Olaparib in gBRCA Mutated Pancreatic Cancer Whose Disease Has Not Progressed on First Line Platinum-Based Chemotherapy (POLO)

A Phase III, Randomised, Double Blind, Placebo Controlled, Multicentre Study of Maintenance Olaparib Monotherapy in Patients With gBRCA Mutated Metastatic Pancreatic Cancer Whose Disease Has Not Progressed on First Line Platinum Based Chemotherapy

A Phase III, Randomised, Double Blind, Placebo Controlled, Multicentre Study of Maintenance Olaparib Monotherapy in Patients with gBRCA Mutated Metastatic Pancreatic Cancer whose Disease Has Not Progressed on First Line Platinum Based Chemotherapy

Study Overview

• Status: Completed
• Conditions: Metastatic Adenocarcinoma of the Pancreas; Germline BRCA1/2 Mutations and
• Intervention / Treatment: Drug: Olaparib; Drug: Olaparib; Drug: Placebo; Drug: Placebo

Detailed Description

Approximately 145 patients will be randomised using an Interactive Voice Response System /Interactive Web Response System (IVR/IWR system) in a 3:2 ratio (Olaparib:placebo) to the treatments as specified below:

• Olaparib tablets p.o. 300 mg twice daily
• Matching placebo tablets p.o. twice daily Eligible patients will be those patients with pancreas cancer previously treated for metastatic disease who have not progressed following completion of at least 16 weeks (can be more) of first line platinum-based chemotherapy. All patients must have a known deleterious or suspected deleterious germline BRCA mutation to be randomised; this may have been determined prior to enrolment into the study or may be assessed as part of the enrolment procedure for the study (via centrally provided MyriadIntegrated BRAC.

Patients will be randomised within 6 weeks after their last dose of chemotherapy (last dose is the day of the last infusion) and treatment started as soon as possible but no less than 4 and no more than 8 weeks of the last chemotherapy dose. At the time of starting protocol treatment, all previous chemotherapy treatment should be discontinued.

Following randomisation, patients will attend clinic visits weekly for the first 4 weeks of treatment (Days 8, 15, 22 and 29). Patients will then attend clinic visits every 4 weeks whilst on study treatment. Patients should continue to receive study treatment until objective radiological disease progression as per RECIST as assessed by the investigator and as long as in the investigator's opinion they are benefiting from treatment and they do not meet any other discontinuation criteria.

Once a patient has progressed the patient will be followed for second progression (PFS2) every 8 weeks and then survival until the final analysis.

