Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomised Phase 3 Trial of Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer: ENZAMET
Brief Summary: The purpose of this study is to determine the effectiveness of enzalutamide, versus a conventional non-steroidal anti androgen (NSAA), when combined with a luteinizing hormone releasing hormone analog (LHRHA) or surgical castration, as first line androgen deprivation therapy (ADT) for newly diagnosed metastatic prostate cancer.


Options:
A: Inclusion Criteria:

* Metastatic Castration-Resistant Prostate Cancer Progression after one or two prior cytotoxic chemotherapies
* At least one chemotherapy must have contained docetaxel
* Eastern Cooperative Oncology Group (ECOG) Performance Status \<= 2
* Medical or surgical castration with testosterone \< 50 ng/dL
* Adequate bone marrow, hepatic and renal function
* Potassium \>= 3.5 mmol/L
* Able to swallow the study drug whole as a tablet
* Informed Consent

Exclusion Criteria:

* More than two prior cytotoxic chemotherapy regimens
* Prior Ketoconazole for prostate cancer
* Prior abiraterone acetate or other CYP17 inhibitor or investigational agents targeting the androgen receptor for prostate cancer
* Uncontrolled hypertension
* Active or symptomatic viral hepatitis or chronic liver disease
* History of pituitary or adrenal dysfunction
* Clinically significant heart disease
* Other malignancy
* Known brain metastasis
* GI disorder affecting absorption
* Not willing to use contraception
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: Men starting first line androgen deprivation therapy for metastatic prostate cancer.

Inclusion criteria:

1. Male aged 18 or older with metastatic adenocarcinoma of the prostate
2. Target or non-target lesions according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1
3. Adequate bone marrow function: Haemoglobin (Hb) ≥100g/L and White Cell Count (WCC) ≥ 4.0 x 109/L and platelets ≥100 x 109/L.
4. Adequate liver function: Alanine transaminase (ALT) \< 2 x Upper Limit of Normal (ULN) and bilirubin \< 1.5 x ULN, (or if bilirubin is between 1.5-2 x ULN, they must have a normal conjugated bilirubin). If liver metastases are present ALT must be \< 5 x ULN
5. Adequate renal function: calculated creatinine clearance \> 30 ml/min (Cockcroft-Gault)
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients with performance status 2 are only eligible if the decline in performance status is due to metastatic prostate cancer.
7. Study treatment both planned and able to start within 7 days after randomisation.
8. Willing and able to comply with all study requirements, including treatment and required assessments
9. Has completed baseline Health-Related Quality of Life (HRQL) questionnaires UNLESS is unable to complete because of limited literacy or vision
10. Signed, written, informed consent

Exclusion Criteria:

1. Prostate cancer with significant sarcomatoid or spindle cell or neuroendocrine small cell components
2. History of

   * seizure or any condition that may predispose to seizure (e.g., prior cortical stroke or significant brain trauma).
   * loss of consciousness or transient ischemic attack within 12 months of randomization
   * significant cardiovascular disease within the last 3 months including: myocardial infarction, unstable angina, congestive heart failure, ongoing arrhythmias of Grade \>2 \[National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.03\], thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism). Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed.
3. Life expectancy of less than 12 months.
4. History of another malignancy within 5 years prior to randomisation, except for either non- melanomatous carcinoma of the skin or, adequately treated, non-muscle-invasive urothelial carcinoma of the bladder (Tis, Ta and low grade T1 tumours).
5. Concurrent illness, including severe infection that might jeopardize the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety

   a. Human Immunodeficiency Virus (HIV)-infection is not an exclusion criterion if it is controlled with anti-retroviral drugs that are unaffected by concomitant enzalutamide.
6. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse;
7. Patients who are sexually active and not willing/able to use medically acceptable forms of barrier contraception.
8. Prior ADT for prostate cancer (including bilateral orchidectomy), except in the following settings:

   * Started less than 12 weeks prior to randomisation AND Prostate Specific Antigen (PSA) is stable or falling. The 12 weeks starts from whichever of the following occurs earliest: first dose of oral anti- androgen, LHRHA, or surgical castration.
   * In the adjuvant setting, where the completion of adjuvant hormonal therapy was more than 12 months prior to randomisation AND the total duration of hormonal treatment did not exceed 24 months. For depot preparations, hormonal therapy is deemed to have started with the first dose and to have been completed when the next dose would otherwise have been due, e.g. 12 weeks after the last dose of depot goserelin 10.8mg.
9. Prior cytotoxic chemotherapy for prostate cancer, but up to 2 cycles of docetaxel chemotherapy for metastatic disease is permitted.
10. Participation in other clinical trials of investigational agents for the treatment of prostate cancer or other diseases.
D: Inclusion Criteria:

* Metastatic castration-resistant prostate cancer (CRPC)
* Previous anti-androgen therapy and progression after withdrawal
* ECOG performance status of either 0 or 1
* Medical or surgical castration with testosterone less than 50 ng/dL
* Life expectancy of at least 6 months

Exclusion Criteria:

* Prior cytotoxic chemotherapy or biologic therapy for CRPC
* Prior ketoconazole for prostate cancer
* Known brain metastasis or visceral organ metastasis
* Use of opiate analgesics for cancer-related pain, including codeine and dextropropoxyphene, currently or anytime within 4 weeks of Cycle 1 Day 1

Answer: C