Study of Durvalumab+Olaparib or Durvalumab After Treatment With Durvalumab and Chemotherapy in Patients With Lung Cancer (ORION) (ORION)

A Phase II Randomized, Multi-Center, Double-Blind, Global Study to Determine the Efficacy and Safety of Durvalumab Plus Olaparib Combination Therapy Compared With Durvalumab Monotherapy as Maintenance Therapy in Patients Whose Disease Has Not Progressed Following Standard of Care Platinum-Based Chemotherapy With Durvalumab in First Line Stage IV Non Small Cell Lung Cancer (ORION)

This is a randomized, double-blind, multi-center, global Phase II study to determine the efficacy and safety of Durvalumab plus Olaparib combination therapy compared with Durvalumab monotherapy as maintenance therapy in patients whose disease has not progressed following Standard of Care (SoC) platinum-based chemotherapy with Durvalumab as first-line treatment in patients with Stage IV non small-cell lung cancer (NSCLC) with tumors that lack activating epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusions.

Study Overview

• Status: Active, not recruiting
• Conditions: Non-small Cell Lung Cancer NSCLC
• Intervention / Treatment: Drug: Durvalumab; Drug: Olaparib; Drug: Nab-paclitaxel+carboplatin; Drug: Gemcitabine+carboplatin; Drug: Pemetrexed+carboplatin; Drug: Gemcitabine+cisplatin; Drug: Pemetrexed+cisplatin; Drug: Placebo for Olaparib

Detailed Description

Adult patients with a histologically or cytologically documented advanced NSCLC not amenable to curative surgery or radiation with tumors that lack activation EGFR mutations and ALK fusions are eligible for enrollment. During the initial therapy phase, patients will receive treatment with Durvalumab along with the Investigator's choice of platinum-based doublet therapy for squamous NSCLC (nab-paclitaxel plus carboplatin or gemcitabine plus carboplatin/cisplatin) and non-squamous NSCLC (nab-paclitaxel plus carboplatin or pemetrexed plus carboplatin/cisplatin) for 4 cycles. Patients who have completed 4 cycles and not progressed throughout the initial therapy phase will be randomized in a 1:1 ratio into the maintenance phase of the study to receive either Durvalumab plus placebo or Durvalumab plus Olaparib maintenance therapy. Patients will receive maintenance treatment until specific discontinuation criteria are met, including clinical disease progression (as assessed by the Investigator) or RECIST 1.1-defined radiological Progressive Disease (PD), unacceptable toxicity, and withdrawal of consent. Tumor evaluation scans will be performed until objective disease progression as efficacy assessments. All patients will be followed for survival until the end of the study.

