A Study of AZD4635 With Durvalumab and With Cabazitaxel and Durvalumab in Patients With mCRPC.

A Phase II, Open-label, Study to Assess the Efficacy, Safety, and Tolerability of AZD4635 in Combination With Durvalumab and in Combination With Cabazitaxel and Durvalumab in Patients Who Have Progressive Metastatic Castrate-Resistant Prostate Cancer (AARDVARC)

This is a Phase II, international, open-label, two-arm, non-randomised study of AZD4635 in participants with metastatic castration-resistant prostate cancer (mCRPC).

This is a Phase II, international, open-label, two-arm, non-randomised study of AZD4635 in participants with mCRPC. Participants in each arm will be stratified by the presence of measurable soft tissue metastasis (per Response Evaluation Criteria in Solid Tumours [RECIST v1.1]) or bone-only metastasis (per Prostate Cancer Working Group 3 [PCWG3 criteria]). There will be no formal comparisons between treatment arms.

AZD4635 plus durvalumab (Arm A) will consist of 80 participants with mCRPC previously treated with one or more approved new hormonal agent(s) (NHAs) and one or more taxanes or participants who are taxane ineligible.

AZD4635 plus durvalumab plus cabazitaxel (Arm B) will consist of 80 participants mCRPC previously treated with docetaxel and one prior NHA.

As of November 2020, the Sponsor stopped enrolment in Arm A following decisions at the program level, not related to any safety issues. Ongoing participants in Arm A may continue treatment as planned.

Inclusion Criteria:

1. Histologically confirmed adenocarcinoma of the prostate.

2. Known castrate-resistant disease.

3. Evidence of disease progression ≤6 months.

4. Body weight >30 kg at screening.

5. Willingness to adhere to the study treatment-specific contraception requirements.

6. Adequate bone marrow reserve and organ function.

7. Adequate organ function for Arm A as demonstrated by all of the following laboratory values:

   • Alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) if no demonstrable liver metastases or ≤5 × ULN in the presence of liver metastases.
   • Aspartate aminotransferase (AST) ≤2.5 × ULN if no demonstrable liver metastases or ≤5 × ULN in the presence of liver metastases
   • Total bilirubin (TBL) ≤1.5 × ULN
   • TBL ≤2.0 × ULN in the case of known Gilbert syndrome with normal direct bilirubin

8. Participants in Arm A must have received the following prior therapy:

   • Maximum of 3 lines of therapy in the mCRPC setting
   • Prior therapy with one or more NHAs (eg, abiraterone acetate, enzalutamide, apalutamide, darolutamide) in either hormone-sensitive or hormone-refractory settings
   • Prior therapy with one or more lines of taxanes (eg, docetaxel and/or cabazitaxel)
   • Alternatively, must be taxane-ineligible
   • Prior therapy can be in either the hormone-sensitive or the hormone-refractory setting

9. Adequate organ function for Arm B as demonstrated by all of the following laboratory values:

   • AST and/or ALT ≤1.5 × ULN
   • TBL ≤ ULN
   • TBL ≤2.0 × ULN in the case of known Gilbert syndrome with normal direct bilirubin

10. Participants in Arm B must have received the following prior therapy:

    • Prior docetaxel (taxane) in either hormone-sensitive or hormone-refractory settings
    • Received no prior cytotoxic chemotherapy other than docetaxel for prostate cancer except for estramustine and except adjuvant/neo-adjuvant treatment completed >3 years ago.
    • Prior therapy with only one NHAs (eg, abiraterone acetate or enzalutamide; prior apalutamide is not permitted) for treatment of mCRPC in either hormone-sensitive or hormone-refractory settings.
    • Be suitable to receive concomitant Granulocyte-colony stimulating factor during all cycles of cabazitaxel.
    • Participants who meet inclusion criteria for Arm B will be allocated preferentially to that arm until recruitment to that arm is completed.

Exclusion Criteria:

1. Active brain metastases or leptomeningeal metastases.
2. There must be no requirement for immunosuppressive doses of systemic corticosteroids for at least 2 weeks prior to study enrollment.
3. History of pneumonitis requiring corticosteroids, second malignancy that is progressing and/or received active treatment ≤3 years before the first dose of study intervention, and hypersensitivity to polysorbate-80 if allocated to cabazitaxel.
4. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases.
5. Creatinine clearance <40 mL/min (calculated by Cockcroft-Gault equation).
6. Prior exposure to immune-mediated therapy including.
7. Ongoing treatment with warfarin (Coumadin).
8. Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study intervention.