A Study of Dato-DXd Versus Investigator's Choice Chemotherapy in Patients With Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer, Who Are Not Candidates for PD-1/PD-L1 Inhibitor Therapy (TROPION-Breast02)

Inclusion Criteria:

Age

1. Participant must be ≥ 18 years at the time of screening. Type of Participant andDisease Characteristics

2. Histologically or cytologically documented locally recurrent inoperable TNBC, whichcannot be treated with curative intent, or metastatic TNBC. TNBC is defined as:

• Negative for ER with < 1% of tumour cells positive for ER on IHC.

• Negative for progesterone receptor with < 1% of tumour cells positive forprogesterone receptor on IHC.

• Negative for HER2 with 0 or 1+ intensity on IHC or 2+ intensity on IHC andnegative by in situ hybridisation per the ASCO-CAP HER2 guideline

3. No prior chemotherapy or other systemic anti-cancer therapy for metastatic orlocally recurrent inoperable breast cancer.

4. Not a candidate for PD-1/PD-L1 inhibitor therapy, defined as:

• Participants whose tumours are PD-L1-negative, or

• Participants whose tumours are PD-L1-positive and have:

1. relapsed after prior PD-1/PD-L1 inhibitor therapy for early-stage breastcancer,

2. comorbidities precluding PD-1/PD-L1 inhibitor therapy, or

3. no regulatory access to pembrolizumab [participant's country does not haveregulatory approval at the time of screening]).

4. At least 1 measurable lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline and can be accurately measured at baseline as ≥ 10 mm in thelongest diameter (except lymph nodes, which must have short axis ≥ 15 mm) withcomputed tomography (CT) or magnetic resonance imaging (MRI), and is suitable foraccurate repeated measurements.

5. ECOG PS 0 or 1 with no deterioration over the previous 2 weeks prior to baseline orday of first dosing.

6. Eligible for one of the chemotherapy options listed as ICC (paclitaxel,nab-paclitaxel, capecitabine, carboplatin, or eribulin), based on DFI and priortaxane exposure, per investigator assessment.

7. Has had an adequate treatment washout period before Cycle 1 Day 1, defined as:

• Major surgery: ≥ 3 weeks.

• Radiation therapy including palliative radiation to chest: ≥ 4 weeks (palliative radiation therapy to other areas ≥ 2 weeks).

• Corticosteroid therapy for central nervous system metastatic disease: > 3 days.

• Anti cancer therapy including hormonal therapy: ≥ 3 weeks (for small moleculetargeted agents: ≥ 2 weeks or 5 half-lives, whichever is longer).

• Nitrosoureas or mitomycin C: ≥ 6 weeks.

• Antibody-based anti cancer therapy: ≥ 4 weeks with the exception of receptoractivator of nuclear factor kappa-B ligand (RANKL) inhibitors (eg, denosumabfor the treatment of bone metastases).

• Immunotherapy (non-antibody-based therapy), retinoid therapy: ≥ 2 weeks or 5times the terminal elimination half-life of the agent, whichever is longer.

• Chloroquine/hydroxychloroquine: > 14 days.

9. Written confirmation of tumour sample needs to be available prior to enrolment andtumour samples should be available prior to randomisation. All participants musthave a FFPE metastatic (excluding bone) or locally recurrent inoperable tumoursample (block preferred, or a minimum of 20 freshly cut slides) available, collected ≤ 3 months prior to screening. If neither an adequate FFPE block nor the minimum of 20 slides are available from the most recent biopsy, or if a biopsy is not feasiblefor safety reasons, and this is clearly documented, an archival tumour specimenobtained before the diagnosis of locally recurrent inoperable or metastatic breastcancer may be submitted, pending approval by the Global Study Team.

10. Participants with a history of previously treated neoplastic spinal cord compressionor asymptomatic, stable brain metastases, who require no treatment withcorticosteroids or anticonvulsants may be included in the study, if they are nolonger symptomatic and have recovered from acute toxic effects of radiotherapy. Aminimum of 2 weeks must have elapsed between the end of radiotherapy and Cycle 1 Day

11. A minimum of 3 days must have elapsed between the end of corticosteroid therapyfor central nervous system metastatic disease and Cycle 1 Day 1.

