Study Evaluating Pembrolizumab +/- Olaparib in TLS Positive Selected Resectable STS Followed by Adjuvant Pembrolizumab

Inclusion Criteria:

* Male or female patients aged ≥ 18 years at time of informed consent signature
* Histologically confirmed diagnosis of high grade (FNCLCC grade 2 or 3) extremity, retroperitoneal, or trunk wall STS of selected histotypes as defined below. Diagnosis must be stated in a pathology report and confirmed by the physician investigator:

Cohort 1: Undifferentiated Pleomorphic Sarcoma (UPS) Cohort 2: Dedifferentiated Liposarcoma (ddLPS)

* R0 resectability at time of enrollment according to expert STS surgeon
* Absence of distant metastasis on screening CT-scan (or equivalent appropriate imaging technique)
* Patients with local relapse after an initial surgical resection can be enrolled if no perioperative chemotherapy or radiation has been previously performed Identification of Tertiary Lymphoid Structures (TLSs) on tumor archival FFPE sample, as assessed by a registered STS expert senior pathologist
* Primary tumor site measurable according to RECIST v1.1 as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and suitable for repeated assessment.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no deterioration from registration date
* Adequate hematologic and organ function, defined by the following laboratory results obtained within 3 days prior to the first study treatment (Cycle 0 Day 1): Absolute neutrophil count (ANC) ≥ 1500 cells/μL, Platelet count ≥ 100.000/μL, Hemoglobin ≥ 10 g/dL, Total bilirubin ≤ 1.5 ULN (subjects with documented/suspected Gilbert's disease may be enrolled with bilirubin ≤ 3 × ULN), Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 x upper normal limit (ULN), Albumin ≥ 28g/L, Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 30 mL/min (according to Cockcroft and Gault formula), International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN. This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such as low-molecular weight heparin or warfarin) should be on stable dose.
* Hepatitis B and C, and HIV screening tests are not required unless

  * Known history of HBV, HCV or HIV infection
  * As mandated by local health authority
* A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

  1. Not a woman of childbearing potential (WOCBP) OR
  2. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for 120 to 180 days (corresponding to time needed to eliminate any study treatment(s) plus the duration of a menstruation cycle: 120 days for pembrolizumab and/or 180 days for olaparib) after the last dose of study treatment.

Male participants:

A male participant must agree to use a contraception - Contraceptive Guidance and Pregnancy Testing of this protocol during the treatment period and for at least 180 to 240 days, corresponding to time needed to eliminate any study treatment(s) plus the duration of a spermatogenesis cycle: 180 for pembrolizumab and/or 240 days for olaparib) after the last dose of study treatment and refrain from donating sperm during this period.

* Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment.
* Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed.
* Patient should be able and willing to comply with baseline mandatory biopsy, as well as study visits and procedures as per protocol.
* Patients must be affiliated to a social security system or beneficiary of an equivalent system.

Exclusion Criteria:

* Has a visceral STS primary site.
* Has a non-resectable or marginally resectable locally advanced STS, as assessed by expert STS surgeon.
* Has evidence of metastatic disease on CT-scan (or equivalent imaging technique).
* Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization.
* Has received prior radiotherapy within 2 weeks of start of study intervention or radiation-related toxicities requiring corticosteroids.
* Has had previous exposure to anti-PD-1, anti-PD-L1, anti-PD-L2 agent or with an agent directed to another stimulatory or co inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).
* Had had previous exposure to olaparib or any other PARP inhibitor.
* Has received a live vaccine or live-attenuated vaccine received within 4 weeks prior to Cycle 0 Day 1 or anticipation that such a live attenuated vaccine will be required during the study. Administration of killed vaccines is allowed.
* Has received treatment with systemic immunostimulatory agents (e.g., IFN and IL-2) within 4 weeks prior to Cycle 0 Day 1.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
* Has had an administration of colony stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior to Cycle 0 Day 1.
* A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization (see Appendix 3 - Contraceptive Guidance and Pregnancy Testing). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
* Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
* Has a history of severe allergic, anaphylactic, or other hypersensitivity reactions to the components of excipients in pembrolizumab and/or olaparib.
* Has any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) or immunodeficiency
* Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (e.g.., thyroxine, insulin, or physiologic corticosteroid)
* Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
* Has a history of allogeneic tissue/organ or hematopoietic stem cell transplantation.
* Has a history of another primary malignancy within 2 years prior to Cycle 0 Day 1
* Has a serious, uncontrolled medical disorder
* Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (e.g., gastrectomy, partial bowel obstruction, and malabsorption).
* Has concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA), Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection, HIV (defined as detectable viral load)
* Has any active infection requiring systemic therapy.
* Major surgical procedure within 20 days prior ty Cycle 0 Day 1 or anticipation of need for a major surgical procedure during the course of the study.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Participant is currently receiving either strong (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 2 weeks. The medication can be restarted as soon as olaparib has been halted.
* Participant is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (e.g., bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents. The medication can be restarted as soon as olaparib has been halted.