1686TiP - Olaparib and durvalumab (MEDI4736) phase II study in patients with metastatic pancreatic cancer and DNA damage repair genes alterations

Background

Patients with metastatic pancreatic cancer (mPC) and germline mutations in BRCA1/2 genes benefit from PARP inhibitors. In addition, some studies have demonstrated that PDL-1 inhibitors therapeutically synergize with PARP inhibitors in tumours with DNA homologous repair deficiency. Our hypothesis is that patients with alterations in DNA damage repair genes (somatic or germline BRCA1, BRCA2, PALB2, RAD51C, RAD51D and other functional DDR genes) who have benefitted from platinum-based therapy might derive additional benefit from the combination of olaparib and durvalumab.

Trial design

This is an open-label, single-arm, phase II clinical trial opened to accrual in 15 Spanish hospitals attesting the combination of olaparib (300 mg (2x150 mg tablets) bid and durvalumab (1500 mg IV infusion Q4W) in patients with mPC. Patients are eligible for the study based on alterations in a panel of specific DDR genes including BRCA1, BRCA2, PALB2, RAD51C, RAD51D and other DDR genes, as determined by a local assay or by the central laboratory (if local assay is not available). Main inclusion criteria: age ≥18 years, alterations in DNA Damage Repair genes, up to 2 lines of prior chemotherapy for metastatic disease, have derived benefit from platinum-based chemotherapy and not presented progression to platinum-based chemotherapy, ECOG performance status 0-1 and adequate bone marrow, renal and liver function. Main exclusion criteria: other malignancies, unless curatively treated with no evidence of disease for ≥5 years. Patients with a history of uncontrolled clinically significant, symptomatic cardiovascular disease within 6 months before trial enrolment are excluded. Primary objective is to evaluate the efficacy of olaparib in combination with durvalumab in terms of overall response rate. Secondary objectives: progression-free survival, overall survival, duration of response, disease control rate and safety and tolerability. Exploratory objectives: impact of baseline and on treatment biomarkers predictive of the efficacy. The trial is in progress; 10 of up to 40 planned patients have been recruited at the end of April 2023 (first patient in November 2022).

Clinical trial identification

NCT05659914.

Editorial acknowledgement

Legal entity responsible for the study

Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD).

Funding

AstraZeneca.

Disclosure

T. Macarulla: Financial Interests, Personal, Advisory Board: Ability Pharmaceutical, SL, AstraZeneca, Basilea Pharma, Batxer, BioLineRX Ltd, Celgene SLU, Eisai, Ipsen Pharma, Incyte; Financial Interests, Personal, Other, Direct research fund: Servier, Merck, Sharp and Dhome, Novocure, QED Therapeutics Inc., Roche, Sanofi-Aventis, Zymeworks; Financial Interests, Personal, Invited Speaker: Lilly, Janssen; Financial Interests, Institutional, Research Grant: Amc Medical Research, ARMO Biosciences, Basilea, BioKeralty Research Institute, Merck Sharp & Dohme, Oncomed Pharmaceuticals, QED Therapeutics, Vcn Biosciences, AbbVie Farmaceútica, Ability Pharmaceuticals, Agios, Amgen, Aslan, AstraZecena, Bayer, BeiGene, Biolinerx, Blueprint Medicines, Boston Biomedical, Bristol Myers Squibb (BMS), Cantargia, Celgene, Eisai, Erytech Pharma, F. Hoffmann-la Roche, FibroGen, Genentech, Hallozyme, Immunomedics, Incyte, Ipsen, Lab. Menarini, Lilly, Loxo Oncology, MedImmune, Merimarck, Novocure, Millenim, Nelum, Novartis, Zymeworks, Pfizer, Pharmacyclics, Roche; Non-Financial Interests, Member: American Society of Clinical Oncology - ASCO, “Sociedad Española de Oncología Médica” – SEOM, Sociedad Europea de Oncología Médica - ESMO. M. Lobo de Mena: Financial Interests, Personal, Invited Speaker: Leo Pharma, Servier. R. Garcia-Carbonero: Financial Interests, Personal, Advisory Board: AAA, Advanz Pharma, Amgen, Bayer, BMS, HMP, Ipsen, Merck, Midatech, MSD, Novartis, PharmaMar, Pierre Fabre, Servier; Financial Interests, Institutional, Research Grant: BMS, MSD, Pfizer; Non-Financial Interests, Leadership Role, Global PI of investigator-initiated clinical trials (AXINET, NICENEC, PEMBROLA): BMS, MSD, Pfizer; Other, Other, Honoraria received by spouse for advisory board or invited speaker roles: AbbieVie, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Genomica, Lilly, MSD, Merck, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, Takeda. R.A. Pazo Cid: Financial Interests, Personal, Advisory Board: Roche, BMS, Servier, Ipsen, Lilly, AstraZeneca; Financial Interests, Personal, Invited Speaker: Servier, BMS, Roche, Eisai; Financial Interests, Personal and Institutional, Local PI, Support for manuscript presentation (funding, provision of study materials, medical writing, article processing charges): Ipsen, Astellas. J. Gallego Plazas: Financial Interests, Personal, Advisory Board: AAA, Amgen, Bayer, BMS, Eisai, Ipsen, Lilly, Merck, MSD, Pierre-Fabre, Roche, Servier; Financial Interests, Personal, Invited Speaker: AAA, Amgen, Bayer, BMS, Ipsen, Lilly, Merck, MSD, Novartis, Servier; Financial Interests, Personal, Other, Educational: Amgen, Ipsen, Merck, Novartis, Pierre-Fabre, Roche; Financial Interests, Institutional, Funding: Astellas, AstraZeneca, BMS, Daiichi Sankyo, Lilly, Servier; Financial Interests, Member of Board of Directors: Spanish Society Medical Oncology, Spanish Group Of Neuroendocrine an Endocrine Tumours; Financial Interests, Project Lead: AGAMENON-SEOM Registry of Esophagohastric Cancer. I.C. Ales Diaz: Financial Interests, Personal, Advisory Board: Lilly, BMS, Merck, AstraZeneca. B. García Paredes: Financial Interests, Personal, Other, Travel and accommodation expenses: Servier, Novartis, Merck, Advanced Accelerator Applications. P. Espinosa Olarte: Financial Interests, Personal, Other, Travel and accommodation expenses: Roche. E. Aranda Aguilar: Financial Interests, Personal, Advisory Board: Amgen, Bayer, Bristol Myers Squibb, Merck, Roche, Sanofi, Servier. All other authors have declared no conflicts of interest.