A Phase III Double-Blind, Randomised, Placebo-Controlled Study Assessing the Efficacy and Safety of Capivasertib+Abiraterone Versus Placebo+Abiraterone as Treatment for Patients With DeNovo Metastatic Hormone-Sensitive Prostate Cancer Characterised by PTEN Deficiency.

Condition: Hormone-Sensitive Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT04493853

Sponsor: AstraZeneca

Phase: Phase 3


  • Age: minimum 18 Years maximum 130 Years
  • Gender: Male

Inclusion Criteria:

  • Asymptomatic or mildly symptomatic, histologically-confirmed de novo hormone-sensitive prostate adenocarcinoma without small-cell tumours diagnosed within 180 days of randomisation
  • 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
  • Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm

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 randomisation
  • 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 3 consecutive ECGs ii. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third-degree heart block) iii. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, potential for torsades de pointes, 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 significantly prolong the QT interval iv. Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or NYHA or Class II to IV heart failure or cardiac ejection fraction measurement of < 50% v. Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure NYHA Grade ≥ 2 vi. Symptomatic hypotension
  • systolic blood pressure (SBP) <90 mmHg and/or diastolic blood pressure (DBP) <50 mmHg vii. Cardiac ejection fraction below the institutional range of normal or <50% (whichever is higher) as measured by echocardiogram (or multiple-gated acquisition [MUGA] scan if an echocardiogram cannot be performed or is inconclusive) viii. 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 109/L ii. Platelet count < 100x 109/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
  • Known additional malignancy that has had progression or has required active treatment in the last 3 years. Exceptions include basal cell carcinoma of the skin, and squamous cell carcinoma of the skin that has undergone potentially curative therapy
  • 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. Potent inhibitors or inducers of CYP3A4 within 2 weeks before the start of study treatment (3 weeks for St John's wort), or sensitive substrates of CYP3A4 with a narrow therapeutic window within 1 week before the start of study treatment
  • Drugs known to significantly prolong the QT interval within 5 half-lives of the first dose of study treatment
  • History of hypersensitivity to active or inactive excipients of capivasertib, abiraterone, or drugs with a similar chemical structure or class
  • Any restriction or contraindication based on the local prescribing information that would prohibit the use of abiraterone

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