Cardiovascular diseases and cancers, the two leading causes of death in Canada, require cholesterol to sustain their progression. All cells require cholesterol, but cancer cells have much higher needs to sustain growth, division and metastasis. The availability of new cholesterol-lowering drugs developed to protect patients from heart diseases has resulted in unprecedented low levels of cholesterol. The combination of atorvastatin, ezetimibe and Repatha, which are 3 cholesterol-lowering drugs used in combination, is safe, well tolerated and efficient over years of treatment. Recent reports indicate that abundant cholesterol supplies are required to sustain the progression of pancreatic ductal adenocarcinomas. This proof-of-concept study aims to verify the feasibility, the acceptability and gain preliminary data on adding a cholesterol shortage on top of FOLFIRINOX (standard chemotherapy) in newly diagnosed patients with locally advanced pancreatic adenocarcinomas or metastatic pancreatic adenocarcinomas. It is expected that a drug-induced cholesterol shortage will slow-down or stop the progression of pancreatic adenocarcinomas while increasing the response to chemotherapy.

Inclusion Criteria:

To be eligible to this trial, patients must fulfill the following inclusion criteria:

1. Have a histologically confirmed, treatment-naive locally advanced and inoperable (LaiPDAC) or metastatic pancreatic ductal adenocarcinoma (mPDAC).

2. Be at least 18 years or older at the time of signing the informed consent.

3. Have a life expectancy of at least 12 weeks.

4. Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale.

5. Have measurable disease as assessed by RECIST v1.1.

6. Agrees and amenable to a tumor (if deemed safe only) and liver biopsy (all participants) at baseline and on day 42 +/- 3 days. Patient that are anticoagulated at baseline are eligible provided it is deemed safe by the investigator to stop anticoagulation momentarily in order to safely proceed to a biopsy.

7. Eligible to standard-dose FOLFIRINOX as assessed by the principal investigator or a sub-investigator. FOLFIRINOX doses can be adapted according to SOC.

8. Demonstrate normal organ function as defined below. These assessments must be done within 7 days of Cycle 1 Day-7.

   Hemoglobin (Hb) ≥ 90 g/L Absolute neutrophil count ≥ 1.5 x 10 9/L Platelet count ≥ 100 x 10 9/L INR ≤ 1.3 (unless patient is anticoagulated*) aPTT ≤ 1.5 x ULN (switching to LMWH will be recommended) Total bilirubin ≤ 1.5 x ULN OR Direct bilirubin (for patients with total bilirubin ≥ 1.5 x ULN) AST and ALT ≤ 3 x ULN CPK ≤ 1.5 x ULN Serum creatinine ≤ 1.5 x ULN OR Estimated GFR (as per institutional standards) ≥ 50 ml/min

9. Provide written informed consent and able to follow the trial treatment and visit schedule.

10. For Women Of Child-Bearing Potential (WOCBP), a negative serum pregnancy test must be obtained prior to receiving the study medication.

11. WOCBP should agree to use 2 different methods of birth control OR abstain from heterosexual intercourse for the duration of the trial and up to 90 days after the last study medication administration.

12. Male subjects should agree to use an adequate method of contraception for the duration of the trial and up to 90 days after the last study medication administration. Male subjects should refrain from donating sperm during this period.

Exclusion Criteria:

To be eligible to this trial, patients must not fulfill any of the following exclusion criteria:

1. Locally advanced pancreatic ductal adenocarcinoma deemed operable.
2. Any pancreatic ductal adenocarcinoma deemed operable or borderline operable that can be treated with neoadjuvant chemotherapy.
3. Known additional malignancy that is progressing or that requires treatment. Exceptions include basal cell carcinoma of the skin, in situ bladder or in situ cervical cancer. Other malignancy may be eligible after consultation with the promotor-investigator.
4. Spinal cord compression or brain metastases unless treated, stable and not requiring steroids for at least 4 weeks prior to the initiation of study treatment.
5. Baseline myalgia or myositis of any etiology.
6. Prior treatment with FOLFIRINOX in the adjuvant setting.
7. History of clinically significant intolerance or myositis with any statin.
8. History of clinically significant intolerance or hypersensitivity to PCSK9 inhibitors or ezetimibe.
9. Baseline grade ≥ 2 ULN Creatine Phosphokinase (CPK) elevation.
10. Liver tumor burden that is deemed unsafe by the investigator.
11. Major surgery or procedure from which the patient has not yet recovered.
12. Any medical condition that puts the patient at high medical risk, including but not limited to active uncontrolled infection or active bleeding diathesis.
13. Any history of disease that, in the opinion of the investigator, puts liver function at risk including but not limited to autoimmune hepatitis or history of hepatitis B, hepatitis C or human immunodeficiency virus (HIV). Screening at baseline for those conditions is not required.
14. Use of any drugs that are contraindicated as per protocol and that cannot be changed or modified to an acceptable alternative.
15. Active smoker. Complete usage of tobacco must have been stopped for at least 3 months.
16. Abnormally low hematocrit, as assessed by the oncologist.