The purpose of this study is to see how well GSK5733584 in combination with standard treatment of choice works as maintenance therapy in participants with advanced or recurrent endometrial cancer (EC) compared to current standard of care. The study will also assess whether drug combination is safe and tolerated well by participants compared to the usual care and will help us better understand its impact on Health-Related Quality of Life of participants.

Inclusion Criteria:

• Is at least 18 years of age and the legal age of consent in the jurisdiction in which the study is taking place at the time of signing the Informed consent form (ICF).

• Has received 6 cycles of first-line therapy (i.e. induction therapy), consisting of platinum-based doublet chemotherapy (carboplatin/paclitaxel) with immune checkpoint inhibition as part of standard of care (either pembrolizumab or dostarlimab) or via trial Run-In (dostarlimab). Completion of 4 cycles is permitted if the reason for discontinuation of therapy was due to chemotherapy toxicity and the participant has completed at least 12 weeks of immunotherapy during induction.

• Is deemed suitable to continue with maintenance therapy with immune checkpoint inhibition (dostarlimab or pembrolizumab).

• Demonstrates no clinical or radiographic progression of disease per investigator after the final dose of induction therapy. Final dose is defined as the last day that either platinum chemotherapy, taxane chemotherapy or immune checkpoint inhibition was given within the last cycle of induction therapy

• Has histologically confirmed endometrial carcinoma including but not limited to endometrioid, serous, clear cell and endometrial carcinosarcoma. Mixed epithelial carcinomas are permitted.

• Meets one of the following criteria:

  • Has newly diagnosed stage III disease [2023 International Federation of Gynecology and Obstetrics (FIGO) staging] with measurable residual disease >1 cm after primary debulking surgery (incomplete cytoreduction).
  • Has newly diagnosed stage III disease (2023 FIGO staging) that is not suitable for primary debulking surgery with measurable disease.
  • Has newly diagnosed stage IV disease (2023 FIGO staging) and any residual disease status (measurable or non-measurable) following debulking surgery. Participants not suitable for primary debulking surgery are also permitted.
  • Has recurrent disease and is naïve to systemic anticancer therapy and any disease status (measurable or non-measurable).
  • Has recurrent disease after receiving prior neo-adjuvant/adjuvant systemic anticancer therapy and had a recurrence >12 months after last dose of neo-adjuvant/adjuvant treatment. Participants with any disease status (measurable or non-measurable) are permitted.

• Has a tumor demonstrating either Mismatch Repair proficient (MMRp) or Microsatellite stable (MSS),(NGS); MSS.

• Has provided a Formalin fixed, paraffin embedded (FFPE) tumor tissue sample sufficient for the central assessment of B7 homolog 4 protein (B7-H4) expression and MMR (if local MMRp/MSS test result(s) not available), with the result of B7-H4 expression testing available prior to date of randomization.

• Is willing to use adequate contraception. Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Exclusion Criteria:

• Mesenchymal tumors of the uterus (uterine sarcomas) and neuroendocrine uterine cancer.
• Has a malignancy (except disease under study) that has progressed or required active treatment within 36 months prior to date of randomization except for basal cell or squamous cell carcinomas of the skin or in-situ carcinomas.
• Any evidence of current Interstitial lung disease (ILD) or pneumonitis or a prior history of ILD or non-infectious pneumonitis.
• Has experienced any of the following with prior immunotherapy: any imAE ≥ Grade 3, immune-mediated severe neurologic events of any grade (e.g., myasthenic syndrome/myasthenia gravis, encephalitis, Guillain-Barré Syndrome, or transverse myelitis), exfoliative dermatitis of any grade (Stevens-Johnson syndrome [SJS], Toxic Epidermal Necrolysis [TEN], or Drug Reaction with Eosinophilia and Systemic Symptoms [DRESS] syndrome, or myocarditis of any grade.
• Has ongoing adverse reaction(s) from prior therapy that has(have) not recovered to ≤ Grade 1 or to the baseline status preceding prior therapy, excluding alopecia, hearing loss, vitiligo, endocrinopathy managed with replacement therapy, and Grade 2 neuropathy, or adverse reactions that the investigator, with the agreement of the sponsor, considers to be not clinically relevant for the tolerability of study intervention in the current clinical study.
• Has had any major surgery within 28 days prior to date of C1D1 or received focal radiotherapy within 21 days prior to date of C1D1.
• Has received treatment with an investigational agent within 30 days prior to C1D1.
• Has received prior therapy with topoisomerase I inhibitors (e.g. irinotecan or topotecan) or Antibody-Drug Conjugate (ADC)with a topoisomerase I inhibitor warhead, B7-H4 targeted therapy, or immune checkpoint inhibitor.
• Has received treatment with strong or moderate inhibitor of Cytochrome P450 (CYP) 3A4 or CYP2D6, strong or moderate inducer of CYP3A4, inhibitor of P-glycoprotein (P-gp) or Breast cancer resistant protein (BCRP), or inducer of P-gp within 14 days prior to date of C1D1 or anticipates their use during study participation and up to 30 days after the last dose of study intervention administration.
• Use drugs known to prolong the QT interval or potentially cause torsades de pointes; or need to continue these medications during the study and up to 30 days after the last dose of study intervention.
• Has received any transfusion of blood products (including platelets or red blood cells) or administration of colony-stimulating factors (including Granulocyte-Colony Stimulating Factor [G-CSF], Granulocyte-Macrophage Colony-Stimulating Factor [GM-CSF], or recombinant erythropoietin) within 14 days prior to C1D1.
• Has an Alanine aminotransferase (ALT) value >2.5 × Upper limit of normal (ULN) or for participants with documented liver metastases/tumor infiltration has an ALT value >5 × ULN.
• Has a total bilirubin value >1.5 × ULN.
• Has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, or persistent jaundice. Participants who exhibit these signs or symptoms as a result of the malignancy under investigation and whose conditions are deemed adequately controlled by the investigator may be eligible for inclusion.
• Has Corrected QT interval (QTc) >470 milliseconds (msec).
• Has a history of congenital long QT syndrome or has a history of or evidence of cardiac abnormalities within 12 months prior to screening such as serious, uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities.
• Has any active renal condition (e.g., infection, requirement for dialysis, or any other significant renal condition that could affect the participant's safety).

Study Sponsor will assess requests from qualified researchers for anonymized individual patient-level data and related study documents. Data sharing is subject to certain criteria, conditions, and exceptions. For further information, refer to https://www.gsk-studyregister.com/gsk-patient-level-data-sharing-july2025.pdf

Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or asset(s) with development terminated across all indications.

Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months, but an extension may be granted, when justified, for up to 6 months.

The independent central reviewer assessing primary outcome data will be masked (blinded) from participants treatment assignment.