Inclusion Criteria

HIGH-RISK NEWLY DIAGNOSED NON-METASTATIC NODE-NEGATIVE DISEASE

Both:

At least two of:

- Stage T3/4, PSA≥40ng/ml or Gleason sum score 8-10

- Intention to treat with radical radiotherapy (unless there is a contra-indication;
exemption can sought in advance of consent, after discussion with MRC CTU)

OR NEWLY DIAGNOSED METASTATIC OR NODE-POSITIVE DISEASE

At least one of:

- Stage Tany N+ M0

- Stage Tany Nany M+

OR PREVIOUSLY TREATED WITH RADICAL SURGERY AND/OR RADIOTHERAPY, NOW RELAPSING1

At least one of:

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

- PSA ≥20ng/ml

- N+

- M+

AND FOR ALL PATIENTS I. Histologically confirmed prostate adenocarcinoma II. Intention to
treat with long-term androgen deprivation therapy III. Fit for all protocol treatment2 and
follow-up, WHO performance status 0-23 IV. Have completed the appropriate investigations
prior to randomisation V. Adequate haematological function: neutrophil count >1.5x109/l
and platelets >100x109/l VI. Estimated creatinine clearance >30ml/min VII. Serum potassium
≥3.5mmol/L VIII. Written informed consent IX. Willing and expected to comply with
follow-up schedule X. Using effective contraceptive method if applicable

PATIENT EXCLUSION CRITERIA Patients must not fulfil any of the criteria, below. I. Prior
systemic therapy for locally advanced or metastatic prostate cancer except as listed in
Section 4.1.3 of the protocol.

II. Metastatic brain disease or leptomeningeal disease

III. 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 IV. Any other previous or current malignant
disease which, in the judgement of the responsible physician, is likely to interfere with
STAMPEDE treatment or assessment V. Patients with active peptic ulceration,
gastrointestinal bleeding, inflammatory bowel disease VI. Symptomatic peripheral
neuropathy grade <2 (NCI CTC)5 VII. Any surgery (e.g. TURP) performed within the past 4
weeks

VIII. Patients with significant cardiovascular disease such that, in the investigator's
opinion, the patient is unfit for any of the study treatments. This might include:

- 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 (NYHA II-IV)6

- Cerebrovascular disease (e.g. stroke or transient ischaemic episode) less than 2
years prior to randomisation

- Patients with uncontrolled hypertension defined as systolic BP greater or equal than
160 mmHg or diastolic BP greater or equal than 95 mmHg IX. Patients who have been
scheduled to have major dental extractions within the next 2 years X. Patients
receiving treatment with drugs known to induce CYP3A4 (including phenytoin,
carbamazepine, Phenobarbital)7 XI. Prior exposure to abiraterone XII. Prior
chemotherapy for prostate cancer XIII. Prior therapy with zoledronic acid other than
short-term treatment for hypercalcaemia XIV. Prior exposure to policy of long-term
hormone therapy before randomisation (unless as described in Section 4.4.2 of the
protocol)

SELECTION CRITERIA FOR COMPARISON OF RESEARCH (M1) RT FOR METASTATIC DISEASE

All patients meeting criteria above are eligible for the trial, but not all can be
allocated to the research (M1) radiotherapy arm. The selection criteria for this "RT to
the prostate" comparison are:

- Newly diagnosed prostate cancer

- Demonstrable M1 disease

- No contraindication to radiotherapy e.g. no previous pelvic radiotherapy,

- No previous radical prostatectomy

Patients meeting these criteria will have a chance to be allocated to Arms A and H.