• Study Type: Interventional
• Enrollment (Actual): 401
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Aalst, Belgium, 9300
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
  • Roeselare, Belgium, 8800
    • Research Site
• Hungary
  • Budapest, Hungary, 1122
    • Research Site
  • Budapest, Hungary, 1088
    • Research Site
  • Debrecen, Hungary, 4032
    • Research Site
  • Deszk, Hungary, 6772
    • Research Site
  • Farkasgyepü, Hungary, 8582
    • Research Site
  • Törökbálint, Hungary, 2045
    • Research Site
• India
  • Ahmedabad, India, 380009
    • Research Site
  • Ahmedabad, India, 380053
    • Research Site
  • Jamnagar, India, 361008
    • Research Site
  • Kochi, India, 682026
    • Research Site
  • Mysuru, India, 570021
    • Research Site
  • Nashik, India, 422004
    • Research Site
  • Nashik, India, 422009
    • Research Site
  • Pune, India, 411001
    • Research Site
  • Thiruvananthapuram, India, 695011
    • Research Site
• Japan
  • Chūōku, Japan, 104-0045
    • Research Site
  • Kanazawa, Japan, 920-8641
    • Research Site
  • Kurume-shi,, Japan, 830-0011
    • Research Site
  • Matsuyama, Japan, 791-0280
    • Research Site
  • Nagoya, Japan, 460-0001
    • Research Site
  • Sendai, Japan, 980-0873
    • Research Site
  • Sunto-gun, Japan, 411-8777
    • Research Site
  • Ube-shi, Japan, 755-0241
    • Research Site
• Mexico
  • Chihuahua City, Mexico, 31200
    • Research Site
  • Culiacán, Mexico, 80230
    • Research Site
  • San Luis Potosí City, Mexico, 78250
    • Research Site
• Netherlands
  • Blaricum, Netherlands, 1261
    • Research Site
  • Harderwijk, Netherlands, 3844
    • Research Site
  • Tilburg, Netherlands, 5022 GC
    • Research Site
• Poland
  • Bialystok, Poland, 15-540
    • Research Site
  • Lodz, Poland, 90-302
    • Research Site
  • Poznan, Poland, 60-693
    • Research Site
  • Prabuty, Poland, 82-550
    • Research Site
• Russia
  • Arkhangelsk, Russia, 163045
    • Research Site
  • Chelyabinsk, Russia, 454092
    • Research Site
  • Kursk, Russia, 305524
    • Research Site
  • Moscow, Russia, 115478
    • Research Site
  • Nal'chik, Russia, 360000
    • Research Site
  • P. Herzen Moscow Oncology Rese, Russia, 125284
    • Research Site
  • Saint Petersburg, Russia, 197022
    • Research Site
  • Sochi, Russia, 354000
    • Research Site
  • Yaroslavl, Russia, 150054
    • Research Site
• South Korea
  • Dongjakgu, South Korea, 07061
    • Research Site
  • Goyang-si, South Korea, 10408
    • Research Site
  • Seodaemun-gu, South Korea, 03722
    • Research Site
  • Seoul, South Korea, 05505
    • Research Site
  • Seoul, South Korea, 06351
    • Research Site
  • Suweonsi Paldalgu, South Korea, 16247
    • Research Site
• Ukraine
  • Dnipro, Ukraine, 49102
    • Research Site
  • Kharkiv Region, Ukraine, 61024
    • Research Site
  • Kirovohrad, Ukraine, 25006
    • Research Site
  • Odesa, Ukraine, 65055
    • Research Site
  • Uzhhorod, Ukraine, 88000
    • Research Site
  • Zaporizhzhia, Ukraine, 69059
    • Research Site
• United Kingdom
  • Dundee, United Kingdom, DD1 9SY
    • Research Site
  • Hull, United Kingdom, HU6 7RX
    • Research Site
• United States
  • Florida
    • Bonita Springs, Florida, United States, 34135
      • Research Site
    • St. Petersburg, Florida, United States, 33705
      • Research Site
    • Tallahassee, Florida, United States, 32308-5304
      • Research Site
    • West Palm Beach, Florida, United States, 33401
      • Research Site
  • Missouri
    • Kansas City, Missouri, United States, 64132
      • Research Site
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18015
      • Research Site
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Research Site
    • Nashville, Tennessee, United States, 37203
      • Research Site
  • Texas
    • Houston, Texas, United States, 77090
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

- Histologically or cytologically documented Stage IV NSCLC not amenable to curative surgery or radiation.

Patients must have tumors that lack activating EGFR mutations and ALK fusions.

• (WHO)/(ECOG) performance status of 0 or 1
• No prior chemotherapy or any other systemic therapy for Stage IV NSCLC
• Adequate organ and marrow function without blood transfusions in the past 28 days,
• At least 1 tumor lesion, not previously irradiated, that can be accurately measured as per RECIST 1.1.

Key Inclusion criteria for randomization to maintenance treatment:

• Documented radiographic evidence of CR, PR, or Stable Disease (SD) as per Investigator-assessed RECIST 1.1 following 4 cycles of platinum-based chemotherapy.
• Creatinine Clearance (CrCl) ≥51 mL/min calculated by the investigator or designee using the Cockcroft-Gault equation or measured by 24-hour urine collection.
• Ability to swallow whole oral medications.
• All patients must provide a formalin-fixed, paraffin embedded tumor sample for tissue-based immunohistochemistry staining and DNA sequencing to determine PD-L1 expression, HRRm status, and other correlatives: either newly acquired or archival tumor samples (<3 years old) are acceptable. If available, a newly acquired tumor biopsy, collected as part of routine clinical practice, is preferred. If not available, an archival sample taken <3 years prior to screening is acceptable. If both an archival sample and a fresh tumor biopsy sample are available, both samples should be submitted for analysis and must be submitted as different samples using different accession numbers. Slides from different blocks cannot be mixed and submitted with the same kit.