• Study Type: Interventional
• Enrollment (Actual): 154
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Campbelltown, Australia, 2560
    • Research Site
  • Randwick, Australia, 2031
    • Research Site
  • St Leonards, Australia, 2065
    • Research Site
• Belgium
  • Antwerpen, Belgium, 2020
    • Research Site
  • Brussel, Belgium, 1070
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
• Canada
  • Toronto, Canada, M5G 2M9
    • Research Site
  • Ontario
    • London, Ontario, Canada, N6A 4L6
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Research Site
    • Sherbrooke, Quebec, Canada, J1G 2E8
      • Research Site
• France
  • Amiens, France, 80054
    • Research Site
  • Besançon, France, 25000
    • Research Site
  • Bordeaux, France, 33075
    • Research Site
  • Brest Cedex, France, 29609
    • Research Site
  • Clichy Cedex, France, 92118
    • Research Site
  • La Roche sur Yon, France, 85925
    • Research Site
  • Lille, France, 59020
    • Research Site
  • Lyon Cedex 03, France, 69437
    • Research Site
  • Nice, France, 06189
    • Research Site
  • Paris, France, 75014
    • Research Site
  • Paris CEDEX 14, France, 75674
    • Research Site
  • Poitiers, France, 86021
    • Research Site
  • STRASBOURG Cedex, France, 67065
    • Research Site
  • Toulouse, France, 31059
    • Research Site
  • Villejuif, France, 94800
    • Research Site
• Germany
  • Berlin, Germany, D-13353
    • Research Site
  • Berlin, Germany, 10967
    • Research Site
  • Bochum, Germany, 44791
    • Research Site
  • Bonn, Germany, 53127
    • Research Site
  • Dresden, Germany, 01307
    • Research Site
  • Frankfurt am Main, Germany, 60596
    • Research Site
  • Hamburg, Germany, 20246
    • Research Site
  • Hamburg, Germany, 22291
    • Research Site
  • Hannover, Germany, 30625
    • Research Site
  • Leipzig, Germany, 04103
    • Research Site
  • München, Germany, 81675
    • Research Site
  • Schweinfurt, Germany, 97422
    • Research Site
  • Ulm, Germany, 89081
    • Research Site
• Israel
  • Beer Sheva, Israel, 84101
    • Research Site
  • Haifa, Israel, 3109601
    • Research Site
  • Holon, Israel, 58100
    • Research Site
  • Nahariya, Israel, 22100
    • Research Site
  • Petah Tikva, Israel, 4941492
    • Research Site
  • Ramat Gan, Israel, 5265601
    • Research Site
  • Rehovot, Israel, 76100
    • Research Site
  • Tel Aviv, Israel, 6423906
    • Research Site
  • Zefir, Israel, 7030000
    • Research Site
• Italy
  • Bologna, Italy, 40138
    • Research Site
  • Milano, Italy, 20132
    • Research Site
  • Milano, Italy, 20133
    • Research Site
  • Padova, Italy, 35128
    • Research Site
  • Parma, Italy, 43126
    • Research Site
  • Pescara, Italy, 65100
    • Research Site
  • Roma, Italy, 00128
    • Research Site
  • Roma, Italy, 00144
    • Research Site
  • San Giovanni Rotondo, Italy, 71013
    • Research Site
  • Verona, Italy, 37134
    • Research Site
• Korea, Republic of
  • Seongnam-si, Korea, Republic of, 13620
    • Research Site
  • Seoul, Korea, Republic of, 03080
    • Research Site
  • Seoul, Korea, Republic of, 6351
    • Research Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Research Site
• Spain
  • Barcelona, Spain, 08035
    • Research Site
  • Girona, Spain, 17007
    • Research Site
  • L'Hospitalet de Llobregat, Spain, 08907
    • Research Site
  • Madrid, Spain, 28034
    • Research Site
  • Madrid, Spain, 28041
    • Research Site
  • Madrid, Spain, 28050
    • Research Site
  • Madrid, Spain, 28007
    • Research Site
  • Málaga, Spain, 29010
    • Research Site
  • Pamplona, Spain, 31008
    • Research Site
  • Sabadell, Spain, 8208
    • Research Site
  • Santiago de Compostela, Spain, 15706
    • Research Site
  • Valencia, Spain, 46009
    • Research Site
  • Zaragoza, Spain, 50009
    • Research Site
• United Kingdom
  • Edinburgh, United Kingdom, EH4 2XR
    • Research Site
  • Glasgow, United Kingdom, G12 0YN
    • Research Site
  • Liverpool, United Kingdom, L69 3GA
    • Research Site
  • London, United Kingdom, SE5 9RS
    • Research Site
  • London, United Kingdom, WC1E 6AG
    • Research Site
  • Manchester, United Kingdom, M20 4BX
    • Research Site
  • Northwood, United Kingdom, HA6 2RN
    • Research Site
  • Nottingham, United Kingdom, NG5 1PB
    • Research Site
  • Surrey, United Kingdom, SM1 2DL
    • Research Site
• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Research Site
  • California
    • Orange, California, United States, 92868
      • Research Site
    • Stanford, California, United States, 94305-5720
      • Research Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Research Site
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Research Site
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Research Site
    • Miami, Florida, United States, 33136
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Research Site
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Research Site
  • New York
    • Commack, New York, United States, 11725
      • Research Site
    • New York, New York, United States, 10016
      • Research Site
    • New York, New York, United States, 10032
      • Research Site
    • New York, New York, United States, 10065
      • Research Site
    • New York, New York, United States, 10022
      • Research Site
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Research Site
  • Texas
    • Houston, Texas, United States, 77030
      • Research Site
  • Washington
    • Seattle, Washington, United States, 98104
      • Research Site

Participation Criteria

Eligibility Criteria

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

Description

Key Inclusion Criteria

• Histologically or cytologically confirmed pancreas adenocarcinoma receiving initial chemotherapy for metastatic disease and without evidence of disease progression on treatment
• Patients with measurable disease and/or non-measurable or no evidence of disease assessed at baseline by CT (or MRI where CT is contraindicated) will be entered in this study.
• Documented mutation in gBRCA1 or gBRCA2 that is predicted to be deleterious or suspected deleterious
• Patients are on treatment with a first line platinum-based (cisplatin, carboplatin or oxaliplatin) regimen for metastatic pancreas cancer, have received a minimum of 16 weeks of continuous platinum treatment and have no evidence of progression based on investigator's opinion.
• Patients who have received platinum as potentially curative treatment for a prior cancer (eg ovarian cancer) or as adjuvant/neoadjuvant treatment for pancreas cancer are eligible provided at least 12 months have elapsed between the last dose of platinum-based treatment and initiation of the platinum-based chemotherapy for metastatic pancreas cancer.

Major Exclusion Criteria:

• gBRCA1 and/or gBRCA2 mutations that are considered to be non detrimental (eg, "Variants of uncertain clinical significance" or "Variant of unknown significance" or "Variant, favour polymorphism" or "benign polymorphism" etc.)
• Progression of tumour between start of first line platinum based chemotherapy for metastatic pancreas cancer and randomisation.

