Study of AZD0754 in Participants With Metastatic Prostate Cancer

Inclusion Criteria:

Age

1. Participant must be 18 years or older at the time of signing the informed consentform. Type of Participant and Disease Characteristics

2. Participants with:

3. A histologically confirmed diagnosis of metastatic adenocarcinoma of theprostate without known neuroendocrine differentiation or small cell features.

4. Castration-resistant prostate cancer as defined by disease progression despitecastration by orchiectomy or ongoing luteinising hormone-releasing hormoneanalogue. Participants receiving medical castration therapy with gonadotropinreleasing hormone analogues should continue this treatment during the study.

5. Measurable PSA >/=1 ng/mL AND

6. Evidence of progression within 6 months prior to screening according to one ofthe following:

(i) Radiographic disease progression in soft tissue based on Response EvaluationCriteria in Solid Tumours Version 1.1 criteria with or without PSA progression asper Prostate Cancer Working Group Criteria 3 (PCWG3) (ii) Radiographic diseaseprogression in bone defined as the appearance of 2 or more new bone lesions on bonescan as per Prostate Cancer Working Group Criteria 3 (PCWG3).

(iii) Evidence of disease progression in bone according to PSMA PET scan results intandem with PSA progression according to PCWG3 criteria."

3. Participant has previously received a NHA (ie, abiraterone, enzalutamide,apalutamide, darolutamide) and taxane as part of their treatment for prostate cancer (whether before or in the metastatic castration-resistant setting) or be ineligiblefor or refuse taxanes.

4. For participants with pathogenic mutations in BRCA1 or BRCA2, they must also havereceived a PARP-inhibitor or be intolerant of this therapy. For participants withnon-BRCA HRR deficiency disease, treatment with a PARP-inhibitor is at thediscretion of the Investigator based on a risk/benefit analysis and discussion withthe participant.

5. For participants who have high microsatellite instability or deficient DNA mismatchrepair they must also have received at least one line of checkpoint inhibitors (ie,pembrolizumab), not be eligible for, or be intolerant to therapy as per NCCN orlocal treatment guidelines.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 prior toapheresis.

7. Minimum life expectancy of > 12 weeks prior to apheresis in the opinion of theInvestigator

8. Adequate organ and marrow function.

9. Consent and provision of tumour material to assess STEAP2 expression and othercorrelative biomarkers retrospectively with pre- and post-treatment biopsies. Freshbaseline and on-treatment biopsies are required unless these are deemed medicallyunfeasible. If the participant is unable to undergo fresh biopsy, an archival tumoursample will be required (age of biopsy cannot be greater than 10 years).

Exclusion Criteria:

1. Participants with weight less than 39 kg

2. History of another primary malignancy except for malignancy treated with curativeintent with no known active disease (≥ 2 years) before the first dose of studyintervention and of low potential risk for recurrence. Such exceptions includenon-melanoma cancer of the skin that has undergone curative therapy or adequatelytreated carcinoma in situ without evidence of disease.

3. Participants with known brain metastases.

4. Prior solid organ transplantation.

5. Active or prior documented autoimmune or inflammatory disorders. The following areexceptions to this criterion:

6. Participants with vitiligo or autoimmune alopecia.

7. Participants with autoimmune hypothyroidism (eg, following Hashimotothyroiditis) stable on hormone replacement.

8. Any chronic inflammatory or autoimmune skin condition that does not requiresystemic therapy.

9. Participants without active disease in the last 5 years may be included, butonly after consultation with the Sponsor.

10. Participants with coeliac disease controlled by diet alone.

11. Stroke, intracranial haemorrhage, or seizure within 6 months of apheresis.

12. Cardiac arrhythmias, (such as multifocal premature ventricular contractions,bigeminy, trigeminy, ventricular tachycardia), which are symptomatic or requiretreatment (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3) unlesscontrolled by pacemaker (discussion with the Study Physician required); symptomaticor uncontrolled atrial fibrillation despite treatment, or asymptomatic sustainedventricular tachycardia.

13. Investigator judgement of one or more of the following:

14. Mean resting corrected QT interval > 470 ms, obtained from triplicateelectrocardiograms (ECGs) performed at screening.

15. History of QT prolongation associated with other medications that requireddiscontinuation of that medication, or any current concomitant medication knownto prolong the QT interval.

