Inclusion Criteria:

Type of Participant and Disease Characteristics

1. Has a histologically-confirmed diagnosis of pure OCCC. Patients with mixed histologies that include a clear cell component will not be eligible for this trial.

2. Has measurable disease per RECIST 1.1 as assessed by the local site investigator/ radiology. Lesions situated in a previously-irradiated area are considered measurable if progression has been shown in such lesions.

3. Patients must have received at least one prior platinum and taxane based chemotherapy regimen. Radiation therapy (including the use of chemotherapy as a radiosensitizer) will not count as a prior systemic regimen.

4. Patients must have also received one prior line containing an immune checkpoint inhibitor (ICI) More than one prior line of ICI treatment will be exclusionary.

5. Participants with known brain metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

6. ECOG performance status 0-1

7. Is an individual of assigned female sex at birth and is at least 18 years of age at the time of providing the informed consent.

8. Participant is not pregnant or breastfeeding, and at least one of the following conditions applies:

   • Is not a Person of Child-Bearing Potential (POCBP) OR

   • Is a POCBP and:

     - Agrees to use of 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), as described in Appendix 5 during the intervention period and for at least the time needed to eliminate the study intervention after the last dose of study intervention. The participant agrees not to donate eggs (ova, oocytes) to others or freeze/store eggs during this period for the purpose of reproduction. The length of time required to continue contraception for Sacituzumab tirumotecan is 210 days.

     ◦ sacituzumab tirumotecan: 210 days

     - The investigator should evaluate the potential for contraceptive method failure (i.e., noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by POCBPs 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.

     • 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 (e.g., 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. Additional requirements for pregnancy testing during and after study intervention are in Section 8.3.5.
     • Abstains from breastfeeding during the study intervention period and for at least 10 days after study intervention.
     • Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy.

Informed Consent 8. The participant (or legally acceptable representative if applicable) provides written informed consent for the study.

Additional Categories 9. Has provided an archival tumor tissue sample (slides or block) for pathologic confirmation of diagnosis at Tufts Medical Center.

10. Participants who have AEs due to previous anticancer therapies must have recovered to Grade ≤1 or baseline (except for alopecia and vitiligo). Participants with endocrine-related AEs who are adequately treated with hormone replacement therapy are eligible.

11. Adequate organ function as defined in the following table (Table 3). Specimens must be collected within 10 days before the start of study intervention.

12. Any other medical condition that will prevent the safe administration of study drugs in the opinion of the treating physician.

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

14. HIV-infected participants must have well-controlled HIV on ART, defined as:

1. Having a CD4+ T-cell count ≥350 cells/mm3 at the time of screening
2. Having achieved and maintained virologic suppression, defined as confirmed HIV RNA level below 50 or the LLOQ using the locally available assay, at the time of screening and for at least 12 weeks before screening.
3. Absence of any AIDS-defining opportunistic infections within the past 12 months
4. 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. Refer to https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Please note that this list is not exhaustive and that investigators should review the locally-approved label for all concomitant therapy to ensure it is not a strong inducer/inhibitor/substrate of CYP3A4.

HIV testing at screening is not otherwise required. 15. Participants who are HBsAg positive are eligible if they have received 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 16. Participants with a history of 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

Exclusion Criteria:

Medical Conditions

1. 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.

2. 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 QTcF interval to >480 ms, and/or other serious cardiovascular and cerebrovascular diseases within 6 months before the first dose of study intervention.

3. Is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.

4. Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid)

5. History of stem cell/solid organ transplant. Prior/Concomitant Therapy

6. Received prior treatment with a TROP2-targeted ADC.

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

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

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

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

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

    Refer to Section 6.2 for information on COVID-19 vaccines.

11. 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.

    Note: A list of strong inducers/inhibitors of CYP3A4 can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Please note that this list is not exhaustive and that investigators should review the locally-approved label for all concomitant therapy to ensure it is not a strong inducer/inhibitor of CYP3A4.

    Prior/Concurrent Clinical Study Experience

12. 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.

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

    Diagnostic Assessments

14. 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 of any organ (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 PSA <10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded.

15. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously-treated brain metastases may participate provided they are radiologically stable (i.e., 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.

16. Has an active infection requiring systemic therapy.

17. 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 investigator.

    Other Exclusions

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

19. 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.

20. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.

21. History or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's ability to cooperate with the requirements of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.