MAZEPPA is open-label, phase II study to assess the efficacy of a genomic-driven maintenance therapy in terms of PFS in Pancreatic ductal adenocarcinoma (PDAC) patients with disease controlled after 4 months of mFOLFIRINOX chemotherapy as following:

Patients with a BRCAness somatic profile: olaparib Arm A. Patients with no BRCAness profile and with KRAS mutation randomization between durvalumab plus selumetinib Arm B, versus FOLFIRI Arm C.

Searching for efficient maintenance therapies in metastatic PDAC patients whose disease has been controlled using an induction chemotherapy is crucial for two main reasons:

1. Patients may stop IV toxic chemotherapy while their tumor remains under control. Although up to 70% of PDAC patients achieve tumor control when treated during induction with mFOLFIRINOX, toxicity of this regimen, particularly neuropathy and fatigue, remains a key concern.
2. Tumor control may be extended, which might improve quality of life (QoL) and survival.

Patients are included in MAZEPPA study based on the genetic profile of their tumor.

• If a BRCA gene mutation is present in the tumor, treatment with the drug olaparib will be proposed (arm A), regardless of the status of the other genes analyzed.
• In the absence of a mutation in the BRCA gene and in the presence of a mutation in the KRAS gene, a treatment combining immunotherapy and targeted therapy (durvalumab and selumetinib - Arm B) or chemotherapy by FOLFIRI (arm C) will be proposed.

Inclusion Criteria:

1. Signed and dated informed consent,

2. Age ≥18 years

3. Body weight >30 kg,

4. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up,

5. Life expectancy of at least 4 months,

6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1,

7. Pathologically confirmed pancreatic adenocarcinoma with distant metastases (stage IV disease),

8. No prior therapy for metastatic disease other than mFOLFIRINOX (in case of previous adjuvant therapy, the interval between the end of adjuvant chemotherapy and relapse must be >6 months),

9. Stability or tumor response (Response evaluation criteria in solid tumors [RECIST] 1.1) after 4 months of mFOLFIRINOX (8 cycles) for metastatic disease,

10. Have tissue from archival tissue sample from surgery or biopsy identified and confirmed as available for study

11. Availability of tumor somatic genetic analyses data, performed during the first 4 months of mFOLFIRINOX (specific informed consent),

12. In case of germinal BRCA gene mutation identified before inclusion the patient can be included until olaparib receives a marketing authorization for the treatment indication of the patients in the study and the treatment is available in the retail pharmacy; it will be prescribed according to the summary product characteristics (SmPC),

13. At least one measurable or evaluable lesion as assessed by CT-scan or MRI according to RECIST 1.1 and feasibility of repeated radiological assessments,

14. Normal organ and bone marrow function prior to administration of study treatment as defined below:

    • Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days,

    • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L,

    • Platelet count ≥ 100 x 109/L,

    • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN),

    • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x institutional ULN unless liver metastases are present in which case

      ≤ 5x ULN,

    • Creatinine clearance (CrCl) ≥ 50 mL/min estimated using the Cockcroft-Gault equation, Estimated CrCl =(140-age [years]) x weight (kg) (x F)a serum creatinine (mg/dL) x 72 a F=0.85 for females and F=1 for males.

15. Absence of known dihydropyrimidine dehydrogenase (DPD) deficiency,

16. Female patients must be surgically sterile, or be post-menopausal, or have negative serum pregnancy test if pre-menopausal at inclusion and must commit to using reliable and appropriate methods of contraception during the study and during at least 6 months after the end of studytreatment (when applicable).

    Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:

    • Women < 50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the postmenopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
    • Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). All female patients with reproductive potential must have a negative pregnancy test (beta human chorionic gonadotropin [β-HCG]) within 72 hours prior to starting the protocol treatment. Breastfeeding is not allowed. Male patients must agree to use effective contraception in addition to having their partner use a contraceptive method as well during the trial and during at least 6 months after the end of the study treatment. Men and women with childhood potential are required to use adequate birth control during the study,

17. Registration in a national health care system (PUMa; Couverture Maladie Universelle included).

Exclusion Criteria:

1. Histology other than PDAC
2. Toxicities after mFOLFIRINOX treatment not resolved to ≥ grade 1 prior to maintenance treatment, except for oxaliplatin induced neuropathy, alopecia, or grade ≥ 2 are permitted
3. Patients with known brain metastases at inclusion,
4. Enrollment in another therapeutic trial
5. Evidence of interstitial lung disease, any active non-infectious pneumonitis, or known active infection including active tuberculosis
6. Hepatitis B virus (HBV; known positive HBV surface antigen (HbsAg) result), hepatitis C virus (HCV), or human immunodeficiency virus (positive HIV ½ antibodies).
7. Active uncontrolled infection, current unstable, or uncompensated respiratory or cardiac conditions, or active digestive hemorrhages less than 3 months,
8. Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study,
9. Live vaccine administration within 30 days prior to the first dose of study treatment,
10. Treatment with any other investigational medicinal product within 28 days prior to study entry,
11. Other malignancy unless curatively treated with no evidence of disease for ≥ 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), and stage 1, grade 1 endometrial carcinoma,
12. Uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, acute coronary syndrome within 6 months prior to starting treatment, prior or current cardiomyopathy, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent,
13. Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the Investigator or patients with congenital long QT syndrome. Mean corrected QT interval (QTc) for heart rate using the QTcF formula ≥ must be <470 ms,
14. Pregnancy/lactation,
15. Uncontrolled massive pleural effusion or massive ascites,
16. Tutelage or guardianship.

Arm A: Specific exclusion criteria for patients with the BRCAness profile in order to receive olaparib

1. Myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/ DS)/acute myeloid leukemia (AML),
2. Unable to swallow orally administered medication and gastrointestinal disorders likely to interfere with absorption of the study medication,
3. Any previous treatment with PARP inhibitor, including olaparib,
4. Concomitant use of known strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors. The required washout period prior to starting olaparib is 2 weeks,
5. Concomitant use of known strong or moderate CYP3A inducers.
6. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
7. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT),
8. Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable outside of 28 days prior to study treatment,
9. Known hypersensitivity to the excipients of the olaparib

Arm B/C: Specific criteria for patients without the BRCAness profile and with KRAS mutation in order to receive durvalumab:

1. Prior treatment with any of the following immune checkpoint inhibitor:

   anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody,

2. Active autoimmune disease that has required systemic treatment in the past 2 years; replacement therapy is considered a form of systemic treatment and is not a criterion of exclusion,

3. Any systemic steroid therapy whatever the duration of this corticotherapy,

4. Active or prior documented autoimmune or inflammatory disorders

Arm B/C: Specific exclusion criteria for patients without BRCAness profile and with KRAS-mutated tumors in order to receive selumetinib:

1. Cardiac conditions
2. Documented antecedent history of retinopathy or retinal disorders as known ophthalmologic conditions
3. Patients with any other significant abnormality on ophthalmic examination (performed by an ophthalmologist) should be discussed for potential ineligibility
4. The last palliative radiotherapy seance within 7 days of the first dose of study treatment