There are additional substudy requirements not reflected here. This list is based solely on the master CSP - Male and female, ≥ 18 years - Documented advanced or metastatic malignancy - Eastern Cooperative Oncology Group performance status of 0 or 1 with no deterioration over the 2 weeks prior to baseline or day of first dosing - All participants must provide a tumour sample for tissue-based analysis - At least 1 measurable lesion not previously irradiated, except Substudy 3 (Prostate Cancer) which allows participants with non measurable bone metastatic disease - Adequate bone marrow reserve and organ function - Minimum life expectancy of 12 weeks - At the time of screening, contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies - All women of childbearing potential must have a negative serum pregnancy test documented during screening - Female participants must be 1 year post-menopausal, surgically sterile, or using 1 highly effective form of birth control. Female participants must not donate, or retrieve for their own use, ova at any time during this study - Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile, avoid intercourse, or use a highly effective method of contraception. Male participants must not freeze or donate sperm at any time during this study. - Capable of giving signed informed consent - Provision of signed and dated written optional genetic research informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative

• Any evidence of diseases which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol - History of another primary malignancy except for adequately resected basal cell carcinoma or in situ squamous cell carcinoma of the skin, or other solid malignancy treated with curative intent - Persistent toxicities caused by previous anticancer therapy, excluding alopecia, not yet improved - Irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator, for example hearing loss - Spinal cord compression or brain metastases unless treated - Leptomeningeal carcinomatosis - Clinically significant corneal disease - Active hepatitis or uncontrolled hepatitis B or C virus infection - Uncontrolled infection requiring IV antibiotics, antivirals or antifungals, for example prodromal symptoms - Known HIV infection that is not well controlled - Known active tuberculosis infection - Mean resting corrected QTcF > 470 ms - In the judgement of the investigator, history of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause TdP - In the judgement of the investigator, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives - Uncontrolled or significant cardiac diseases - History of non-infectious Interstitial lung disease (ILD)/pneumonitis, including radiation pneumonitis that required steroids - Has severe pulmonary function compromise - Prior exposure to chloroquine/hydroxychloroquine without an adequate treatment washout period - Receipt of live, attenuated vaccine within 30 days prior to the first dose of study intervention - Prior exposure to anticancer therapies without an adequate treatment washout period prior to enrolment or any concurrent anticancer treatment - Palliative radiotherapy with a limited field of radiation within ≤ 2 weeks or to more than 30% of the bone marrow within ≤ 4 weeks before the first dose of study intervention - Major surgical procedure or significant traumatic injury within ≤ 3 weeks of the first dose of study intervention or an anticipated need for major surgery during the study - Prior treatment with TROP2-directed therapies or other antibody-drug conjugate (ADCs) with deruxtecan payload - Herbal or natural products intended as treatment or prophylaxis for any type of cancer that may interfere with the activity of the study intervention - Previous treatment in the present study - Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks prior to first dose of study intervention or concurrent enrolment in another clinical study - Severe hypersensitivity to Dato-DXd or any of the excipients, including but not limited to polysorbate 80 or other monoclonal antibodies - Involvement in the planning and/or conduct of the study - Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements - Females that are pregnant, breastfeeding, or planning to become pregnant - Female participants should refrain from breastfeeding from enrolment throughout the study and for at least 7 months after last dose of Dato-DXd