The intention of the study is to demonstrate superiority of AZD5335 versus standard of care by assessment of progression-free survival (PFS) in women with high-grade, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, expressing high or low FRα levels.

Approximately 1100 adult participants will be enrolled after central FRα testing into two independent cohorts (about 550 FRα-high and 550 FRα-low) and randomized 1:1 within each cohort to receive AZD5335 or the relevant standard of care (mirvetuximab soravtansine in FRα-high; investigator's choice single-agent chemotherapy in FRα-low). Participants will remain on assigned treatment and undergo regular tumor evaluations per RECIST v1.1 until disease progression or another reason for treatment discontinuation.

All participants will be followed for overall survival. An independent data monitoring committee (IDMC) of external experts will periodically review unblinded safety and interim efficacy to confirm participant safety and study integrity.

Key Inclusion criteria

• Participants with confirmed diagnosis of high-grade serous EOC, primary peritoneal cancer, or fallopian tube cancer.
• Participants must have platinum-resistant disease:
• Participants who have only had one prior line of platinum-based therapy must have received at least 4 cycles of platinum, must have had a response (CR or PR) and then progressed between > 3 months and ≤ 6 months after the date of the last dose of platinum.
• Participants who have received 2 or 3 lines of platinum therapy must have progressed ≤ 6 months after the date of the last dose of platinum.
• Participants must have radiologically progressed on or after their most recent line of therapy.
• Participants must have received at least one, but no more than 3, prior systemic lines of anti-cancer therapy, and for whom single-agent therapy is appropriate as the next line of treatment
• Participants with documented BRCA mutation (germline and/or somatic) must have received prior PARPi if the participant is eligible per approved label and standard-of-care institutional guidelines, except in cases of documented contraindication, precaution or intolerance.
• Provision of an FFPE tumour tissue sample

Key Exclusion criteria

• Participants with endometrioid, clear cell, mucinous, or sarcomatous histology, mixed tumours containing any of the above histologies, or low-grade or borderline ovarian tumour.
• Primary platinum-refractory disease, defined as disease that did not respond to or has progressed ≤ 3 months after the last dose of first line platinum-containing chemotherapy.
• Participants with active or chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring
• Current signs, symptoms, or clinical investigations consistent with bowel obstruction, including sub-occlusive disease.
• Participant has non-infectious ILD/pneumonitis or has a history of non-infectious ILD/pneumonitis that required oral or IV steroids or supplemental oxygen, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• Prior treatment with any FRα-targeted therapy, including MIRV, or any TOP1i ADC.
• Major surgical procedure within 4 weeks of the first dose of study intervention

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles.

When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment https://vivli.org/. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.