12. Adequate organ and bone marrow function within 7 days before randomisation asfollows:

• Haemoglobin ≥ 9.0 g/dL (red blood cell/plasma transfusion is not allowed within 1 week prior to screening assessment).

• Absolute neutrophil count ≥ 1.5 × 10^9/L (granulocyte colony stimulating factoradministration is not allowed within 1 week prior to screening assessment).

• Platelet count ≥ 100 × 10^9/L (platelet transfusion is not allowed within 1week prior to screening assessment).

• Total bilirubin (TBL) ≤ 1.5 × upper limit of normal (ULN) or < 3 × ULN in thepresence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia).

• Except in the setting of HBV, Alanine aminotransferase (ALT) and aspartateaminotransferase (AST) ≤ 2.5 × ULN for AST/ALT (< 5 × ULN in participants withliver metastases). See Exclusion Criterion 5 for requirements in the setting ofHBV.

• Calculated CrCL ≥ 30 mL/minute as determined by Cockcroft Gault

12. Minimum life expectancy of 12 weeks. Sex

13. Male or female. Contraceptive use by men or women should be consistent with localregulations regarding the methods of contraception for those participating inclinical studies. Reproduction

14. Negative pregnancy test (serum) for women of childbearing potential.

15. Female participants must be at least 1 year post-menopausal, surgically sterile, orusing at least 1 highly effective form of birth control (a highly effective methodof contraception is defined as one that can achieve a failure rate of less than 1%per year when used consistently and correctly.) Women of childbearing potential whoare sexually active with a non sterilised male partner must agree to use at least 1highly effective method of birth control. They should have been stable on theirchosen method of birth control for a minimum of 3 months before Cycle 1 Day 1 andcontinue for at least 7 months after the last dose. Female participants must refrainfrom egg cell donation or retrieval for their own use, and breastfeeding fromenrolment throughout the study and for at least 7 months after the last dose ofstudy drug. Any non sterilised male partner of a woman of childbearing potentialmust use a male condom plus spermicide (condom alone in countries where spermicidesare not approved) throughout this period.

16. Male participants who intend to be sexually active with a female partner ofchildbearing potential must be surgically sterile or use an acceptable method ofcontraception from the time of screening throughout the total duration of the studyand the drug washout period (at least 6 months after the last dose of studyintervention), in addition to the female partner using a highly effectivecontraceptive method, to prevent pregnancy in a partner. Male participants must notdonate or bank sperm during this same time period. Preservation of sperm should beconsidered prior to randomisation. Not engaging in heterosexual activity (sexualabstinence) for the duration of the study and drug washout period is an acceptablepractice, if this is the preferred usual lifestyle of the participant. Periodic oroccasional abstinence, the rhythm method, and the withdrawal method are notacceptable methods of contraception. Informed Consent

17. Capable of giving signed informed consent, which includes compliance with therequirements and restrictions listed in the ICF and in this protocol.

18. Provision of signed and dated written Optional Genetic Research Information informedconsent prior to collection of sample for optional genetic research that supportsGenomic Initiative.

Exclusion Criteria:

Medical Conditions

1. As judged by the investigator, any evidence of diseases (such as severe oruncontrolled systemic diseases, uncontrolled hypertension, history of allogeneicorgan transplant, and active bleeding diseases, ongoing or active infection, orsignificant cardiac or psychological conditions), and/or substance abuse which, inthe investigator's opinion, makes it undesirable for the participant to participatein the study or that would jeopardise compliance with the protocol.

2. History of another primary malignancy except for malignancy treated with curativeintent with no known active disease within 3 years before the first dose of studyintervention and of low potential risk for recurrence (per investigator assessment).Exceptions include adequately resected non-melanoma skin cancer (basal cellcarcinoma of the skin or squamous cell carcinoma of the skin) and curatively treatedin situ disease.

