This study specifically aims to evaluate how well mocertatug rezetecan (Mo-Rez) works in treating ovarian cancer compared to standard treatments. The study also assesses whether Mo-Rez is safe and tolerated well by participants compared to standard treatments and aims to provide a better understanding of the main side effects of the drug.

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 epithelial ovarian cancer, inclusive of primary peritoneal or fallopian-tube cancer with a histologically confirmed diagnosis of high grade serous, high grade endometrioid, or clear cell carcinoma, or carcinosarcoma that is resistant to platinum-based therapy.

Platinum-resistance is defined as follows:

• Participants who have only had 1 line of platinum-based therapy must have received at least 4 cycles of platinum therapy, must have had a response (CR, PR, stable disease) and then progressed from >3 months to ≤6 months after the last dose of platinum therapy.

• Participants who have received >1 line of platinum therapy must have progressed on or ≤6 months after the date of the last dose of platinum therapy.

  • Has received at least 1 but no more than 4 prior lines of systemic anti-cancer therapy. Prior lines of therapy are defined as follows:

• Adjuvant ± neoadjuvant are considered one line of therapy.

• Maintenance therapy (e.g., bevacizumab, [poly adenosine diphosphate-ribosylation (ADP) ribose polymerase inhibitor (PARPi)] will be considered as part of the preceding line of therapy (i.e., not counted independently).

• Therapy changed to another agent in the same class due to toxicity in the absence of progression will be considered as part of the same line of therapy (i.e., not counted independently).

• Unplanned addition or switching to a new drug in a different class is considered a separate line of therapy.

• Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance.

  • Must have received prior treatment with the following therapies unless they have a contraindication per label or institutional guidelines as described below:

• Mirvetuximab soravtansine (MIRV),.

• The tumor demonstrates positive folate receptor alpha FRα expression (≥ 75% of viable tumor cells with moderate (2+) and/or strong (3+) membrane staining) per a test compliant to local regulation, AND

• Does not have a documented contraindication per label or local institutional guidelines, including but not limited to chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring, such as uncontrolled glaucoma, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, monocular vision, peripheral neuropathy, interstitial lung disease, or hypersensitivity. AND

• It is available in the enrolment country. A regimen is considered available if it is approved and reimbursed (covered by national healthcare or private insurance) in the participating country.

• Bevacizumab, unless the participant has a documented contraindication per label or local institutional guidelines. Contraindications include but are not limited to vascular disorders (uncontrolled hypertension, arterial thromboembolic events), fistula, gastro-intestinal disorders (rectosigmoid involvement, bowel obstruction), delayed wound healing, bleeding diathesis (haemoptysis, epistaxis, pulmonary haemorrhage, acquired coagulopathy), nephrotic syndrome or significant proteinuria, or osteonecrosis of the jaw, or hypersensitivity

• PARPi, in participants with known or suspected deleterious germline or somatic BRCA mutations and who achieved a complete or partial response to platinum-based chemotherapy must have been treated with a poly ADP-ribose polymerase PARPi as maintenance treatment, if a PARPi is available in the enrolment country, unless the participants is not eligible for treatment with PARPi. A regimen is considered available if it is approved and reimbursed (covered by national healthcare or private insurance) in the participating country.

  • Has at least one Target lesion (TL) per RECIST 1.1, as determined by the investigator. Measurable lesions that have been previously irradiated and have been shown to be progressing following irradiation may be considered as TLs.
  • Has provided a Formalin fixed, paraffin embedded (FFPE) tumor tissue sample of sufficient quantity and quality for the central assessment of B7 homolog 4 protein (B7-H4) expression, with B7-H4 expression result available prior to date of randomization.

AND

• FR alpha expression
• In countries where mirvetuximab is available, an FR alpha expression result from a test compliant with local regulation or by central testing is required to determine eligibility.
• In countries where mirvetuximab is unavailable, an FFPE tumor tissue sample confirmed to be of sufficient quantity and quality must be provided. The FR alpha expression result is not required prior to randomisation or to determine eligibility.

