic

* WBC ≥ 2,000/mm\^3
* Absolute neutrophil count ≥ 1,000/mm\^3
* Platelet count ≥ 100,000/mm\^3

Hepatic

* Bilirubin ≤ 1.5 times upper limit of normal (ULN) (2.5 times normal if hepatic metastases are present)
* AST and ALT ≤ 1.5 times ULN (2.5 times normal if hepatic metastases are present)

Renal

* Creatinine ≤ 150 μmol/L

Cardiovascular

* No symptomatic coronary disease
* No congenital cardiac insufficiency
* No New York Heart Association class III or IV cardiovascular disease
* No other severe cardiovascular disease

Other

* No severe peripheral neuropathy
* No active infection
* No other malignancy within the past 5 years except basal cell skin cancer
* No familial, social, geographical, or psychological situation that would preclude study compliance and follow-up
* No other serious disease that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

* Not specified

Chemotherapy

* No prior chemotherapy for metastatic prostate cancer
* Prior chemotherapy allowed provided all of the following are true:

  * Chemotherapy was completed \> 1 year ago
  * Prostate-specific antigen level has remained stable
  * No development of metastases within 1 year after completion of chemotherapy

Endocrine therapy

* Prior hormonal therapy within the past 2 months allowed for metastatic prostate cancer

Radiotherapy

* More than 4 weeks since prior radiotherapy to metastatic sites

Surgery

* No prior surgical castration

Other

* No other concurrent investigational drugs
B: DISEASE CHARACTERISTICS:

* Histologically or cytologically confirmed adenocarcinoma of the prostate

  * Metastatic disease by imaging or clinical examination
* Hormone-refractory disease, defined as prostate-specific antigen (PSA) level \> 10 µg/L AND rising between 2 sequential measurements
* Testosterone within castration levels by orchiectomy or medical castration comprising luteinizing hormone-releasing hormone (LHRH) analogues

PATIENT CHARACTERISTICS:

Age

* Over 18

Performance status

* WHO 0-2

Life expectancy

* Not specified

Hematopoietic

* Neutrophil count ≥ 1,500/mm\^3
* Hemoglobin ≥ 11.0 g/dL
* Platelet count ≥ 100,000/mm\^3

Hepatic

* ALT and AST ≤ 2.5 times upper limit of normal (ULN)
* Bilirubin normal
* Alkaline phosphatase ≤ 6 times ULN (unless due to the presence of extensive bone disease)
* No serious liver disease

Renal

* Creatinine ≤ 1.5 times ULN

Cardiovascular

* No ischemic or thromboembolic cardiac disease
* No myocardial infarction within the past 12 months
* No other serious cardiac disease

Pulmonary

* No pulmonary emboli

Immunologic

* No active infection
* No autoimmune disease, including any of the following:

  * Lupus
  * Scleroderma
  * Rheumatoid polyarthritis

Other

* No active peptic ulcer
* No unstable diabetes mellitus
* No contraindication to corticosteroids
* No other malignant disease within the past 5 years except basalioma
* No functional iron deficiency (i.e., transferrin saturation \< 20%) that cannot be treated with iron supplementation
* No other serious illness or medical condition

PRIOR CONCURRENT THERAPY:

Biologic therapy

* More than 2 months since prior recombinant human epoetin alfa or any other erythropoiesis-stimulating drug

Chemotherapy

* At least 3 weeks since prior estramustine

Endocrine therapy

* See Disease Characteristics
* At least 3 weeks since prior antiandrogen treatment
* Concurrent chemical castration with LHRH allowed provided patient has begun treatment prior to study entry

  * No initiation of chemical castration therapy during study treatment

Radiotherapy

* No prior radiotherapy to \> 25% of bone marrow
* No prior radioisotope therapy
* Concurrent local palliative radiotherapy for pain allowed

Surgery

* See Disease Characteristics
* At least 4 weeks since prior surgery

Other

* No other prior cytostatic treatment
* Concurrent bisphosphonates allowed provided patient has begun treatment prior to study entry

  * No initiation of bisphosphonates during study treatment
C: Inclusion Criteria:

Fit for the treatments and estimates life expectancy of 10 years Registration with eligible primary care practice

Exclusion Criteria:

Unable to give written informed consent. Concomitant or past malignancy.
D: Inclusion Criteria Participants must fulfil all the criteria in one of the following three categories. Additionally, all patients must fulfil the criteria in Section 4.