Exclusion criteria

• Mixed small-cell lung cancer and sarcomatoid variant NSCLC histology.
• Prior exposure to any chemotherapy agents (except chemotherapy or chemoradiation for non-metastatic disease), polyadenosine 5'diphosphoribose [poly (ADP ribose)] polymerase (PARP) therapy, or immunomediated therapy
• Active or prior documented autoimmune or inflammatory disorders.
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of Investigational Product (IP)
• untreated (CNS) metastases and/or carcinomatous meningitis
• Active infection.

Exclusion criteria to be randomized to maintenance treatment:

• Inability to complete 4 cycles of platinum-based chemotherapy for any reason or discontinuation of Durvalumab during initial therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Durvalumab/Olaparib Combination Therapy; Durvalumab/Olaparib Combination Therapy: Durvalumab/SoC chemotherapy (initial therapy phase) followed by Durvalumab/Olaparib (maintenance phase)	Drug: Durvalumab; Initial therapy phase: IV infusion q3w for 4 cycles. Maintenance phase: IV infusion q4w.; Other Names: MEDI4736 (Durvalumab); Drug: Olaparib; 150-mg tablets (2 × 150-mg tablets for 300-mg dose) 100-mg tablet available if dose reductions are required; Other Names: AZD2281 (Olaparib); Drug: Nab-paclitaxel+carboplatin; Standard of Care chemotherapy (squamous and non-squamous patients); Drug: Gemcitabine+carboplatin; Standard of Care chemotherapy (squamous patients only); Drug: Pemetrexed+carboplatin; Standard of Care chemotherapy (non-squamous patients only); Drug: Gemcitabine+cisplatin; Standard of Care chemotherapy (squamous patients only); Drug: Pemetrexed+cisplatin; Standard of Care chemotherapy (non-squamous patients only)
Experimental: Durvalumab Monotherapy; Durvalumab Monotherapy: Durvalumab/SoC chemotherapy (initial therapy phase) followed by Durvalumab/placebo (maintenance phase)	Drug: Durvalumab; Initial therapy phase: IV infusion q3w for 4 cycles. Maintenance phase: IV infusion q4w.; Other Names: MEDI4736 (Durvalumab); Drug: Nab-paclitaxel+carboplatin; Standard of Care chemotherapy (squamous and non-squamous patients); Drug: Gemcitabine+carboplatin; Standard of Care chemotherapy (squamous patients only); Drug: Pemetrexed+carboplatin; Standard of Care chemotherapy (non-squamous patients only); Drug: Gemcitabine+cisplatin; Standard of Care chemotherapy (squamous patients only); Drug: Pemetrexed+cisplatin; Standard of Care chemotherapy (non-squamous patients only); Drug: Placebo for Olaparib; Matching tablet; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Progression-free survival (PFS) based on investigator assessments according to Response Evaluation Criteria in Solid Tumours version 1.1. PFS is defined as time from date of randomization until the date of objective radiological disease progression using Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) or death (by any cause in the absence of progression).	From randomization until date of objective radiological disease progression or death, or last evaluable assessment in the absence of progression, up to 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall survival (OS) across the maintenance phase. OS is defined as time from date of randomization until the date of death by any cause	From randomization until the date of death due to any cause, up to 18 months.
Objective Response Rate	Objective response rate (ORR) defined as number of participants with complete response (CR) or partial response (PR) after randomization	From randomization until date of objective radiological disease progression or death, or last evaluable assessment in the absence of progression, up to 18 months
Duration of Response	Duration of response (DoR) defined as time from the date of first documented response following randomization until the first date of documented progression or death in the absence of disease progression. Percentage of participants remaining in response at 3, 6, 9 and 12 months estimated using the Kaplan-Meier method.	From date of first documented response until objective radiological disease progression or death, up to 18 months.
Progression-free Survival in Homologous Recombination Repair Related Gene Mutation (HRRm) Population	Progression-free survival in homologous recombination repair related gene mutation (HRRm) population defined as time from date of randomization until the date of objective radiological disease progression in HRRm population using Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) or death (by any cause in the absence of progression).	From randomization until date of objective radiological disease progression or death, or last evaluable assessment in the absence of progression, up to 18 months
Concentration of Durvalumab	Concentration (pharmacokinetics) of durvalumab	Assessed from start of initial therapy up to 2 years.
Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-Lung Cancer (LC)13	Disease-related symptoms assessed by change from baseline (for maintenance phase) in EORTC QLQ-LC13. Average adjusted mean over first 11 cycles is presented. The EORTC QLQ-LC13 was scored according to the published scoring manual. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales in the EORTC QLQ-LC13. Higher scores on symptom scales represent greater symptom severity.	From randomization until date of objective radiological disease progression or death, or last evaluable assessment in the absence of progression, up to 18 months
Time to Deterioration in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-Lung Cancer (LC)13	Disease-related symptoms assessed by time to deterioration (for maintenance phase) in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-Lung Cancer (LC)13. Symptom deterioration is defined as an increase in the score from baseline of less than or equal to 10) that is confirmed at a subsequent assessment, or death (by any cause) in the absence of a clinically meaningful symptom deterioration. NA is "not applicable". The upper confidence limit was not calculable because of an insufficient number of participants with events.	From randomization until date of objective radiological disease progression or death, or last evaluable assessment in the absence of progression, up to 18 months
Change From Baseline in EORTC Quality of Life Questionnaire (QLQ) QLQ-C30	Disease-related symptoms and health-related quality of life (HRQoL) assessed by change from baseline (for maintenance phase) in EORTC QLQ-C30. Average adjusted mean over first 11 cycles is presented. The EORTC QLQ-C30 was scored according to the published scoring manual. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales, each of the function scales, and the global health status/QoL scale in the EORTC QLQ-C30. Higher scores on the global health status and function scales indicate better health status/function. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / quality of life (QoL) represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.	Includes all assessments occurring within the first 12 months of randomization or until disease progression, up to 18 months.
Time to Deterioration in EORTC Quality of Life Questionnaire (QLQ) QLQ-C30	Disease-related symptoms and health-related quality of life (HRQoL) assessed by time to deterioration (for maintenance phase) in EORTC QLQ-C30. NA is "not applicable". The upper confidence limit was not calculable because of an insufficient number of participants with events.	From randomization until date of first symptom deterioration that is confirmed, up to 18 months.
Presence of Anti-drug Antibodies (ADAs) for Durvalumab	Presence of anti-drug antibodies (ADAs) for durvalumab, as assessed at 3, 6, 12, 16 and 20 weeks after start of treatment and every 12 weeks thereafter until 3 and 6 months after last dose of durvalumab	Assessed from start of initial therapy up to 2 years.
Number of Participants With Treatment-Related Adverse Events	Number of Participants with Treatment-Related Adverse Events as Assessed by Common Terminology Criteria for Adverse Events (CTCAE)	From randomization until date of objective radiological disease progression or death, or last evaluable assessment in the absence of progression, up to 18 months

