Please select the eligibility criteria that correspond to the clinical trial below.
Title: The ProtecT Trial - Evaluating the Effectiveness of Treatments for Clinically Localised Prostate Cancer
Brief Summary: RATIONALE: Radical prostatectomy is surgery to remove the entire prostate. Radiation therapy uses high-energy x-rays or other types of radiation to kill tumor cells. Sometimes the tumor may not need treatment until it progresses. In this case, active surveillance may be sufficient. It is not yet known which treatment regimen is more effective for localized prostate cancer.

PURPOSE: This randomized phase III trial is studying active monitoring to see how well it works compared with radical prostatectomy or radiation therapy in treating patients with localized prostate cancer.


Options:
A: 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
B: 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

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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

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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
C: Inclusion Criteria:

* Histologically or cytologically confirmed prostate cancer
* Metastatic disease
* On androgen-deprivation therapy for \< 120 days
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

  * PS 2 eligible only if decline in PS is due to metastatic prostate cancer
* Absolute neutrophil count ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Bilirubin ≤ upper limit of normal (ULN)
* Alanine aminotransferase (ALT) ≤ 2.5 times ULN
* Creatinine clearance ≥ 30 mL/min
* Prothrombin time (PT) and international normalized ratio (INR) ≤ 1.5 times ULN (unless on therapeutic anticoagulation)
* Partial thromboplastin time (PTT) ≤ 1.5 times ULN (unless on therapeutic anticoagulation)
* Fertile patients must use effective contraception
* At least 4 weeks since prior major surgery and recovered from all toxicity prior to randomization
* Prior adjuvant or neoadjuvant hormonal therapy allowed provided the following are true:

  * Therapy was discontinued ≥ 12 months ago AND there is no evidence of disease, as defined by 1 of the following:

    * PSA \< 0.1 ng/dL after prostatectomy plus hormonal therapy
    * PSA \< 0.5 ng/dL and has not doubled above nadir after radiotherapy plus hormonal therapy
  * Therapy lasted no more than 24 months

    * Last depot injection must have expired by the 24-month mark
* Prior palliative radiotherapy allowed if commenced within 30 days before starting androgen deprivation
* Anti-androgen therapy allowed as single-agent therapy ≤ 7 days before medial castration to prevent flare
* More than 30 days (or 6 half-lives) (whichever is longer) since prior participation in another clinical trial
* Concurrent participation in nontherapeutic trials allowed
* Concurrent antiandrogen therapy (e.g., bicalutamide or flutamide) allowed, but not as sole hormonal therapy

Exclusion Criteria:

* Prostate-specific antigen (PSA) level has risen and met criteria for progression from its lowest point between the start of androgen-deprivation therapy and randomization
* Prior malignancy in the past 5 years except for basal cell or squamous cell carcinoma of the skin

  * Other malignancies that are considered to have low potential to progress (e.g., grade 2, T1a transitional cell carcinoma) may be allowed if approved by study chair
* Peripheral neuropathy \> grade 1
* History of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80
* Active cardiac disease, including the following:

  * Active angina
  * Symptomatic congestive heart failure
  * Myocardial infarction within the past 6 months
* Prior chemotherapy in adjuvant or neoadjuvant setting
* Prior hormone therapy in the metastatic setting
* Concurrent 5-alpha reductase inhibitors
* Simultaneous enrollment on Cancer and Leukemia Group B (CALGB) 90202
D: 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.

Answer: D