3. Persistent toxicities caused by previous anti-cancer therapy, excluding alopecia,not yet improved to Grade ≤ 1 or baseline. Participants with irreversible toxicitythat is not reasonably expected to be exacerbated by study intervention in theopinion of the investigator may be included (eg, hearing loss).

4. Uncontrolled infection requiring IV antibiotics, antivirals or antifungals;suspected infections (eg, prodromal symptoms); or inability to rule out infections (participants with localised fungal infections of skin or nails are eligible).

5. Known active or uncontrolled hepatitis B or C virus infection.

6. Known human immunodeficiency virus (HIV) infection that is not well controlled. Allof the following criteria are required to define an HIV infection that is wellcontrolled: undetectable viral RNA, cluster of differentiation (CD)4+ count > 350cells/mm3, no history of an acquired immune deficiency syndrome-definingopportunistic infection within the past 12 months, and stable for at least 4 weekson the same anti-HIV medications.

7. Uncontrolled or significant cardiac disease including:

• Myocardial infarction or uncontrolled/unstable angina within 6 months prior toCycle 1 Day 1

• Congestive heart failure (New York Heart Association Class II to IV), or

• Uncontrolled or significant cardiac arrhythmia, or

• Uncontrolled hypertension (resting systolic blood pressure > 180 mmHg ordiastolic blood pressure > 110 mmHg).

8. Resting ECG with clinically abnormal findings.

9. Uncontrolled hypercalcaemia: > 1.5 mmol/L (> 6 mg/dL) ionised calcium, or serumcalcium (uncorrected for albumin) > 3 mmol/L (> 12 mg/dL), or corrected serumcalcium > ULN, or clinically significant (symptomatic) hypercalcaemia.

10. History of non-infectious ILD/pneumonitis that required steroids, has currentILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out byimaging at screening

11. Has severe pulmonary function compromise.

12. Leptomeningeal carcinomatosis.

13. Clinically significant corneal disease.

14. Known active tuberculosis infection (clinical evaluation that may include clinicalhistory, physical examination and radiographic findings, or tuberculosis testing inline with local practice). Prior/Concomitant Therapy

15. Prior exposure to:

• Any treatment (including ADC) containing a chemotherapeutic agent targetingtopoisomerase I

• TROP2-targeted therapy

• Prior treatment with same ICC agent

• Chloroquine/hydroxychloroquine without an adequate treatment washout period of > 14 days prior to randomisation.

16. Any concurrent anti cancer treatment.

17. Concurrent use of systemic hormone replacement therapy (HRT; eg, oestrogen andprogesterone). However, concurrent use of hormones for other non-cancer-relatedconditions (eg, insulin for diabetes or levothyroxine for hypothyroidism) isacceptable.

18. Major surgical procedure (excluding placement of vascular access) or significanttraumatic injury within 3 weeks of the first dose of study intervention or ananticipated need for major surgery during the study.

19. Receipt of live, attenuated vaccine within 30 days prior to the first dose of studytreatment.

20. Concomitant use of chronic systemic (IV or oral) corticosteroids or otherimmunosuppressive medications except for managing AEs (inhaled steroids or intraarticular steroid injections are permitted in this study). Prior/Concurrent Clinical Study Experience

21. Previous randomisation in the present study.

22. Participation in another clinical study with a study intervention or investigationalmedicinal device administered in the last 4 weeks prior to first dose of studyintervention (unless the safety profile is known prior to randomisation),randomisation into a prior T-DXd or Dato DXd study regardless of treatmentassignment, or concurrent enrolment in another clinical study, unless it is anobservational (non interventional) clinical study or during the follow-up period ofan interventional study.

23. Participants with a known history of severe hypersensitivity reactions to either thedrug or any excipients (including but not limited to polysorbate 80) of Dato-DXd orICC.

24. Known history of severe hypersensitivity reactions to other monoclonal antibodies. Other Exclusions

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

26. Judgment by the investigator that the participant should not participate in thestudy if the participant is unlikely to comply with study procedures, restrictionsand requirements.

27. Currently pregnant (confirmed with positive pregnancy test) or breast feeding orplanning to become pregnant.