AND

• PD-L1 expression, where a result from a local test is NOT available, an FFPE tumor tissue sample confirmed to be of sufficient quantity and quality must be provided. The PD-L1 expression result is not required prior to randomisation or to determine eligibility.

  • Is eligible to receive 1 of the standard of care interventions if randomized to physician's choice arm.
  • A female participant is eligible to participate if they are not pregnant or breastfeeding, and one of the following conditions applies:

• Is a Participant of non-childbearing potential (PONCBP) OR

• Is a Participant of childbearing potential (POCBP) and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, 30 days prior to Cycle 1 Day 1 (C1D1) and during the study intervention period and for at least 8 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention.

  • A POCBP must have a negative, highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention

• If a urine test is positive or ambiguous and cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

  • Is capable of giving signed informed consent, including compliance with the requirements and restrictions listed in the ICF and in the study protocol.
  • Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Has adequate organ function

Exclusion Criteria:

• Has primary platinum-refractory Ovarian Cancer (OC), defined as disease that did not respond to or has progressed within <3 months of the final dose of first line platinum containing chemotherapy.
• 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, in-situ carcinomas (e.g., breast, cervix, bladder) that have been resected with no evidence of metastatic disease, or that is otherwise considered cured by the investigator.
• Has known sensitivity to study intervention components or excipients or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
• Has untreated brain or CNS metastases or brain/CNS metastases that have progressed (e.g., evidence of new or enlarging brain metastasis or new neurologic symptoms attributable to brain/CNS metastases). Participants with previously treated and clinically stable brain/CNS metastases and who have completed all corticosteroid therapy for ≥14 days prior to date of C1D1 are not excluded from participation.
• Has any evidence of current ILD or pneumonitis, or a prior history of ILD or non-infectious pneumonitis.
• 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 e.g., alopecia, hearing loss, vitiligo, endocrinopathy managed with replacement therapy, and Grade 2 neuropathy, or 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 any serious and/or unstable medical condition (including infection) or any serious and/or unstable psychiatric disorder or other condition(s) (including laboratory assessment abnormalities) that could interfere with the participant's safety, obtainment of informed consent, or compliance to the study procedures, including requirements for the Follow-up Period of the study.
• For participants selected to receive the pembrolizumab-containing regimen as the intended physician's choice only: Has experienced any of the following with prior immunotherapy-any immune-mediated adverse event (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
• For participants selected to receive bevacizumab as part of the pembrolizumab + paclitaxel ± bevacizumab intended physician's choice regimen only: Has a history of vascular disorders (uncontrolled hypertension, arterial thromboembolic events), fistula, gastro-intestinal disorders (rectosigmoid involvement, bowel obstruction), delayed wound healing, bleeding diathesis (hemoptysis, epistaxis, pulmonary hemorrhage, acquired coagulopathy), nephrotic syndrome or significant proteinuria, or osteonecrosis of the jaw, or hypersensitivity.
• 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 date of C1D1.
• Has received treatment with any cytotoxic chemotherapy drugs or other anti-tumor drugs (including endocrine therapy, molecular targeted therapy, immunotherapy, biotherapy, or investigational agent) within 30 days or 5 half-lives, whichever is shorter, prior to date of C1D1; or need to continue these drugs during study participation.
• Has ever received prior therapy with topoisomerase I inhibitors (e.g., topotecan) or ADC with a topo1i payload, or B7-H4 targeted therapy.
• Has received any live vaccine within 30 days prior to date of C1D1.
• 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, or recombinant erythropoietin) within 14 days prior to date of C1D1.
• For participants receiving PLD only: Has baseline Left ventricular ejection fraction (LVEF) <50% or lower than institutional lower limits of normal. Intolerance to PLD does not exclude a participant from the study if a different physician's choice option is chosen prior to randomization.

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.