Inclusion criteria, exclusion criteria and study summary
1. Patient must be ≥ 18 years of age (≥ 20 years of age in Japan), at the time of signing the informed consent. 2. Histologically-confirmed prostate adenocarcinoma. Note: adenocarcinoma must be the predominant histological pattern in previous biopsies and patients with neuroendocrine or small cell cancers in any previous prostate biopsies are not eligible. 3. 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). Note: Local lymph node involvement is not considered metastatic disease. 4. Patient must have been previously treated with a next generation hormonal agent (NHA), ie, 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. 5. Evidence of mCRPC with progression of disease despite androgen deprivation therapy (ADT) and after anti-androgen withdrawal, if applicable, as documented by one or more of the following: a. Progression of measurable soft tissue disease b. Bone scan progression (appearance of ≥ 2 new lesions on bone scan, attributable to prostate cancer) c. Rising PSA, as defined by increasing levels on at least two consecutive assessments, following a prior assessment taken as a reference value, where all of the following are met: • The assessments are at least 1 week apart, with the first assessment at least 1 week later than the reference value • Progressive increase of at least 50% in each of the 2 assessments after the reference value, without an intervening decrease between assessments. The last value prior to study entry is ≥ 2 ng/mL 6. Serum testosterone level ≤ 50 ng/dL. 7. Candidate for docetaxel and steroid therapy. 8. Ongoing ADT with LHRH agonist, LHRH antagonist, or bilateral orchiectomy. 9. Eastern Cooperative Oncology Group (ECOG)/World Health Organisation (WHO) performance status 0 to 1 and anticipated minimum life expectancy of 12 weeks. 10. Able and willing to swallow and retain oral medication. 11. 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 (see Section 8.7.2). (Patient consents to provision of this tissue sample; this inclusion criterion does not apply to patients in China). 12. Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm: • Sterilisation (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). • Patients should use barrier contraception (ie, condoms) during sexual intercourse from the time of screening until 16 weeks after discontinuation of study drug. It is not known whether the pre clinical changes seen in the male animal reproductive organs, after treatment with capivasertib, will be fully reversible or will permanently affect the ability to produce healthy sperm following treatment. Therefore, if patients wish to father children, they should be advised to arrange for collection of sperm samples prior to the start of study treatment; refer to Section 5.3.4. Female partners of childbearing potential should be advised to use a highly effective form of contraception during their partner’s participation on the trial and for 16 weeks after discontinuation of study treatment. 13. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and CSP. 14. Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative.
1. Radiotherapy with a wide field of radiation (affecting ≥ 30% of the bone marrow) within 4 weeks before the start of study treatment. • Samarium must have been completed 4 weeks prior to the first dose of therapy. • Strontium and lutetium Lu 177 therapy must have been completed at least 12 weeks prior to the first dose of therapy. • Radium-233 must have been completed at least 6 weeks prior to the first dose of therapy. 2. 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. 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. Investigator judgment of 1 or more of the following cardiac criteria: • Mean resting corrected QT corrected by Fridericia’s formula (QTcF) interval > 470 ms, obtained from triplicate electrocardiograms (ECGs) performed at screening. • Medical history significant for arrhythmia (eg, multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Patients with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted to enter the study. • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia of Grade ≥1, potential for Torsades de Pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first-degree relative, history of QTc prolongation associated with other medications that required discontinuation of the medication. See Appendix D for guidance on patients receiving any concomitant medication known to prolong the QTc interval and with the potential to interact with capivasertib. • Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, vascular stent, myocardial infarction, unstable angina pectoris, congestive heart failure New York Heart Association (NYHA) Grade ≥ 2. • Uncontrolled hypotension: systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 50 mmHg. • Cardiac ejection fraction outside institutional range of normal or < 50% (whichever is higher) as measured by echocardiogram (ECHO) (or multiple-gated acquisition [MUGA] scan if an ECHO cannot be performed or is inconclusive). 5. Clinically significant abnormalities of glucose metabolism as defined by any of the following: • Diabetes mellitus type I or diabetes mellitus type II requiring insulin treatment. • HbA1c ≥ 8.0% (63.9 mmol/mol). 6. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: • Absolute neutrophil count < 1.5 x 109/L (If sites only collected % differential of neutrophils, the absolute neutrophil count will need to be calculated for eligibility, based on leukocytes [white blood cell] (WBC) and % of neutrophils). • Platelet count < 100 x 109/L. • Haemoglobin < 9 g/dL (< 5.59 mmol/L). [Note: any blood transfusion must be > 14 days prior to the determination of a haemoglobin ≥ 9 g/dL (≥ 5.59 mmol/L)] (If anaemia is present, it must be able to be managed by standard supportive care). • Alterations in hepatic function tests defined as any one of the following: - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x upper limit of normal (ULN) if no demonstrable liver metastases or > 5 x ULN in the presence of liver metastases - Total bilirubin > 1.5 x ULN (> 3 x ULN in the presence of documented Gilbert's syndrome) - Serum alkaline phosphatase (ALP) levels > 6 x ULN, plus either bilirubin > ULN or AST and/or ALT > 3.5 × ULN. 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. • Creatinine clearance (CrCL) < 50 mL/min per the Cockcroft-Gault formula (using actual body weight) without the need for chronic dialysis therapy. 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. Screening for chronic conditions is not required. 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 (eg, 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. 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. 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). Known history of drug or alcohol abuse within 1 month of screening. Note, please see Appendix D for restricted concomitant medications with capivasertib, including select antiretroviral therapy. 14. Treatment with any of the following: • Prior chemotherapy for CRPC. Chemotherapy for metastatic or localized HSPC (including docetaxel) is allowed provided that chemotherapy was completed ≥ 6 months before randomisation and progression of the prostate cancer occurred ≥ 6 months after the completion of therapy. • Prior exposure to AKT inhibitors or PI3K inhibitors • 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. • Any other immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents (except ADT) 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) as agreed by the sponsor. • 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 (See Appendix D for details). • Due to the important potential risk of QT prolongation derived from the capivasertib non-clinical development programme, it is recommended that administration of any drugs, other than ADT (at screening or during study conduct), considered essential for patient management which are known to prolong the QT interval is discussed with the medical monitor and that consideration should be given for close monitoring of QT interval prolongation through frequent ECG and electrolyte monitoring. See Appendix D for additional guidance regarding drugs known to prolong the QT interval and that are at risk for a potential PK interaction with capivasertib. 15. Participation in another clinical study with an investigational product administered in the last 30 days or 5 half-lives, whichever is longer. 16. History of hypersensitivity to active or inactive excipients of capivasertib, docetaxel, or drugs with a similar chemical structure or class. 17. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 18. 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. 19. Any restriction or contraindication based on the local prescribing information that would prohibit the use of docetaxel.
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