A multicentre prospective, randomised, phase II interventional study in mCRPC patients previously treated with 1-2 lines of chemotherapy and at least 12 weeks of abiraterone with a safety run-in and single stage phase II expansion cohort.

Patients with mCRPC will receive enzalutamide and AZD5363 (or enzalutamide and placebo in the randomised phase II) until confirmed disease progression.

The trial aims to identify the safety and tolerability of enzalutamide and AZD5363 and identify recommended phase II dose of AZD5363 (phase I safety run-in). The randomised phase II will estimate and compare the anti-tumour activity of AZD5363 and enzalutamide, and placebo and enzalutamide as measured by response. The single stage phase II expansion cohort will estimate the anti-tumour activity of AZD5363 and enzalutamide in patients who have previously progressed on enzalutamide alone.

Inclusion Criteria:

1. Written informed consent.

2. Histological diagnosis of adenocarcinoma of the prostate and with tumour tissue accessible for research analyses for this trial (e.g. Phosphatase and Tensin Homologue (PTEN) testing). Patients who have no histological diagnosis must be willing to undergo a biopsy to prove prostate adenocarcinoma.

3. Metastatic Castration-Resistant Prostate Cancer (mCRPC).

4. Progressed after 1 or 2 lines of taxane based chemotherapy.

5. Progressed after abiraterone (pre or post chemotherapy). Patients must have received at least 12 weeks of treatment with abiraterone.

6. Age ≥18 years.

7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.

8. PSA ≥ 10ng/ml.

9. Documented willingness to use an effective means of contraception while participating in the study and for 12 months post last dose of treatment

10. Documented ongoing castrate serum testosterone <50 ng/dL (<2.0 nM).

11. Received prior castration by orchiectomy and/or ongoing Luteinizing Hormone-Releasing Hormone (LH-RH) agonist treatment.

12. Progression of disease by PSA utilizing PCWG2 criteria and at least another of the following criteria;

    1. Bone scan: disease progression as defined by at least 2 new lesions on bone scan.
    2. Soft tissue disease progression defined by modified RECIST 1.1.
    3. Clinical progression with worsening pain and the need for palliative radiotherapy for bone metastases.

    PHASE I SAFETY RUN IN and EXPANSION COHORT - inclusion criteria:

13. Willing to have a biopsy to obtain tumour tissue for biomarker analyses prior to and after treatment.

    SINGLE STAGE PHASE II EXPANSION COHORT ONLY - inclusion criteria:

14. Prior exposure to enzalutamide of at least 12 weeks is required with documented disease progression biochemically and/or radiologically by PCWG2 or RECIST 1.1 criteria. Patients should have received at least 12 weeks of enzalutamide outside of the trial with evidence of disease progression (by PSA with 3 rising values as per PCWG2 criteria or soft tissue progression as per RECIST v1.1).

15. Archival tumour tissue available for the analysis of PTEN loss by the central laboratory

Exclusion Criteria:

1. Prior treatment with enzalutamide (MDV3100) (not applicable for the phase I safety run in or for the single stage phase II expansion cohort, see inclusion criteria 14).

2. Prior treatment with Phosphatidylinositide 3-kinases (PI3K), AKT, TOR kinase or Mammalian target of rapamycin (mTOR) inhibitors (see Appendix C).

3. Surgery, chemotherapy, or other anti-cancer therapy within 4 weeks prior to trial entry/randomisation into the study (6 weeks for bicalutamide). Any other therapies for prostate cancer, other than Gonadotropin-releasing hormone (GnRH) analogue therapy, such as progesterone, medroxyprogesterone, progestins (megestrol), or 5-alpha reductase inhibitors (e.g., finasteride or dutasteride), must be discontinued at least 2 weeks before the first dose of study drug.

4. Participation in another clinical trial and any concurrent treatment with any investigational drug within 4 weeks prior to trial entry / randomisation.

5. Prior limited field radiotherapy within 2 weeks or wide field radiotherapy within 4 weeks of trial entry / randomisation.