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

17. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeknown infection, cardiomyopathy of any aetiology, symptomatic congestive heartfailure defined by New York Heart Association class ≥ 3), interstitial lung disease,uncontrolled hypertension, uncontrolled diabetes mellitus, unstable angina pectoris,history of myocardial infarction within the past 6 months prior to apheresis, knownbleeding diathesis such as haemophilia, von Willebrand disease, etc.

18. Active, uncontrolled epilepsy. Participants without active/uncontrolled epilepsy inthe last 5 years may be included.

19. Persistent toxicities (CTCAE Grade ≥ 2) caused by previous anticancer therapy,excluding alopecia. Participants with irreversible toxicity that is not reasonablyexpected to be exacerbated by study intervention may be included (eg, hearing loss)after consultation with the Study Physician or Medical Monitor. Participants withGrade 2 neuropathy will be evaluated on a case-by-case basis after consultation withthe Study Physician or Medical Monitor.

20. Seropositive for human immunodeficiency virus (HIV).

21. Active hepatitis C infection (HCV). Participants testing positive for HCV antibodyare eligible only if the polymerase chain reaction is negative for HCV RNA.

22. Participants with hepatitis B virus (HBV) may be included under the followingcircumstances:

23. Negative for hepatitis B surface antigen (HbsAg) and positive for anti-HBcantibody

24. Positive for HbsAg, but for > 6 months have had normal transaminases and HBVDNA levels between 0 - 2000 IU/mL (inactive carrier state) and willing to startand maintain antiviral treatment for at least the duration of the study.

25. HBV DNA levels > 2000 IU/mL but on prophylactic antiviral treatment for thepast 3 months and will maintain the antiviral treatment during the study.

26. Local requirements for the testing for infectious diseases and exclusions ofapplicable participants should be followed per local regulations. Prior/Concomitant Therapy

27. Participants may not receive full-dose long-acting oral (eg, warfarin) or parenteralanticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic)purpose from the time of informed consent to 28-days post infusion of AZD0754. Useof short acting direct oral anticoagulants (eg, rivaroxaban) for therapeutic andprophylactic purposes are permitted.

28. Received the following:

29. Major surgery within 2 weeks prior to apheresis, or planned major surgerywithin 4 weeks of the study treatment administration (Note: participants withplanned surgical procedures to be conducted under local anaesthesia mayparticipate after discussion with the Sponsor).

30. Corticosteroids (except inhaled corticosteroids) or other immunomodulators (including interleukins, interferons, and thymosins) of systemic therapeuticdose, and systemic corticosteroids at doses exceeding 10 mg/day of prednisoneor equivalent < 7 days prior to apheresis.

31. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy,endocrine therapy targeted therapy, biologic therapy, tumour embolisation, ormonoclonal antibodies, investigational product) within 5 half-lives or ≤ 21 days (whichever is shorter) prior to apheresis. Radiotherapy within 14 days. However, ifthe radiation portal covered ≤ 5% of the bone marrow reserve, the participant iseligible irrespective of the end date of radiotherapy. If sufficient washout timehas not occurred due to the schedule or PK properties of an agent, a longer washoutperiod will be required, as agreed by AstraZeneca and the Investigator.

32. Any concurrent anticancer treatment with the following exceptions:

33. Protocol-defined LDC

34. Hormonal therapy for non cancer-related conditions (eg, hormone replacementtherapy)

35. Androgen deprivation therapy with a luteinising-hormone replacement hormoneagonist/antagonist is required if needed to maintain testosterone level in thecastration range (levels < 50 ng/dL) and should be continued (unless bilateralorchiectomy) throughout the trial. Following apheresis, bridging therapy ispermitted (if required) as outlined in Section 6.1.2

36. Participants should not have received any live vaccines within 30 days prior toapheresis. Participants can receive coronavirus (COVID)-19 vaccines, at thediscretion of the Investigator, following a benefit/risk evaluation for theindividual participant and in accordance with local rules and regulations andvaccination guidelines. Note: If a COVID-19 vaccine is administered, it shouldideally be done at least one week prior to LDC or after completion of the DLTperiod. Prior/Concurrent Clinical Study Experience

37. Prior treatment with a CAR-T therapy directed at any target or any therapy that istargeted to STEAP2.

38. Participants with a known life-threatening allergy, hypersensitivity, or intoleranceto AZD0754 or any of the excipients of the product, including dimethylsulfoxide.

In addition to the above, the following exclusion criteria is applicable for study participants in Australia:

• Participants with human T-lymphotropic virus (HTLV).