Patients with localised prostate cancer can be treated by radical prostatectomy (prostate gland removal surgery) or radiotherapy. Around 15% of men with prostate cancer are diagnosed with high risk disease meaning they are more likely to suffer treatment failure, disease progression and mortality. To date little progress has been made towards identifying effective treatment strategies that might delay or prevent disease recurrence in this patient population. Better identification of patients at high risk of relapse and improvements in therapy are therefore research priorities.

A protein named Mammalian Target of Rapamycin (mTOR) is known to play an important role in the development of prostate cancer. mTOR forms two protein complexes (mTORC1 and mTORC2) and sends signals helping cancer cells to grow while controlling their energy use. Blocking the function of mTOR, with an inhibitor such as AZD2014, might shut down the supply of energy supply to tumour cells leading to reduced cell growth and potentially slowing the progression of the disease.

The purpose of this study is to investigate the molecular pharmacology of AZD2014 treatment given to patients with prostate cancer prior to radical prostatectomy. The feasibility, safety and tolerability of a short course of AZD2014 will also be assessed.

Eligible patients will be required to take 50mg AZD2014 tablets twice daily for 15 days prior to radical prostatectomy.

Immunohistochemistry will be carried out on prostate tumour biopsies taken at baseline and at radical prostatectomy in order to detect phosphorylated biomarkers of mTOR signalling and determine the amount of mTORC1 and mTORC2 signalling inhibition caused by AZD2014 treatment.

On the day of radical prostatectomy, blood samples will be collected pre- and at specified times post- dose for pharmacokinetic analyses.

Additional blood samples will be collected to study any genetic changes to the DNA, RNA and circulating tumour DNA (ctDNA) which may have been caused by AZD2014 treatment.

Refer to the "outcome measures" section for further information.

Inclusion Criteria:

• Men aged 18 years old or older
• ECOG performance status of 0 or 1
• Clinical diagnosis of Intermediate (one or more of stage T2, or PSA >10ng/mL, or Gleason score of at least 7) or High Risk Prostate Cancer (one or more of stage T2c, or PSA >20ng/mL, or Gleason score of at least 8)
• Patient suitable for radical prostatectomy, following discussion at specialist MDT and subsequent review by surgical team
• Willing to use barrier contraceptive method, e.g. condom & spermicide
• Adequate bone marrow reserve or organ function (as specified in the study protocol)
• Normal chest radiograph and oxygen saturations, OR normal CT thorax

Exclusion Criteria:

• Contraindication to AZD2014 (as specified in the study protocol)
• Patients who have experienced any of the following procedures in the past 12 months: coronary artery bypass graft; angioplasty; vascular stent; myocardial infarction; angina pectoris; congestive heart failure (New York Heart Association grade of 2 or above); ventricular arrhythmias requiring continuous therapy; supraventricular arrhythmias including atrial fibrillation, which are uncontrolled; haemorrhagic or thrombotic stroke including transient ischaemic attacks or any other CNS bleeding.
• Previous chemotherapy, biological therapy, radiation therapy, androgens, thalidomide, immunotherapy, other anticancer agents and/or investigational agents within 28 days of starting study treatment.
• Major surgery within 4 weeks prior to study entry (excluding placement of vascular access), or minor surgery within 2 weeks of entry into the study
• Potent or moderate inhibitors and inducers of CYP2C8 if taken within the stated wash-out period: Gemfibrozil, trimethoprim, glitazones, montelukast, deferasirox and quercetin (1-week minimum wash out period)
• Any haematopoietic growth factors, e.g. G-CSF, GM-CSF, within 4 weeks prior to receiving study drug
• As judged by the Investigator, any evidence of severe or uncontrolled systemic disease (as specified in the study protocol)
• Abnormal ECHO or MUGA at baseline
• Mean resting QTc of 470msec or above (as per local reading)
• Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation, or risk of arrythmic events (examples specified in study protocol). History of Torsades de Pointes.
• Patients with Diabetes Type I or uncontrolled Type II as judged by the investigator
• Judgement by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.
• Unable to provide informed consent