Clinical Trials

Inclusion Criteria: 

Age

• Male ≥ 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place), at the time of signing the ICF.

Type of Participant and Disease Characteristics

• Histologically documented prostate adenocarcinoma which is de novo or recurrent and castration-sensitive. Participants with pathologic features of small cell, neuroendocrine, sarcomatoid, spindle cell, or signet cell histology are not eligible.

• Metastatic disease as documented by the investigator prior to randomisation, with clear evidence of ≥ 1 bone lesion (defined as 1 lesion with positive uptake on bone scan) and/or ≥ 1 soft tissue lesion (measurable and/or non-measurable) that can be accurately assessed at baseline and is suitable for repeated assessment with CT and/or MRI. Participants with metastatic disease identified by PSMA-PET only, will not be eligible. Participants with disease limited to regional pelvic lymph nodes only are not eligible.

• Participant is receiving ADT with a GnRH analogue or has undergone bilateral orchiectomy starting ≥ 14 days and < 4 months prior to randomisation with no radiographic evidence of disease progression or rising PSA levels prior to first day of dosing. Participant must remain on ADT throughout the study and be a candidate for treatment with an NHA. Combination with first generation AR antagonists to counter testosterone flare is permitted until randomisation. Note: Due to the interaction between relugolix and enzalutamide, this combination of ADT and NHA is not allowed. Relugolix is otherwise permitted.

• ECOG performance status of 0 or 1 with no deterioration over the 2 weeks prior to randomisation.

• Minimum life expectancy of 6 months.

• Provision of a FFPE tumour tissue sample and a blood sample (for ctDNA) as specified in the Laboratory Manual is required to determine HRRm status (refer to Section 8.8 and to Table 7).

• Confirmed HRRm status by central tumour tissue and/or ctDNA test is required to determine cohort eligibility as described below:

  • Participants will be considered eligible for the HRRm Cohort if a loss of function mutation (deleterious/pathogenic or suspected deleterious/likely pathogenic in at least one of the genes BRCA1, BRCA2, ATM, CDK12, PALB2, RAD51B, RAD51C, RAD51D, and BARD1) is detected by either central tumour tissue or central ctDNA test, ie, a positive HRRm result reported by one assay (tissue or ctDNA) is sufficient irrespective of the result of the other assay;

  • Participants will be considered eligible for the Non-HRRm Cohort if no gene mutation (in any of BRCA1, BRCA2, ATM, CDK12, PALB2, RAD51B, RAD51C, RAD51D, and BARD1) is detected by either tumour tissue or ctDNA test and a participant must have a non-HRRm tumour tissue test result. Participants without a valid non-HRRm tumour tissue result will not be eligible for randomisation into the Non-HRRm Cohort. For details see Table 7.  

• Adequate organ and bone marrow function as follows:

  • Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the 14 days prior to randomisation;

  • Absolute neutrophil count ≥ 1.5 × 10^9 /L with no growth factor support in the 28 days prior to randomisation;

  • Platelet count ≥ 100 × 10^9 /L;

  • Serum albumin ≥ 3.0 g/dL;

  • INR ≤ 1.5. Participants receiving oral anticoagulants may be enrolled with an INR < 2. Participants with other causes of INR increase such as haematologic disorders or impaired hepatic synthesis should be excluded;

  • Total bilirubin ≤ 1.5 × the ULN or ≤ 3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinaemia);

  • Alanine aminotransferase and AST ≤ 2.5 × ULN; for participants with hepatic metastases, ALT and AST ≤ 5 × ULN (please see Appendix E 6 and Appendix E 4.2);

  • Estimated GFR (eGFR) of ≥ 45 mL/min/1.73 m^2 as determined by CKD-EPI formula (Inker et al 2021):

    • For participants with SCr ≤ 0.9 mg/dL (≤ 79.56 µmol/L), use the following formula: 142 x (SCr/0.9)-0.302 × 0.9938Age (years);

    • For participants with SCr > 0.9 mg/dL (> 79.56 µmol/L), use the following formula: 142 x (SCr/0.9)-1.200 × 0.9938Age (years).

