This clinical trial is designed to evaluate the efficacy and safety of T-DXd in combination with bevacizumab versus bevacizumab monotherapy as first-line maintenance therapy, in participants with human epidermal growth factor 2 (HER2)-expressing (immunohistochemistry [IHC] 3+/2+/1+) advanced high-grade epithelial ovarian cancer.

A non-randomized safety run-in phase will be conducted prior to randomization phase to assess the safety of T-DXd in combination with bevacizumab.

Key Inclusion Criteria:

1. Sign and date the tissue prescreening ICF, prior to HER2 central testing. Sign and date the Main ICF, prior to the start of any trial- specific qualification procedures. Consent to optional PGx prior to any PGx procedures.

   *For participants in the safety run-in phase, a safety run-in ICF needs to be signed and dated prior to the start of any trial-specific qualification procedures.

2. Adults ≥18 years of age on the day of signing the ICF. Follow local regulatory requirements if the legal age of consent for trial participation is >18 years old.

3. Has histologically confirmed diagnosis of epithelial high-grade ovarian, fallopian tube or primary peritoneal carcinoma per local assessment (including but not limiting to serous, endometrioid, clear cell, carcinosarcoma, mucinous).

4. Is newly diagnosed FIGO Stage III or IV.

5. Has HER2 expression per 2016 ASCO-CAP gastric cancer IHC scoring (3+/2+/1+) guidelines1 by prospective central testing.

   *For participants in the safety run-in phase, HER2 expression assessed by either local (require using ASCO-CAP gastric cancer IHC scoring [IHC 3+/2+/1+] guidelines) or central assessment (if available) is acceptable. Submission of the pathology report is required for participants enrolled based on local HER2 IHC results.

6. Has adequate tumor tissue sample available for assessment of HER2 by central laboratory. Tumor tissue block or sufficient tissue slides are required for HER2 testing and retrospective HRD status determination.

   *Participants in the safety run-in phase who are enrolled based on local HER2 IHC results are recommended to provide tumor tissue sample from the same specimen for central assessment.

7. Has a local HRD or BRCA test result available. Participants with BRCA-wildtype will have a local HRD test results, as applicable.

8. Has received up to 6 cycles of standard of care bevacizumab in combination with frontline platinum- based chemotherapy as per approved indication and clinical guidelines and is eligible to continue single agent bevacizumab maintenance per standard of care and investigator discretion.

Key Exclusion Criteria:

1. Has ovarian, fallopian tube, or peritoneal cancer of non-epithelial origin.

2. Has a known or suspected deleterious BRCA alteration as per local test that makes the patient eligible for PARP inhibitor.

3. Participant to receive PARP inhibitor as maintenance per standard of care and investigator discretion. Reasons for which the participant is not eligible for PARP inhibitor will be recorded in the eCRF as follows:

   • HRD negative
   • HRD positive with SD as best response after platinum
   • HRD positive non-serous histology Note: For participants enrolled from the Republic of Korea
   • HRD tested, but inconclusive
   • HRD positive but safety concern (safety concern to be specified).

4. Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug products and other monoclonal antibodies.

5. Previous Cerebral-Vascular Accident, Transient Ischemic Attack or Sub- Arachnoids Hemorrhage within 6 months prior to randomization.

   *Note: For participants enrolled from the Republic of Korea,

6. Has evidence of bleeding diathesis or significant coagulopathy (in the absence of anticoagulation therapy).

7. Has a history of hemorrhagic disorders, abdominal fistula, gastrointestinal perforation, or active gastrointestinal bleeding within 6 months before randomization.

8. Evidence of active or ongoing bowel obstruction.

9. Has a medical history of myocardial infarction within 6 months before randomization, symptomatic congestive heart failure (New York Heart Association Class II to IV).

   Participants with troponin levels above the upper limit of normal at Screening (as defined by the manufacturer), and without any myocardial infarction related symptoms should have a cardiologic consultation during the Screening Period to rule out myocardial infarction.

10. Has a corrected QT interval prolongation to >480 msec based on average of the Screening triplicate 12-lead ECG.

11. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.

Ovarian Cancer

De-identified individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.

Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.

This is an open-label study.