1. High-Risk Newly-Diagnosed Non-Metastatic Node-Negative (N0/Nx) Disease

   Both:

   • At least two of: T category T3/4, PSA≥40ng/ml or Gleason sum score 8-10

   • Intention to treat with radical radiotherapy (unless there is a contra-indication)

   OR
2. Newly-Diagnosed Metastatic Or Node-Positive Disease

   At least one of:
   * Stage Tany N+ M0
   * Stage Tany Nany M+

   OR
3. Previously Radically Treated, Now Relapsing (Prior Radical Surgery And/or Radiotherapy)

   At least one of:

   • PSA ≥4ng/ml and rising with doubling time less than 6 months

   • PSA ≥20ng/ml

   • N+

   • M+

   AND
4. General Inclusion Criteria Required For All Participants

<!-- -->

1. Histologically confirmed prostate adenocarcinoma
2. Intention to treat with long-term androgen deprivation therapy
3. Fit for all protocol treatment and follow up, WHO performance status 0-2
4. Have completed the appropriate investigations prior to randomisation
5. Adequate haematological function: neutrophil count ≥1.5x109/l and platelets ≥100x109/l
6. Adequate renal function, defined as GFR ≥30ml/min/1.73m2
7. Written informed consent
8. Willing and expected to comply with follow up schedule
9. Using effective contraceptive method if applicable

<!-- -->

1. Medical contraindications to the trial medications are given in Section 6
2. For WHO performance status definitions see Appendix A

5. General Exclusion Criteria

Patients must not fulfil any of the criteria below:

1. Prior systemic therapy for locally-advanced or metastatic prostate cancer (1) (except as listed in the protocol section 4.3)
2. Prior exposure to hormone therapy for a duration of \> 12 months, or prior exposure completing \< 12 months before randomisation (see section 4.3.1 for permitted prior exposure details)
3. Metastatic brain disease or leptomeningeal disease
4. Abnormal liver functions consisting of any of the following:

   • 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)

   • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 x ULN - site must indicate at randomisation whether one or both tests are performed at site. Where both results are available both must confirm eligibility.
5. Any other previous or current malignant disease which, in the judgement of the responsible clinician, is likely to interfere with STAMPEDE treatment or assessment
6. Any surgical wound (e.g. TURP) which in the judgement of the responsible clinician may interfere with or be exacerbated by protocol treatment
7. Participant with significant cardiovascular disease, including:

   • Severe/unstable angina

   • Myocardial infarction less than 6 months prior to randomisation

   • Arterial thrombotic events less than 6 months prior to randomisation

   • Clinically significant cardiac failure requiring treatment, defined as New York Heart Association (NYHA) class II or above (1)

   • Cerebrovascular disease (e.g. stroke or transient ischaemic episode) less than 6 months prior to randomisation
   * Any other significant cardiovascular disease that in the investigator's opinion means the participant is unfit for any of the study treatments.

     1. Excluding participants receiving docetaxel as part of SOC
     2. NYHA classifications can be found in Appendix A

6. Comparison-specific eligibility criteria

In addition to the general inclusion and exclusion criteria, the following comparison-specific eligibility criteria apply.

For Randomisation to the "Metformin Comparison"

Please note from protocol v20 only patients willing to participate in the metabolic sub study should be randomised to the metformin comparison. The sub study will be conducted in a limited number of sites, see section 4.7.4 for further information.

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":

• HbA1c \<48mmol/mol (equivalent to \<6.5%) (1)

• Adequate renal function, defined as GFR ≥45ml/min/1.73m (except for Switzerland (2))

• No history of lactic acidosis or pre-disposing conditions

* Not current or previous treatment with metformin
* No contra-indications to metformin
* No current or previous medication for treatment of diabetes
* Willingness to join the metabolic sub study

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.

(2) Except Switzerland, please refer to SAKK appendix for local guidance

For Randomisation To The "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":

• ≤8 weeks of anti-androgen (AR-antagonists) use

• Maximum of 1 dose of monthly or 4-weekly LHRH agonist/antagonist

• No prior LHRH agonist injection with a stated duration of effect greater than 1 month

• ≤12 weeks since first dose of any hormone therapy

• Not had a bilateral orchidectomy

• No use of cyproterone acetate (36) prior to randomisation

• No known porphyria

* No known history of deep vein thrombosis or pulmonary embolism confirmed radiologically
* No known thrombophilic disorder (e.g. Protein C, Protein S, antithrombin deficiency)
* Not yet started SOC abiraterone, enzalutamide or apalutamide

Answer: D