A Multi-arm, Open-label Phase I/IIa Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of AZD5305 in Combination With New Hormonal Agents in Patients With Metastatic Prostate Cancer (PETRANHA)

For whole study:

• Age ≥ 18 at the time of screening.
• Histologically confirmed diagnosis of metastatic prostate cancer.
• Candidate for treatment with enzalutamide, abiraterone acetate, or darolutamide with documented current evidence of metastatic prostate cancer.
• Surgically or medically castrated.
• Adequate organ and marrow function.
• Eastern Cooperative Oncology Group Performance Status (ECOG PS): 0-1 with no deterioration over the previous 2 weeks.
• Life expectancy ≥ 16 weeks.
• Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to approximately 6 months after the last dose of study treatment .

For Patients Recruited Specifically to tumour Pharmacodynamic Cohorts:

• Patients must have at least 1 tumour suitable for paired biopsies

For Part A:

• Patients with Metastatic Castrate ion-Resistant Prostate Cancer (mCRPC) or Metastatic Castration Sensitive Prostate Cancer (mCSPC).

For Part B:

• Patients must have mCSPC (de novo or recurrent) with a baseline PSA value of ≥ 0.2 ng/mL

For Part A mCRPC patients only:

• Any previous treatment with a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor, Lu-PSMA, platinum chemotherapy
• Patients recruited to the PDc cohorts should not have received a prior use of new hormonal agents (NHA).

For Part A and Part B mCSPC Patients:

• Any previous treatment with a PARP inhibitor, platinum, NHA, Immuno-oncology (IO), radiopharmaceutical therapy, or prior treatment with docetaxel in mCSPC setting.
• Concomitant use of medications or herbal supplements known to be:
1. Strong and moderate CYP3A4 inducers/inhibitors (applies for all arms)
2. For Arm 1 (enzalutamide) patients: Strong CYP2C8 inhibitors
3. For Arm 3 (darolutamide) patients: Strong P-glycoprotein inducers
• Concomitant use of drugs that are known to prolong or shorten QT and have a known risk of Torsades de Pointes.
• Treatment with any of the following:
1. Any investigational agents or study interventions from a previous clinical study within 5 half lives or 3 weeks (whichever is longer) of the first dose of study treatment.
2. Any other anticancer treatment within the following time periods prior to the first dose of study treatment: (i) Cytotoxic and non-cytotoxic treatment: 3 weeks or 5 half-lives (whichever is shorter). (ii) Biological products including immuno-oncology agents: 4 weeks before enrolment.
3. Any live virus or bacterial vaccine within 28 days of the first dose of study treatment.
• Any concurrent anticancer therapy or concurrent use of prohibited medications.
• Major surgery within 4 weeks prior to the first dose of study treatment.
• Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks of the first dose of study treatment.
• With the exception of alopecia, and peripheral neuropathy; any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of study enrolment.
• Any history of persisting (> 2 weeks) severe pancytopenia.
• Spinal cord compression, or brain metastases unless asymptomatic and treated and stable.
• Any evidence of severe or uncontrolled systemic diseases, including, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV).
• Patients with any known predisposition to bleeding (eg, active peptic ulceration, recent [within 6 months] haemorrhagic stroke, proliferative diabetic retinopathy.
• Any clinically significant cardiac disorders including QT prolongation, abnormal electrocardiogram (ECG).
• Any clinically significant cardiovascular diseases including symptomatic heart failure, uncontrolled hypertension, acute coronary syndrome, cardiomyopathy, valvular heart disease, atrial fibrillation, stroke.
• Patients with history of myelodysplastic syndrome (MDS)/ acute myeloid leukaemia (AML).
• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection.
• Known allergy or hypersensitivity to investigational product(s) or any of the excipients of the investigational product(s).
• Any condition that would interfere with evaluation of the study treatment or interpretation of patient safety or study results.
• Uncontrolled intercurrent illness within the last 12 months, including but not limited to, active interstitial lung disease, serious chronic gastrointestinal (GI) conditions associated with diarrhoea, or psychiatric illness/social situations
• History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study treatment and of low potential risk for recurrence.
• Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
• Arm 1 (Enzalutamide) only: History of seizure or any condition that may predispose to seizure (eg, prior cortical stroke, significant brain trauma).
• Arm 2 (Abiraterone acetate) only: (i) Active infection or other medical condition that would contraindicate the use of systemic steroids (prednisone/prednisolone). (ii) Low serum potassium (< 3.5 mmol/L). (iii) History of uncontrolled pituitary or adrenal dysfunction.