Sex and Contraceptive/Barrier Requirements

• Male participants:

  • Must not father children or donate sperm from signing ICF, during the study intervention and for 6 months after the last dose of study intervention. For participants wishing to father children, arrangement of donation of sperm prior to signing ICF must be made. Male participants may be rejected as a sperm donor after the study;

  • Must use a condom (with spermicide – where permitted) from signing ICF, during study intervention, and for 6 months after the last dose of study drug, with all sexual partners. Female partners who are women of childbearing potential should use a highly effective method of contraception for the same period (See Appendix G).

Informed Consent

• Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.

• Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of sample for optional genetic research that supports the Genomic Initiative (see Appendix D 2).

Exclusion Criteria:

Medical Conditions

• Participants with a history of MDS/AML or with features suggestive of MDS/AML (as determined by prior diagnostic investigation). Specific screening for MDS/AML is not required.

• Participants with any known predisposition to bleeding (eg, active peptic ulceration, recent [within 6 months] haemorrhagic stroke, proliferative diabetic retinopathy).

• Any history of persisting (> 2 weeks) severe cytopenia due to any cause (eg, absolute neutrophil count < 0.5 × 10^9 /L or platelets < 50 × 10^9 /L).

• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD5305 and/or the assigned NHA.

• History of another primary malignancy, with the following exceptions:

  • Adequately resected non-melanoma skin cancer;

  • Curatively treated in situ disease;

  • Malignancy treated with curative intent ≥ 3 years before the first dose of study intervention, and with no known active disease during the intervening time period.

• Persistent toxicities (CTCAE Grade ≥ 2) caused by previous anticancer therapy. Participants with side effects that are not reasonably expected to affect the safety of the participant on study intervention in the opinion of the investigator (eg, ADT-related side effects) may be included if agreed with the Study Clinical Lead.

• Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention. A minimum of 2 weeks must have elapsed between the end of brain radiotherapy and signing the main study ICF.

• Any of the following cardiac criteria:

  • Mean resting corrected QT interval (QTcF) > 470 milliseconds obtained from triplicate ECGs and averaged, recorded 5 minutes apart;

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

• History of arrhythmia (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. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted upon discussion with the AstraZeneca study physician.

• Other cardiovascular disease as defined by any of the following:

  • Symptomatic heart failure (as defined by New York Heart Association class ≥ 2);

  • Acute coronary syndrome /acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention or coronary artery bypass grafting within 6 months prior to randomisation;

  • Cardiomyopathy of any aetiology;

  • Presence of clinically significant valvular heart disease;

  • Left ventricular ejection fraction ≤ 50% measured by echocardiogram or MUGA scan at screening or based on assessment performed within 6 months prior to randomisation;

  • Transient ischaemic attack, or stroke within 6 months prior to randomisation;

  • Participants with symptomatic hypotension at screening;

  • Uncontrolled hypertension despite medical management.

• Evidence of active and uncontrolled hepatitis B and/or hepatitis C. Screening for hepatitis B and hepatitis C is not required. Participants previously exposed to hepatitis B or hepatitis C are eligible if they meet 1 of the following criteria:

  • Are negative for HBsAg and anti-HBc; or

  • Are HBsAg+ and anti-HBc+ (chronic hepatitis B), and meet conditions i to iii below:

    • HBV DNA viral load < 2000 IU/L;

    • Have normal aminotransferase values, or, if liver metastases are present, abnormal aminotransferase, with a result of AST/ALT < 3 x ULN, which are not attributable to HBV infection;

    • Start antiviral treatment at least 2 weeks prior to the first dose of study intervention and maintain antiviral treatment during the interventional period. For permitted concomitant therapies, refer to Appendix I.

  • Are anti-HBc positive, HBsAg negative, and have HBV DNA < 2000 IU/L;

  • Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA;

  • NOTE: Inclusion of this group of participants should be carefully considered if participant has no access to hepatology service and/or is currently in need of antiviral treatments.

• Evidence of active and uncontrolled HIV infection. Participants with controlled HIV need to meet the following criteria: undetectable viral RNA load less than 400 copies/mL in the last 4 weeks prior to first dose of study intervention, CD4+ count of ≥ 350 cells/µL, no history of AIDS-defining opportunistic infection within the past 12 months, and stable on the same anti-HIV medications (as permitted in Appendix I) for at least 6 months. Screening for HIV is not required. NOTE: Inclusion of this group of participants should be carefully considered if participant has no access to specialist service and/or is not stabilised on antiviral treatments.

• Active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).

• Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study. Participants should have fully recovered from any clinically significant AEs.

• As judged by the investigator, any other evidence of diseases (such as severe or uncontrolled systemic diseases or active uncontrolled infections, including but not limited to uncontrolled major seizure disorder, active bleeding diseases, superior vena cava syndrome, or history of allogenic organ transplant, which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or would jeopardise compliance with the protocol.

Prior/Concomitant Therapy

• Any prior treatment with a PARP inhibitor or platinum chemotherapy.

• Any prior treatment with a GnRH analogue or NHA. The following exceptions are permitted:

  • ≤ 4 months ADT for metastatic disease (per inclusion criterion 4);

  • For localised disease and so long as there was ≥ 12 months between completion of therapy and subsequent recurrence:

    • ADT for a maximum of 39 months (note: for injectable depot preparations of ADT, completion of therapy is defined as last dose plus 1 times the dosing interval [eg, 12 weeks for goserelin 10.8 mg]);

    • NHA for a maximum of 30 months.

• Any prior anticancer pharmacotherapy (including but not limited to chemotherapy, immunotherapy, and systemic radiopharmaceuticals) or surgery for metastatic prostate cancer. The following exceptions are permitted:

  • ≤ 4 months ADT for metastatic disease (per inclusion criterion 4);

  • Radiation therapy (for example radiation therapy to the prostate for participants with low volume metastatic disease or palliative radiation therapy to treat symptoms resulting from metastatic disease). Radiation therapy needs to have been completed > 4 weeks prior to randomisation for wide field radiation therapy and > 2 weeks for limited field radiation therapy. Participants should have fully recovered from any clinically significant adverse events;

  • Surgical therapy to treat symptoms from metastatic disease if it was completed at least 4 weeks prior to first day of dosing and participant fully recovered from any clinically significant AEs.

• Prior treatment within 14 days with blood product support or growth factor support.

• Initiation of treatment with a bisphosphonate or denosumab for the management of bone metastasis ≤ 28 days prior to randomisation. Participants should be either on a stable dose of such agents for ≤ 28 days prior to randomisation, or agree not to initiate such therapy until radiographic progression is documented. Bisphosphonates and denosumab at doses for prevention of osteoporosis are allowed.

• Concomitant use of the following types of medications or herbal supplements within 21 days or at least 5 half-lives (whichever is longer), of randomisation:

  • Strong and moderate inducers and inhibitors of CYP3A4 (applies to AZD5305 and all NHAs);

  • Strong CYP2C8 inhibitors or inducers (applicable only to enzalutamide combination);

  • Strong P-glycoprotein inducers (applicable only to darolutamide combination);

  • The above includes, but may not be limited to, the prohibited medications and herbal supplements listed in Appendix I. 22 Concomitant use of drugs that are known to prolong QT and have a known risk of TdP (Appendix I).

Prior/Concurrent Clinical Study Experience

• Concurrent enrolment in another clinical study (unless the study is non interventional, or the participant is in the follow-up period of an interventional study).

Other Exclusions

• Participants who are unevaluable for both bone and soft tissue progression as defined by meeting both of the following criteria:

  • A bone scan referred to as a superscan showing an intense symmetric activity in the bones and no or limited technetium excretion by the kidneys; and

  • No soft tissue lesion (measurable or non-measurable) that can be assessed by RECIST 1.1 criteria.

• Participants with a known hypersensitivity to AZD5305, the physician’s choice NHA, or any excipients of these products.

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

• Previous randomisation in the present study.

• Participants with any contraindication or restriction based on the local prescribing information that would prohibit the use of the intended physician’s choice NHA, including:

  • For combination with abiraterone:

    • Active infection or other medical condition that would contraindicate the use of systemic steroids (prednisone/prednisolone);

    • Any chronic medical condition requiring a systemic dose of corticosteroid > 10 mg prednisone/prednisolone per day;

    • History of uncontrolled pituitary or adrenal dysfunction;

    • Serum potassium < 4.0 mmol/L.

  • For combination with enzalutamide:

    • History of seizure or any condition (as assessed by investigator) that may predispose to seizure (eg, prior cortical stroke, significant brain trauma), including any history of loss of consciousness or transient ischaemic attack within 12 months of enrolment.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 9/22/23. Questions regarding updates should be directed to the study team contact.