This is an open-label Phase II modular study in participants with prostate cancer which will assess safety, efficacy, and tolerability of AZD4635 in combination with other therapeutic agents in different treatment arms (referred to as modules).

Combinations to be studied include: 1) Module 1: AZD4635 plus durvalumab; 2) Module 2: AZD4635 plus oleclumab.

This is an open-label Phase II modular study in participants with prostate cancer which will assess safety, efficacy, and tolerability of AZD4635 in combination with other therapeutic agents in different treatment arm (referred to as modules).

Combinations to be studied include: 1) Module 1: AZD4635 plus durvalumab; 2) Module 2: AZD4635 plus oleclumab.

All participants will be allocated into a module using an Interactive Web Response System (IWRS). Randomization will occur when patients meet eligibility criteria for two or more modules that are currently recruiting. If participants only meet the criteria for one currently recruiting module, they will be allocated to that module without randomization taking place.

The primary objective of the clinical study is to evaluate the efficacy of each combination therapy by: 1) assessing the objective response rate (ORR) of participants with measurable disease (response will be determined by Response Evaluation Criteria in Solid Tumours [RECIST 1.1]); 2) assessing the prostate-specific antiget (PSA) confirmed response rate of each combination therapy (PSA confirmed response rate is defined as the proportion of participants with a reduction in the PSA level of ≥50% measured from baseline to the lowest post-baseline PSA result measured twice, at least 3 weeks apart by the Prostate Cancer Working Group 3 criteria [PCWG3]).

The safety endpoints include assessment of adverse events and serious adverse events, physical examinations, vital signs, and collection of clinical chemistry/hematology parameters

There will be approximately 30 PSA evaluable participants in each module, and approximately 20 participants will have RECIST measurable disease at baseline in each module. If any of the required participants for PSA and/or ORR are not evaluable for PSA response or tumor response, respectively, they may be replaced at the sponsor's discretion.

Inclusion Criteria for all Patients in all Modules:

1. Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses
2. Participant must be ≥18 years of age at the time of signing the inform consent form (ICF)
3. Participants must have prostate cancer with histological or cytological confirmation
4. Participants must have previously received and progressed on standard-of-care therapy(ies)
5. Participants must be able to provide an archival tumor tissue sample. If archival tumor tissue is not available, then tissue from a fresh tumor biopsy is required.
6. All participants will be required to have a site of disease that is safely accessible for biopsy (paired) upon enrollment unless there are sufficient paired samples for the analysis. Accessible lesions are defined as those which are biopsiable (at screening) and amenable to repeat biopsy (after 2 weeks of AZD4635 therapy), unless clinically contraindicated. The provision of paired biopsies will be closely monitored to ensure the desired number of biopsiable participants are enrolled and investigators are aware of this requirement at all times.
7. Participants with measurable disease must have at least 1 documented lesion on either a bone scan or a computed tomography (CT)/ magnetic resonance imaging (MRI) scan that can be followed for response and is suitable for repeated measurement, or participants with non-measurable disease must have measurable PSA ≥1.0 ng/mL if the confirmed rise is the only indication of progression (excluding small cell carcinoma) 8 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no clinical deterioration over the previous 2 weeks prior to the 28-day screening period and likely able to complete at least 12 weeks of treatment.

9. Ability to swallow and retain oral medication. 10. Must have life expectancy of at least 12 weeks 11. Body weight ≥ 35 kg at screening 12. Willingness to adhere to the study treatment-specific contraception requirements: Participants must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) for the duration of the study (from the time they sign ICF) and for 3 months after the last dose of AZD4635 to prevent pregnancy in a female partner. Male participants must not donate or bank sperm for 24 weeks after treatment.

Inclusion Criteria for Modules 1 and 2:

1. Participants must have metastatic castrate resistant prostate cancer with histological or cytological confirmation. Participant may have bone-only metastatic disease.

2. Participants must have had either orchiectomy or be on luteinizing hormone-releasing hormone (LHRH) agonist or antagonist therapy with testosterone <50 ng/dL and agree to stay on LHRH agonist or antagonist therapy during the study

3. Participants must have previously received and progressed on ≥2 lines of approved systemic therapy for metastatic castration-resistant prostate cancer (mCRPC), including a second generation hormonal agent (e.g, abiraterone, enzalutamide, or apalutamide)

4. Participants must have evidence of mCRPC that progressed within 6 months prior to screening according to one of the following:

   1. PSA progression as defined by a minimum of 2 rising PSA levels with an interval of ≥1 week between each assessment, where the PSA value at screening should be ≥ 1.0 ng/mL.
   2. Radiographic disease progression in soft tissue based on RECIST Version 1.1 criteria with or without PSA progression.
   3. Radiographic disease progression in bone defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression.

Exclusion Criteria for all Participants in all Modules:

1. History or presence of another primary invasive malignancy except for: malignancy treated with curative intent and with no known active disease ≥2 years before the first dose of study drug and of low potential risk for recurrence; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated carcinoma in situ without evidence of disease; localized non-invasive primary carcinoma under surveillance

2. Refractory nausea and vomiting, chronic gastrointestinal diseases, or previous significant small bowel resection that would preclude adequate absorption of AZD4635.

3. Previously untreated brain metastases. Participants who have received radiation or surgery for brain metastases are eligible if therapy was completed at least 21 days previously and there is no evidence of central nervous system (CNS) disease progression or mild neurologic symptoms.

