CAPItello-280

1) Histologically-confirmed prostate adenocarcinoma without neuroendocrine or small cell cancers.

2) Metastatic disease documented prior to randomisation by clear evidence of ≥ 1 bone lesion (defined as 1 lesion with positive uptake on bone scan) and/or ≥ 1 soft tissue lesion (measurable or non-measurable).

3) Patient must have been previously treated with a next generation hormonal agent (NHA), i.e., abiraterone, enzalutamide, apalutamide or darolutamide, for prostate cancer for at least 3 months and shown evidence of disease progression (radiological or via PSA assessment) while receiving the NHA.

4) Evidence of mCRPC with progression of disease despite androgen deprivation therapy (ADT) and after anti-androgen withdrawal if applicable.

5) Serum testosterone level ≤ 50 ng/dL.

6) Candidate for docetaxel and steroid therapy.

7) Ongoing ADT with LHRH agonist, LHRH antagonist, or bilateral orchiectomy.

8) Eastern Cooperative Oncology Group (ECOG)/World Health Organisation (WHO) performance status 0 to 1 and anticipated minimum life expectancy of 12 weeks.

9) Confirmation that archival formalin-fixed paraffin-embedded (FFPE) tumour tissue sample which meets the minimum pathology and sample requirements is available to send to the central laboratory.

10) Able and willing to swallow and retain oral medication.

11) Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm.

1) Radiotherapy with a wide field of radiation within 4 weeks before start of study treatment.

2) Major surgery (excl. placement of vascular access, transurethral resection of prostate, bilateral orchiectomy, internal stents) within 4 weeks of start of study treatment.

3) 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).

4) Any of the following cardiac criteria:
|— a) Mean resting corrected QT interval (QTc) >470 msec from 3 consecutive ECGs.
|— b) Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG.
|— c) 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 prolong the QT interval.
|— d) Experience of any of the following procedures or conditions in the preceding 6months: coronary artery bypass graft, vascular stent, myocardial infarction, unstable angina pectoris, congestive heart failure NYHA Grade ≥2.
|— e) Uncontrolled hypotension – systolic blood pressure <90 mmHg and/or diastolic blood pressure <50 mmHg.
|— f) Cardiac ejection fraction outside institutional range of normal or <50% (whichever is higher) as measured by echocardiogram (or multiple-gated acquisition scan if an echocardiogram cannot be performed or is inconclusive).

5) Clinically significant abnormalities of glucose metabolism as defined by any of the following:
|— a) Patients with diabetes mellitus (DM) type 1 or DM type 2 requiring insulin treatment ii. HbA1c ≥8.0% (63.9 mmol/mol).

6) Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
|— a) Absolute neutrophil count < 1.5x 10^9/L.
|— b) Platelet count < 100x 10^9/L.
|— c) Haemoglobin < 9 g/dL (< 5.59 mmol/L).
|— d) 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.
|— e) Total bilirubin > 1.5x ULN (participants with confirmed Gilbert’s syndrome may be included in the study with a higher value).
|— f) Creatinine clearance < 50 mL/min per the Cockcroft and Gault formula without the need for chronic dialysis.

7) As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, renal transplant and active bleeding diseases), which, in the investigator’s opinion, makes it undesirable for the patient to participate in the study or that would jeopardise compliance with the protocol.

8) 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.

9) Any other disease, 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.

10) Previous allogeneic bone marrow transplant or solid organ transplant.

11) History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥5 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy.

12) Persistent toxicities (CTCAE Grade ≥2) caused by previous anticancer therapy, excluding alopecia. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (e.g., hearing loss) after consultation with the medical monitor.

13) Known to have active hepatitis infection, positive hepatitis C antibody, hepatitis B virus surface antigen, or hepatitis B virus core antibody at screening.

14) Known to have human immunodeficiency virus (HIV) with a CD4+ T-cell count < 350 cells/uL or a history of an acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the past 12 months.

15) Known to have active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).

16) Treatment with any of the following:
|— a) Prior chemotherapy for CRPC. Chemotherapy for metastatic or localized HSPC (including docetaxel) is allowed provided that chemotherapy was completed ≥ 6months before randomisation and progression of the prostate cancer occurred ≥ 6months after the completion of therapy.
|— b) Prior exposure to AKT inhibitors or PI3K inhibitors.
|— c) 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.
|— d) Any other immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents (except ADT) within 3 weeks of the first dose of study treatment.
|— e) Strong inhibitors or inducers of cytochrome P450 (CYP)3A4 within 2 weeks prior to the first dose of study treatment (3 weeks for St John’s wort), or drugs that are sensitive to inhibition of CYP3A4 within 1 week prior to the first dose of study treatment.

17) Drugs known to prolong the QT interval within 5 half-lives of the first dose of study treatment.

18) History of hypersensitivity to active or inactive excipients of capivasertib, docetaxel, or drugs with a similar chemical structure or class.

19) Any restriction or contraindication based on the local prescribing information that would prohibit the use of docetaxel.

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