A Study of HER3-DXd in Subjects With Locally Advanced or Metastatic Solid Tumors

Inclusion Criteria Participants must meet all of the following criteria to be eligible for enrollment into the study: 1. Sign and date the informed consent form prior to the start of any study-specific qualification procedures. A separate tissue screening consent will be obtained from all subjects to meet the baseline tumor tissue requirement. 2. Participants aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is \>18 years old). 3. Has locally advanced unresectable or metastatic disease (not curable by surgery or radiation) as follows: Cutaneous (acral and non-acral) melanoma 1. Histologically or cytologically confirmed cutaneous (acral or non-acral) melanoma 2. Disease progression while on or after having received treatment with ≥1 prior line of anti-programmed cell death protein (PD-1) or anti-programmed death-ligand 1 (PD-L1) based therapy (previous use of other immune checkpoint inhibitors \[ICIs\] \[ie, anti-CTLA4, anti- LAG-3\] is acceptable). Prior anti-PD-(L)1 therapy in the adjuvant setting is allowed if there is recurrence within 12 weeks of the last dose. If the participant had BRAFm melanoma, they must have had disease progression on BRAF/MEK inhibitor therapy as well. Squamous cell carcinomas of the head and neck 3. Squamous cell carcinoma of the head and neck (with a primary location of oral cavity,oropharynx, larynx, hypopharynx) that is human papillomavirus (HPV) positive or negative (as determined by local standard). Excludes tumor location in the nasopharynx, nasal cavity, paranasal sinuses, and unknown primary locations. 4. Disease progression after having received treatment with ≥1 and \<3 prior lines of systemic therapy in the unresectable recurrent or metastatic setting. Must have had disease progression on anti-PD-(L)1 (either as monotherapy or in combination with chemotherapy or other therapies). Must also have had disease progression on a platinum-based chemotherapy (PBC) regimen either in the recurrent or metastatic setting or in the locally advanced setting with curative intent. Gastric or GEJ adenocarcinoma 5. Tumor tissue must be confirmed as negative for HER2 expression (immunohistochemistry \[IHC\] 0/1+ or IHC 2+/in situ hybridization negative) as classified by American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines and determined prior to enrollment by assessment in a local laboratory that is Clinical Laboratory Improvement Amendments certified (US sites) or accredited based on specific country regulations. 6. Disease progression after having received treatment with ≥2 prior lines of therapy that include PBC with or without anti-PD-1 therapy. Ovarian Carcinoma 7. Pathologically documented high-grade serous epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. 8. Documented disease progression ≥4 weeks after the last dose of PBC and \<6 months of last dose of PBC in the advanced or metastatic setting. Prior use of folate reductase alpha targeting antibody-drug conjugate (ADC) (ie, mirvetuximab soravtansine) is allowed. Cervical Cancer 9. Pathologically or cytologically documented recurrent or persistent squamous, adenosquamous, or adenocarcinoma of the uterine cervix. 10. Disease progression after having received ≥1 line of systemic therapy in the recurrent or metastatic setting. This may include prior anti-PD-(L)1 treatment and/or tissue factor directed ADC (tisotumab vedotin \[TV\]) per regional standard of care. Endometrial Cancer 11. Pathologically or cytologically documented endometrial cancer (carcinoma of any histological sub-type or endometrial carcinosarcoma), irrespective of microsatellite instability (MSI) or mismatch repair (MMR) status. 12. Documented disease progression after having received ≥1 prior line of therapy (maximum of 3) PBC containing systemic treatment and an anti-PD(L)-1 therapy-containing regimen (combined or sequential) in the advanced/metastatic setting. Bladder Cancer 13. Pathologically or cytologically documented locally advanced/unresectable or metastatic urothelial carcinoma of the bladder, renal pelvis, ureter, or urethra. Histological variants are allowed if urothelial histology is predominant. Small cell/neuroendocrine tumors are not allowed even if mixed histology. 14. Relapsed or progressed after treatment with ≥1 prior line of therapy (maximum of 3) that contains anti-PD-(L)1 therapy in the perioperative or metastatic setting. At least 1 line of therapy must also contain one of the following treatment modalities: chemotherapy or enfortumab vedotin. Prior fibroblast growth factor receptor (FGFR)-inhibitor treatment for those who are eligible are allowed. * Required treatments can be given in combination or sequentially * Prior cisplatin-based therapy or PD-(L)1 inhibitor therapy given for the treatment of muscle invasive urothelial carcinoma is counted as 1 line of therapy * The same regimen administered twice in different disease settings will be counted as 1 line of prior therapy * Participants in the second-line setting who have previously received enfortumab vedotin and pembrolizumab in combination can be enrolled. Esophageal Carcinoma 15. Pathologically or cytologically documented esophageal squamous cell carcinoma. 16. Must have documented disease progression after having received 2 prior lines of therapy including previous PBC with or without an anti-PD-1 therapy-containing regimen (combined or sequential) in the advanced/metastatic setting. Pancreatic Carcinoma 17. Pathologically or cytologically documented unresectable or metastatic pancreatic adenocarcinoma. 18. Relapsed or disease progression after having received 1 prior line of systemic therapy in the locally advanced/metastatic setting. Prostate Cancer 19. Pathologically or cy