This study will assess the efficacy and safety of capivasertib plus abiraterone (+prednisone/prednisolone) plus androgen deprivation therapy (ADT) versus placebo plus abiraterone (+prednisone/prednisolone) plus ADT in participants with mHSPC whose tumours are characterised by PTEN deficiency. The intention of the study is to demonstrate that in participants with mHSPC, the combination of capivasertib plus abiraterone (+prednisone/prednisolone) plus ADT is superior to placebo plus abiraterone (+prednisone/prednisolone) plus ADT in participants with mHSPC characterised by PTEN deficiency with respect to radiographic progression-free survival (rPFS) per 1) Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for soft tissue and/or Prostate Cancer Working Group (PCWG3) for bone as assessed by the investigator 2) death due to any cause.

Inclusion Criteria:

• Asymptomatic or mildly symptomatic, histologically-confirmed de novo hormone-sensitive prostate adenocarcinoma without small-cell tumours diagnosed within 180 days of randomisation
• Consent to provide a FFPE tissue block (preferred) or slides. Tissue from bone metastases is not acceptable
• A valid PTEN IHC result indicating PTEN deficiency (centralized testing)
• Metastatic disease documented prior to randomisation by clear evidence of ≥ 1 bone lesion and/or ≥ 1 soft tissue lesion accurately assessed at baseline and suitable for repeated assessment with CT and/or MRI. PSMA PET identification only will not be eligible
• Candidate for abiraterone and steroid therapy
• Ongoing ADT with GnRH analogue, or LHRH agonists or antagonist, or bilateral orchiectomy (regardless of method) is from 0 days to a max. of 93 days prior to randomisation
• Eastern Cooperative Oncology Group (ECOG)/WHO performance status 0 to 1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks
• Able and willing to swallow and retain oral medication
• 7-day Brief Pain Inventory-Short Form (BPI-SF) and Brief Fatigue Inventory(BFI) questionnaires and the analgesic diary during screening completed. Participants must complete a minimum of 4 successful assessments within a 7-day period prior to randomisation.
• Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm
• Capable of giving signed informed consent
• Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples

Exclusion Criteria:

• Prior radical prostatectomy or definitive radiotherapy with therapeutic intent for prostate cancer. Palliative radiotherapy is allowed providing any wide field radiation therapy is completed more than 4 weeks before the start of study treatment

• Major surgery (excluding placement of vascular access, transurethral resection of prostate, bilateral orchiectomy, or internal stents) within 4 weeks of the start of study treatment

• Brain metastases, or spinal cord compression (unless spinal cord compression is asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment)

• Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease

• Any of the following cardiac criteria:

  i. Mean resting corrected QT interval (QTc) > 470 msec obtained from triplicate ECGs ii. History of QT prolongation associated with other medications that required discontinuation of that medication.

iii. Family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.

iv. Medical history significant for arrhythmia which is symptomatic or requires treatment, symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia.

v. Any clinically important abnormalities in conduction or morphology of resting ECG (eg, complete left bundle branch block, third-degree heart block) vi. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalaemia, potential for torsades de pointes, congenital long QT syndrome, or any concomitant medication known to significantly prolong the QT interval vii. Experience of any of the following procedures or conditions in the preceding 3 months: coronary artery bypass graft, angioplasty, myocardial infarction, angina pectoris.

viii. Congestive heart failure NYHA Grade ≥ 2 ix. Symptomatic hypotension - systolic blood pressure (SBP) <90 mmHg and/or diastolic blood pressure (DBP) <50 mmHg x. Uncontrolled hypertension (SBP ≥ 160 mmHg or DBP ≥ 95 mmHg).

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

  i. Patients with diabetes mellitus type 1 or diabetes mellitus type 2 requiring insulin treatment ii. HbA1c ≥8.0% (63.9 mmol/mol)

• Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

  i. Absolute neutrophil count < 1.5x 10^9/L ii. Platelet count < 100x 10^9/L iii. Haemoglobin < 9 g/dL (< 5.59 mmol/L) iv. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2.5x upper limit of normal (ULN) if no demonstrable liver metastases or > 5x ULN in the presence of liver metastases. Elevated alkaline phosphatase (ALP) is not exclusionary if due to the presence of bone metastases and liver function is otherwise considered adequate in the investigator's judgement v. Total bilirubin > 1.5x ULN (participants with confirmed Gilbert's syndrome may be included in the study with a higher value) vi. Creatinine clearance < 50 mL/min (measured or calculated by Cockcroft and Gault equation)

• As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, or known active infection including hepatitis B, hepatitis C, and HIV

• unevaluable for both bone and soft tissue progression as defined by meeting both of the following criteria: i. a "superscan" of bone scan, and ii. no soft tissue lesion that can be assessed by RECIST criteria

• Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection, or other condition that would preclude adequate absorption of capivasertib

• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent

• Evidence of dementia, altered mental status, or any psychiatric condition that would prohibit understanding or rendering of informed consent

• Previous allogeneic bone marrow transplant or solid organ transplant

• History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer and curatively treated in situ disease.

• Treatment with any of the following:

  i. Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment ii. Any investigational agents or study drugs from a previous clinical study within 30 days or 5 half-lives (whichever is longer) of the first dose of study treatment iii. Any other chemotherapy, immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents within 3 weeks of the first dose of study treatment. A longer washout may be required for drugs with a long half-life (eg, biologics) iv. Strong inhibitors or strong inducers of CYP3A4 within 2 weeks before the start of study treatment (3 weeks for St John's wort). Note that adequate washout or dose reduction may be required for some CYP3A substrates prior to initiating Capivasertib dosing.

• Drugs known to significantly prolong the QT interval and associated with Torsades de Pointes within 5 half-lives of the first dose of study treatment

• Participation in another clinical study with an investigational product administered in the last 30 days or 5 half-lives, whichever is longer.

• History of hypersensitivity to active or inactive excipients of capivasertib, abiraterone, or drugs with a similar chemical structure or class.

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.

• Any restriction or contraindication based on the local prescribing information that would prohibit the use of abiraterone.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. "Yes", indicates that AZ are accepting requests for IPD, but this does not mean all requests will be approved.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA/PhRMA Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data via secure research environment Vivli.org. A Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.