Randomized Phase III Trial Testing Maintenance Olaparib Versus Observation After Adjuvant Chemoradiation for p53abn Endometrial Cancer

Key inclusion criteria for RAINBO program:

• Histologically confirmed diagnosis of EC (all grades and the following histologicsubtypes : endometrioid, serous, clear cell, de-/undifferentiated carcinomas, anduterine carcinosarcoma).

• Molecular classification performed following the diagnostic algorithm described inWHO 2020 (adapted from Vermij et al.)

• TLH-BSO or TAH-BSO with or without lymphadenectomy or sentinel node biopsy, withoutmacroscopic residual disease after surgery

• No distant metastases as determined by pre-surgical or post-surgical imaging (CTscan of chest, abdomen and pelvis or PET-CT scan)

• Written informed consent prior to any study specific procedures

• Age >= 18 years

• Patients must have a life expectancy ≥ 16 weeks

• Patients must be accessible for treatment and follow-up

• Written informed consent for one of the RAINBO trials and the overarching researchproject according to the local Ethics Committee requirements.

Inclusion criteria specific for p53abn-RED Trial:

• WHO Performance score 0-1

• Histologically confirmed Stage I to III EC with myometrial invasion

• Molecular classification: p53abn EC*

• Body weight > 30 kg

• Patient must receive or have received a sequential radiotherapy and chemotherapypreferably given according to the PORTEC-3 regimen and should be started within 6 to 8 weeks after surgery and no later than 10 weeks: two cycles of intravenouscisplatin 50mg/m² in the first and fourth week of the pelvic external beamradiotherapy (EBRT) +/- vaginal brachytherapy followed by four cycles of intravenouscarboplatin AUC 5 and paclitaxel 175 mg/m² at 21-day intervals.

However the sequence of chemotherapy , number of cycles and inclusion of cisplatin may be altered according to local practice at the investigator's discretion.

This may include;

• 4 cycles carboplatin & paclitaxel before or after radiotherapy with 2 cyclescisplatin

• 4 cycles carboplatin & paclitaxel before or after radiotherapy (no cisplatin)

• 6 cycles carboplatin & paclitaxel before or after radiotherapy (no cisplatin)

• Patients registered after their standard treatment must:

• provide a tumor assessment performed within the 4 weeks before the start ofRT/CT. This will be considered as the M0.

• have started RT/CT 6 to 8 weeks after surgery. A maximum gap of 10 weeks isaccepted.

• be randomized within two weeks before maintenance or observation.

• Adequate systemic organ function: Patients must have normal organ and bonemarrow function measured within 28 days prior to administration of studytreatment as defined below:

• Creatinine clearance (> 50 cc/min): Patients must have creatinine lessthan 1.5 ULN or calculated creatinine clearance estimated of ≥ 51 mL/minusing the Cockcroft-Gault equation or based on a 24 hour urine test.Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F) /serum creatinine (mg/dL) x 72

• Adequate bone marrow function : hemoglobin ≥10.0 g/dl with no bloodtransfusion in the past 28 days, Absolute neutrophil count (ANC) ≥1.5 x 109/l, platelet count ≥ 100 x 109/l.

• Adequate liver function: bilirubin ≤1.5 x institutional upper limit ofnormal (ULN). This will not apply to patients with confirmed Gilbert'ssyndrome (persistent or recurrent hyperbilirubinemia that is predominantlyunconjugated in the absence of hemolysis or hepatic pathology), who willbe allowed only in consultation with their physician.

• ALT (SGPT) and/or AST (SGOT) ≤2.5 x ULN

• *Molecular classification must be performed according to the diagnosticalgorithm presented in the WHO 2020 (Vermij et al. 2020). For the p53abn-REDtrial this means that MMR and POLE status must be determined, and must be pMMRand POLE wildtype (or non-pathogenic) for inclusion. For details on themolecular classification see 7.1: Diagnostic algorithm for molecularclassification.

• Patient should understand, sign, and date the written informed consent formprior to any protocol-specific procedures performed. Patient should be able andwilling to comply with study visits and procedures as per protocol.

• Patients must be affiliated to a social security system or beneficiary of thesame

Exclusion Criteria:

Exclusion criteria for RAINBO program

• FIGO Stage IV disease of any histology even if there is no evidence of disease aftersurgery

• Prior pelvic irradiation

Exclusion criteria specific for p53abn-RED Trial:

• Other malignancy unless curatively treated with no evidence of disease for ≥5 yearsexcept: adequately treated non-melanoma skin cancer, curatively treated in situcancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrialcarcinoma.

• Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, asjudged by the investigator (eg., unstable ischemia, uncontrolled symptomaticarrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolytedisturbances, etc.), or patients with congenital long QT syndrome.

• Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade

2. caused by previous cancer therapy, excluding alopecia.

• Immunocompromised patients, e.g., patients who are known to be serologicallypositive for human immunodeficiency virus (HIV).

• Patients receiving any systemic chemotherapy or radiotherapy (except for palliativereasons) within 3 weeks prior to study treatment

• Patients considered a poor medical risk due to a serious, uncontrolled medicaldisorder, non-malignant systemic disease or active, uncontrolled infection. Examplesinclude, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstablespinal cord compression, superior vena cava syndrome, extensive interstitialbilateral lung disease on High Resolution Computed Tomography (HRCT) scan or anypsychiatric disorder that prohibits obtaining informed consent.

• Major surgical procedure (as defined by the Investigator) within 2 weeks priorrandomization and patients must have recovered from any effects of any majorsurgery.

• Significant traumatic injury within 4 weeks of the first dose of olaparib.

• History of allogenic organ transplantation.

• Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantiallyincrease risk of incurring AEs or compromise the ability of the patient to givewritten informed consent.

• Patient with severe hepatic impairment

• Any previous treatment with a PARP inhibitor, including olaparib.

• History of active primary immunodeficiency

• History or evidence of hemorrhagic disorders within 6 months prior to randomization

• Patients with myelodysplastic syndrome/acute myeloid leukemia history or withfeatures suggestive of MDS/AML.

• Previous allogenic bone marrow transplant or double umbilical cord bloodtransplantation (dUCBT)

• Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and TB testing in line withlocal practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),hepatitis C, or human immuno-deficiency virus (positive HIV 1/2 antibodies).Patients with a past or resolved HBV infection (defined as the presence of hepatitisB core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive forhepatitis C (HCV) antibody are eligible only if polymerase chain reaction isnegative for HCV RNA.

• Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The requiredwashout period prior to starting olaparib is 2 weeks.

• Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) ormoderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washoutperiod prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3weeks for other agents.

• Patients unable to swallow orally administered medication and patients withgastrointestinal disorders likely to interfere with absorption of the studymedication.

• Medical or psychological condition which in the opinion of the investigator wouldnot permit the patient to complete the study or sign meaningful informed consent.

• Patient under guardianship or deprived of his liberty by a judicial oradministrative decision or incapable of giving its consent

• Patients with a known hypersensitivity to olaparib or any of the excipients of theproduct.

• Treatment with an unlicensed or investigational product within 4 weeks of trialentry.

• Breastfeeding patients