Inclusion Criteria:

Informed Consent

1. The participant provides written informed consent for the study.

2. Be willing and able to comply with study procedures, laboratory tests, and other requirements of the study.

   Disease Characteristics

3. Histologically confirmed diagnosis of metastatic or locally advanced unresectable:

   • Cohort 1: papillary renal carcinoma (pRCC).
   • Cohort 2: variant histology urothelial carcinoma (VH-UC) including the following subtypes:

   nested, microcystic, micropapillary, lymphoepithelioma-like, plasmacytoid, giant cell, poorly differentiated, lipid-rich, clear cell, sarcomatoid) bladder cancer and non-urothelial bladder cancer of epithelial origin including squamous cell carcinoma and adenocarcinoma (urachal and non-urachal).

   Note: Variant histology tumors and non-urothelial tumors of ureter, urethra, urachus, or renal pelvis are included.

   Note: Patients with mixed cell type are eligible if the predominant histology (over 50%) is variant or non-urothelial. All histological classifications will follow the 2022 world health organization (WHO) Classifications.

4. Disease progression after standard treatment or lack of available standard treatment options:

   • Cohort 1: Prior treatment with PD-1/PD-L1 and or tyrosine kinase inhibitors (TKIs)
   • Cohort 2: Disease progression after standard treatment. Some VH such as micropapillary, small cell, and sarcomatoid variants are considered highly aggressive and no standard treatments are clearly defined, being considered an orphan disease, so they might be included in the first line in case of lack of available standard treatment options.

5. Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology.

   Note: Lesions situated in a previously-irradiated area are considered measurable if progression has been shown in such lesions.

   Demographics

6. Is an individual of any sex/gender and is at least 18 years of age at the time of providing the informed consent.

   Patient Status

7. Has an eastern cooperative Oncology Group Performance status (ECOG PS) of 0 - 1.

8. Participants who have AEs due to previous anticancer therapies must have recovered to Grade ≤1 or baseline (except for alopecia and vitiligo).

   Note: Participants with endocrine-related AEs who are adequately treated with hormone replacement therapy are eligible.

9. Adequate organ function. Specimens must be collected within 10 days before the start of study intervention:

   absolute neutrophil count (ANC) ≥1500/µL * Platelets ≥100,000/µL Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L * Measured or calculated creatinine clearance (CrCl) ≥30 mL/min Total bilirubin ≤1.5 × upper limit normal (ULN) OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases) Albumin ≥3.0 g/dL ** international normalized ratio (INR) or prothrombin time (PT) / activated patial thromboplastin (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

   * without colony-stimulating factors, erythropoietin dependency, and without packed red blood cell (pRBC) transfusion within the preceding 2 weeks.

   ** without albumin supplementation within the last 72 hours.

10. Has provided an archival tumor tissue sample or most recently obtained core, incisional, or excisional biopsy of a tumor lesion from any site (primary or metastasis) not previously irradiated. Sites should follow local guidelines regarding fresh tissue collection. Tissue is required for determination of TROP-2 status by the central laboratory. No central pathological review and TROP-2 expression level assessment will be needed to include the patient in the trial.

11. HIV-infected participants must have well-controlled HIV on antirretroviral therapy (ART), defined as:

    • Having a CD4+ T-cell count ≥350 cells/mm3 at the time of screening
    • Having achieved and maintained virologic suppression, defined as confirmed HIV RNA level below 50 or the lower limit of quantification using the locally available assay, at the time of screening and for at least 12 weeks before screening
    • Absence of any AIDS-defining opportunistic infections within the past 12 months
    • Being on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before randomization and agreeing to continue ART throughout the study Note: The ART regimen must not contain any antiretroviral medications that are strong CYP3A4 inducers/inhibitors/substrates.
    • HIV testing at screening is not required unless:

    There is a known history of HIV infection Mandated by local guidelines

12. Participants who are HBsAg positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load before randomization.

    Note: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention.

    - Hepatitis B testing at screening is not required unless: There is a known history of HBV infection Mandated by local guidelines

13. Participants with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening.

    Note: Participants must have completed curative antiviral therapy at least 4 weeks before randomization.