4. With the exception of alopecia, lymphopenia, and hypothyroidism, any unresolved toxicities from prior therapy greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0) Grade 1 at the time of starting study treatment

5. Participants with prior ≥ Grade 3, serious, or life threatening immune-mediated reactions following prior anti-PD-1, anti-PD-L1, or other immuno-oncology therapies.

6. Prior history of myocardial infarction, transient ischemic attack, or stroke in the last 3 months

7. Participants must have normotensive or well controlled blood pressure (<150/90), with or without current antihypertensive treatment. If there is a diagnosis or history of hypertension, participant must have adequately controlled blood pressure on antihypertensive medications, as demonstrated by 2 blood pressure measurements taken in the clinical setting by a medical professional within 1 week prior to enrollment. Patients on a hypertensive medication must be willing and able to measure and record blood pressure readings twice-daily for a minimum of 3 weeks.

8. As judged by the Investigator or Medical Monitor, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, or active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B virus [known positive HBV surface antigen (HBsAg) result], hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies), or active hepatitis A. Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Participants positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Screening for chronic conditions is not required.

9. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis, Crohn's disease], diverticulitis, celiac disease, systemic lupus erythematous, Wegener's syndrome, myasthenia gravis, Grave's disease, rheumatoid arthritis, hypophysitis, uveitis, autoimmune pneumonitis, autoimmune nephritis or nephropathy, etc.) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion: a) vitiligo or alopecia, b) hypothyroidism (e.g., following Hashimoto's disease) stable on hormone replacement, c) psoriasis or eczema not requiring systemic therapy for disease control, d) celiac disease controlled by diet alone.

10. Prior/concomitant therapy with AZD4635 or any other A2AR antagonist.

11. Ongoing corticosteroid use, at doses above physiologic replacement therapy. The following are exceptions to this criterion: a) use of intranasal, inhaled, topical orticosteroids, local steroid injections (e.g. intra-articular injections), b) steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication) are permitted, c) systemic corticosteroids at physiologic doses below 10 mg/day of prednisone or equivalent.

12. The following intervals between the end of the prior treatment and first dose of study drug must be observed: a) anticancer therapy: ≥21 days or 5 half-lives (whichever is shorter) of the first dose of study drug. At least 7 days must have elapsed between the last dose of such agent and the first dose of study drug. (Exception: androgen-deprivation therapy is required to maintain castrate levels of testosterone (˂50 ng/dL), b) concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.

13. Major surgery (as defined by the Medical Monitor, excluding placement of vascular access) within 4 weeks of the first dose of study treatment.

14. Minor surgical procedures (as defined by the Medical Monitor) within 7 days of the first dose of study treatment.

15. Participant is receiving medications or other products known to be sensitive breast cancer resistance protein (BCRP) or organic anion transporter polypeptide 1 (OATP1B1), OATP1B3, organic anionic transporter 1 (OAT1), organic cation transporter 1 (OCT1), OCT2, multidrug and toxin extrusion protein 1 (MATE1) and P glycoprotein (P-gp) substrates or potent or moderate inhibitors/inducers of CYP1A2, which cannot be discontinued 2 weeks prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of AZD4635.

16. Concomitant medications with another A1R antagonist that would increase risk of seizure (e.g., theophylline, aminophylline).

17. Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment

18. Ongoing treatment with Coumadin

19. Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug

20. Herbal preparations/medications are not allowed throughout the study, including but not limited to: St. John's wort, kava, ephedra (ma huang), ginkgo biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Participants should stop using these herbal medications 7 days prior to the first dose of AZD4635. Exceptions may be agreed upon, but the circumstances must be reviewed by the Medical Monitor in advance.

21. 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.

22. Enrollment into another therapeutic clinical trial. (Exception: Participants are allowed to participate in investigational imaging or non-interventional studies.)

23. History of hypersensitivity to AZD4635 or drugs with a similar chemical structure or class to AZD4635.

24. Any of the following cardiac criteria:

    • Mean resting corrected QT interval (QTcF) >470 msec obtained from 3 ECGs
    • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block
    • Any concomitant medication with known QT interval prolongation. Participants receiving a medication(s) known to prolong the QT interval may be discussed with the Medical Monitor or Sponsor for study approval.
    • Ejection fraction <55% or the lower limit of normal of the institutional standard

25. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

    • Absolute neutrophil count <1.5 x 10⁹/L
    • Platelet count <100 x 10⁹/L
    • Hemoglobin <9.0 g/dL
    • Alanine aminotransferase (ALT) >2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases
    • Aspartate aminotransferase (AST) >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases
    • Total bilirubin (TBL) >1.5 times ULN
    • Creatinine >1.5 times ULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN.

26. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and its representatives and/or staff at the study site).

27. Judgment by the Investigator or Medical Monitor that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements.

28. Participation in another clinical interventional study or if participant has already received at least one dose of study drug in the present study

Exclusion Criteria for Module 1:

1. Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.
2. History of active primary immunodeficiency.
3. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice)

Exclusion Criteria for Module 2:

1. Prior receipt of any immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies and agents targeting CD73, CD39, or adenosine receptors, excluding therapeutic anticancer vaccines.
2. Known history of allergy or reaction to any component of oleclumab formulation or history of anaphylaxis to any human gammaglobulin therapy.
3. History of venous thrombosis within the past 3 months.

This study will enroll only male participants because the condition being studied is metastatic castration-resistant prostate cancer.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.