A Phase 2, Open-label, Multicenter, Randomized Study of Trastuzumab Deruxtecan Versus Investigator's Choice Chemotherapy in Recurrent Ovarian Cancer That Progressed on Prior PARP Inhibitor Therapy: TROY (APGOT-OV14)
Ovarian, fallopian tube, and peritoneal cancers are often diagnosed at an advanced stage, requiring chemotherapy. Recently, the standard treatment, platinum-based chemotherapy plus PARP inhibitors, has extended disease-free survival (PFS). However, most patients eventually develop resistance to PARP inhibitors and become unresponsive to conventional treatments. Therefore, an effective standard treatment for patients who relapse after PARP inhibitor resistance has not yet been established. Meanwhile, HER2 protein expression has been identified in some patients, drawing attention as a new therapeutic target. Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC) targeting HER2, has already demonstrated efficacy and safety in other HER2-positive cancers. This study aimed to explore the potential of T-DXd as a new treatment option by evaluating the efficacy and safety of T-DXd in patients with ovarian, fallopian tube, and peritoneal cancer who relapsed after PARP inhibitor treatment and who express HER2. Participants will: * Arm A: T-DXd +/- Bevacizumab, IV, every 3weeks * Arm B: Platinum-based chemotherapy +/- Bevacizumab, IV
• 1\. Adults ≥18 years of age on the day of signing the Informed Consent Form. Follow local regulatory requirements if the legal age of consent for trial participation is \>18 years old.
• 2\. Patient has signed the Informed Consent (ICF) and is able to comply with protocol requirements.
• 3\. Has HER2 expression per 2016 ASCO-CAP gastric cancer IHC scoring (3+/2+/1+) guidelines by local tests.
• 4\. Availability of tumor tissue for translational research: A formalin-fixed paraffin-embedded (FFPE) tumorblock (preferred) or at least 20 slides (unstained, freshly cut, serial sections) must be submitted.
• 5\. Histologically confirmed high grade serous or high grade endometrioid ovarian, primary peritoneal, and/or fallopian tube cancer that is recurrent.
• 6\. Patient with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
• 7\. Radiologically confirmed/documented disease progression while on PARP inhibitor therapy in either first or second-line maintenance setting Note: Documentation of disease progression must be within 180 days of last PARPi dose taken. Surgical salvage intervention and/or focal ablative therapies are allowed.
⁃ Clinically benefited from PARPi maintenance prior to documented progression, as defined by at least 6 months of treatment duration with no progressive disease observed.
⁃ Progression on first-line maintenance PARP inhibitor: Participants are allowed maximum 1 additional line of platinum-based chemotherapy before study entry (note: treatment-free interval on platinum rechallenge must be \> 6 months, with documented disease progression prior to study entry.
⁃ Progression on second-line maintenance PARP inhibitor: Participants are not allowed any additional systemic anticancer treatment before study entry.
‣ 8\. Patient with measurable disease according RECIST 1.1 criteria. 9. LVEF ≥50% within 28 days before randomization. 10. Patient has adequate organ function, defined as follows:
• a) Absolute neutrophil count ≥ 1,500 cells/μL b) Platelets ≥ 100,000 cells/μL c) Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L d) Serum creatinine ≤ 1.5× upper limit of normal (ULN) or calculated creatinine clearance ≥ 50mL/min using the Cockcroft-Gault equation for patients with creatinine levels \> 1.5× institutional ULN e) Total bilirubin ≤ 1.5× ULN (≤ 2.0 x ULN in patients with known Gilbert's syndrome) or direct bilirubin ≤ 1× ULN f) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5× ULN unless liver metastases are present, in which case they must be ≤ 5× ULN g) International normalized ratio or prothrombin time (PT) ≤1.5× ULN and activated partial thromboplastin time ≤1.5× ULN. Patients receiving anticoagulant therapy must have a PT or partial thromboplastin within the therapeutic range of intended use of anticoagulants.
• 11\. Patient must have a negative serum pregnancy test within 72 hours of the first dose of study medication, unless they are of nonchildbearing potential. Nonchildbearing potential is defined as follows:
⁃ Patient is ≥ 45 years of age and has not had menses for \> 1 year.
⁃ A follicle-stimulating hormone value in the postmenopausal range upon screening evaluation if amenorrhoeic for \< 2 years without a hysterectomy and oophorectomy.
⁃ Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation:
• Documented hysterectomy or bilateral oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound, MRI, or CT scan.
• Tubal ligation must be confirmed with medical records of the actual procedure.
• Information must be captured appropriately within the site's source documents. 12. Patient of childbearing potential must agree to use a highly effective method of contraception with their partners starting from time of consent through 150 days after the last dose of study treatment. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient (Information must be captured appropriately within the site's source documents) 13. Has proteinuria \<2+. If proteinuria is ≥2+, 24-hour urine must demonstrate \<1 g of protein in 24 hours.