    - Hepatitis C testing at screening is not required unless: There is a known history of HCV infection Mandated by local guidelines

    Male Participants

14. If capable of producing sperm, the participant agrees to the following during the intervention period and for at least 120 days after the last dose of sacituzumab tirumotecan:

    • Refrains from donating sperm.
    • Uses a penile/external condom when having penile-vaginal intercourse with a nonparticipant of childbearing potential who is not currently pregnant plus partner use of an additional contraceptive method, as a condom may break or leak.

    Note: If the participant is azoospermic (vasectomized or secondary to medical cause, documented from the site personnel's review of the participant's medical records, medical examination, or medical history interview), no contraception is required.

    Female Participants

15. A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies:

    • Is not a women of childbearing potential (WOCBP) OR
    • Is a WOCBP and:

Has a negative highly sensitive pregnancy test (urine or serum) as required by local regulations within 24 hours (for a urine test) or 72 hours (for a serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

Medical history, menstrual history, and recent sexual activity has been reviewed by the physician investigator to decrease the risk for inclusion of a WOCBP with an early undetected pregnancy.

The participant agrees not to donate eggs (ova, oocytes) to others or freeze/store eggs during this period for the purpose of reproduction.

Uses a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or is abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) during the intervention period and for at least 210 days after the last dose of sacituzumab tirumotecan.

Note: The physician investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by WOCBPs should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.

Abstains from breastfeeding during the study intervention period and for at least 10 days after study intervention.

Exclusion Criteria:

Medical Conditions

1. Symptomatic brain metastases or leptomeningeal disease. Note: Participants with previously-treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during study screening, are clinically stable, and have not required steroid treatment for at least 14 days before the first dose of study intervention.

2. Has an active infection requiring systemic therapy other than those permitted in the inclusion criteria.

3. Has a history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing.

4. Has a history of (noninfectious) pneumonitis/interstitial lung disease (ILD) that required steroids or has current pneumonitis/interstitial lung disease or has suspected ILD or pneumonitis that cannot be ruled out by standard diagnostic assessments at screening

5. Has uncontrolled, significant cardiovascular disease or cerebrovascular disease, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, prolongation of cardiac QT interval corrected by Fridericia formula (QTcF) to >480 ms, and/or other serious cardiovascular and cerebrovascular diseases within 6 months before the first dose of study intervention.

6. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.

   Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (excluding carcinoma in situ of the bladder) who have undergone potentially curative resection are not excluded.

   Note: Participants with low-risk early-stage prostate cancer (T1-T2a, Gleason score ≤6, and prostate specific antigen <10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded.

7. Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study, interfere with the individual's ability to cooperate with the requirements of the study, or interfere with the individual's participation for the full duration of the study, such that it is not in the best interest of the individual to participate, in the opinion of the treating physician investigator.

   Prior/Concomitant Therapy

8. Received prior treatment with a TROP-2-targeted antibody drug conjugate (ADC).

9. Received prior treatment with a topoisomerase 1 inhibitor-containing ADC.

10. Received prior systemic anticancer therapy within 2 weeks before the first dose of study intervention.

11. Received prior radiotherapy within 2 weeks before the first dose of study intervention, has radiation-related toxicities, requiring corticosteroids, and/or has had radiation pneumonitis.

    Note: Two weeks or fewer of palliative radiotherapy for non-central nervous system disease is permitted. The last radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention.

12. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.

13. Is currently receiving a strong inducer/inhibitor of CYP3A4 that cannot be discontinued for the duration of treatment with study intervention. The required washout period before starting study intervention is 2 weeks.

    Prior/Concurrent Clinical Study Experience

14. Is currently enrolled on another therapeutic clinical trial. Concurrent enrollment on another therapeutic clinical trial or any trial designed to impact the efficacy of anti-cancer therapy is prohibited.

15. Has received an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention.

    Other Exclusions

16. Severe hypersensitivity (Grades ≥3) to study intervention, any of their excipients, and/or to another biologic therapy.

17. Has had major surgery or significant traumatic injury within 4 weeks before the first dose of study intervention. Anticipation of the need for major surgery during the course of treatment with study intervention is also exclusionary.

Note: Participants who underwent major surgery must have adequately recovered from toxicity and/or complications from the surgery before starting study intervention.