6. History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumours, brain metastases, or alcoholism.

7. History of loss of consciousness or transient ischemic attack within the previous 12 months of trial entry / randomisation.

8. Known brain or leptomeningeal involvement.

9. Use of potent inhibitors or inducers of Cytochrome P450 isoenzymes (CYP3A4, CYP2C9, CYP2C19 and CYP2D6) (see Appendix B) within 2 weeks before trial entry / randomisation (3 weeks for St John's Wort) must be avoided.

10. Clinically significant abnormalities of glucose metabolism as defined by any of the following:

    1. Diagnosis of diabetes mellitus type I

    2. Fasting plasma glucose ≥ 7.0 mmol/L for those patients without a pre-existing diagnosis of Type 2 diabetes mellitus

       ≥ 9.3 mmol/L for those patients with a pre-existing diagnosis of Type 2 diabetes mellitus

    3. Glycosylated haemoglobin (HbA1C) ≥8.0% at screening (63.9 mmol/mol) (conversion equation for HbA1C [IFCC-HbA1C (mmol/mol) = [DCCT-HbA1C (%) - 2.15] x 10.929)

    4. Requirement for insulin for routine diabetic management and control

    5. Requirement for more than two oral hypoglycaemic medications for routine diabetic management and control

11. Inadequate organ and bone marrow function as evidenced by:

    1. Haemoglobin <85 g/L
    2. Absolute neutrophil count <1.0 x 109/L
    3. Platelet count < 75 x 109/L
    4. Albumin ≤25 g/dL
    5. Aspartate Transaminase (AST) / Serum Glutamic-Oxaloacetic Transaminase (SGOT) and/or Alanine Transaminase (ALT) / Serum Glutamic Pyruvate Transaminase (SGPT) ≥ 2.5 x Upper Limit of Normal (ULN) (≥ 5 x ULN if liver metastases present)
    6. Total bilirubin ≥ 1.5 x ULN (except for patient with documented Gilbert's disease)
    7. Serum Creatinine > 1.5 x ULN

12. Inability or unwillingness to swallow oral medication.

13. Malabsorption syndrome or other condition that would interfere with enteral absorption.

14. Any of the following cardiac criteria;

    1. Mean resting corrected QT interval (QTcF) >470msec obtained from 3 consecutive ECGs taken within 5 minutes
    2. Any clinically important abnormalities in rhythm, conduction, or morphology of a resting ECG (e.g., complete left bundle branch block, third degree heart block)
    3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval or with a potential for Torsades de Pointes
    4. Experience of any of the following procedures or conditions in the preceding six months:coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure New York Heart Association (NYHA) ≥ Grade2
    5. Uncontrolled hypotension defined as - systolic blood pressure (BP) <90 mmHg and/or diastolic BP <50 mmHg

15. Clinically significant history of liver disease consistent with Child-Pugh Class B or C, including viral or other hepatitis, current alcohol abuse, or cirrhosis.

16. Any other finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patients at high risk from treatment complications.

17. Need for chronic corticosteroid therapy of >10 mg of prednisolone or >0.5mg of dexamethasone per day or an equivalent dose of other anti-inflammatory corticosteroid, for the use of concomitant steroids on this trial please refer to section 12.1. Patients in which corticosteroids cannot be stopped prior to entering the trial are allowed a maximum of 10mg of prednisolone per day or equivalent. In the case of corticosteroid discontinuation, a 2-week (14 days) washout is required with a mandatory PSA check prior to starting the trial. If the PSA has declined compared to the value obtained prior to stopping corticosteroids, patients will not be eligible for study. Patients can only enter the study with a confirmed PSA increase.

18. Malignancies other than prostate cancer within 5 years prior to trial entry / randomisation, except for adequately treated basal or squamous cell skin cancer.

19. Unresolved clinically significant toxicity from prior therapy except for alopecia and Grade 1 peripheral neuropathy.

20. Inability to comply with study and follow-up procedures.

21. Patients with predominately small cell or neuroendocrine differentiated prostate cancer are not eligible.](streamdown:incomplete-link)