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Myung-Ju Ahn, MD, Sungkyunkwan University School of Medicine, 135-710, Seoul, Korea

Publications and helpful links

General Publications

• Ahn MJ, Bondarenko I, Kalinka E, Cho BC, Sugawara S, Galffy G, Shim BY, Kislov N, Nagarkar R, Demedts I, Gans SJM, Mendoza Oliva D, Stewart R, Lai Z, Mann H, Shi X, Hussein M. Durvalumab in Combination With Olaparib Versus Durvalumab Alone as Maintenance Therapy in Metastatic NSCLC: The Phase 2 ORION Study. J Thorac Oncol. 2023 Nov;18(11):1594-1606. doi: 10.1016/j.jtho.2023.06.013. Epub 2023 Jun 29.

Helpful Links

• Related Info
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Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2018
• Primary Completion (Actual): January 11, 2021
• Study Completion (Estimated): September 27, 2026

Study Registration Dates

• First Submitted: November 27, 2018
• First Submitted That Met QC Criteria: December 11, 2018
• First Posted (Actual): December 14, 2018

Study Record Updates

• Last Update Posted (Actual): May 1, 2026
• Last Update Submitted That Met QC Criteria: April 30, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: NSCLC; Olaparib; Maintenance; Durvalumab; Homologous Recombination Repair (HRR)
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents, Immunological; Poly(ADP-ribose) Polymerase Inhibitors; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; durvalumab; olaparib
• Other Study ID Numbers: D9102C00001; 2018-003460-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No