• Cytotoxic chemotherapy or non-hormonal targeted therapy within 28 days of Cycle

  1 Day 1 is not permitted.

• Exposure to an investigational product within 30 days or 5 half lives (whichever is longer) prior to randomisation
• Any previous treatment with a PARP inhibitor, including Olaparib

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Olaparib; Olaparib tablets po. 300 mg twice daily	Drug: Olaparib; Tablet -100mg; Drug: Olaparib; Tablet-150mg
Placebo Comparator: Placebo; Placebo tablets twice daily	Drug: Placebo; Match Olaparib 100mg placebo; Drug: Placebo; Match Olaparib 150mg placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) Using Modified Response Evaluation Criteria in Solid Tumours. This Study Used Modified RECIST Version (v) 1.1 (RECIST v1.1)	To determine the efficacy of olaparib maintenance monotherapy compared to placebo by PFS. The PFS was defined as the time from randomisation until the date of objective radiological disease progression according to modified RECIST v1.1 or death (by any cause in the absence of disease progression) regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to disease progression.	Up to 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	To determine the efficacy by assessment of OS of olaparib maintenance monotherapy compared to placebo. The OS was defined as the time from the date of randomization until death due to any cause.	Upto 4 years
Time From Randomisation to Second Progression (PFS2)	To determine efficacy by assessment of PFS2 of olaparib maintenance monotherapy compared to placebo. The PFS2 was defined as the time from the date of randomisation to the earliest of the progression event subsequent to that used for the primary variable PFS or death.	Up to 4 years
Time From Randomisation to Second Subsequent Therapy or Death (TSST)	To determine the efficacy by assessment of TSST of olaparib maintenance monotherapy compared to placebo. The TSST was defined as time to second subsequent therapy or death.	Up to 4 years
Time From Randomisation to First Subsequent Therapy or Death (TFST)	To determine the efficacy by assessment of TFST of olaparib maintenance monotherapy compared to placebo. The TFST was defined as time to first subsequent therapy or death.	Up to 4 years
Time From Randomisation to Study Treatment Discontinuation or Death (TDT)	To determine the efficacy by assessment of TDT compared to placebo. compared to placebo. The TDT was defined as time to study treatment discontinuation or death.	Up to 4 years
Number of Participants With Objective Response Rate (ORR) by BICR Using Modified RECIST 1.1	To determine efficacy by assessment of objective response rate according to modified RECIST 1.1 of olaparib maintenance monotherapy compared to placebo. The ORR is defined as the number of with a BoR of CR and PR according to the BICR data divided by the number of patients in the treatment group with measurable disease at baseline.	Up to 4 years
Disease Control Rate (DCR) by BICR Using Modified RECIST 1.1	Efficacy by assessment of disease control rate according to modified RECIST 1.1 of olaparib maintenance monotherapy compared to placebo.	At 16 weeks
Adjusted Mean Change From Baseline up to 6 Months in Global Quality of Life (QoL) Score From the EORTC-QLQ-C30 Questionnaire	To assess the effect of olaparib on health-related quality of life (QoL) as measured by the EORTC-QLQ-C30 global QoL scale. The EORTC-QLQ-C30 is defined as EORTC QLQ-C30: a questionnaire (30 questions) used to evaluate disease symptoms, functional impacts (eg, physical functioning), and HRQoL and to characterize clinical benefit from the patient perspective. The HRQoL score ranges from 0 to 100. A higher score indicates better QoL. A score change of 10 points was pre-defined as clinically meaningful. bd twice daily.	From baseline up to 6 months
Number of Participants With Adverse Events (AEs)	To assess the safety and tolerability of olaparib maintenance monotherapy. SAE: serious adverse events CTCAE: Common Terminology Criteria for Adverse Events	Up to 4 years

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Merck Sharp & Dohme LLC; Myriad Genetic Laboratories, Inc.

Publications and helpful links

General Publications

• Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, Park JO, Hochhauser D, Arnold D, Oh DY, Reinacher-Schick A, Tortora G, Algul H, O'Reilly EM, McGuinness D, Cui KY, Schlienger K, Locker GY, Kindler HL. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med. 2019 Jul 25;381(4):317-327. doi: 10.1056/NEJMoa1903387. Epub 2019 Jun 2.
• Lowery MA, Kelsen DP, Capanu M, Smith SC, Lee JW, Stadler ZK, Moore MJ, Kindler HL, Golan T, Segal A, Maynard H, Hollywood E, Moynahan M, Salo-Mullen EE, Do RKG, Chen AP, Yu KH, Tang LH, O'Reilly EM. Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma. Eur J Cancer. 2018 Jan;89:19-26. doi: 10.1016/j.ejca.2017.11.004. Epub 2017 Dec 8.
• Amin S, Joo S, Nolte S, Yoo HK, Patel N, Byrnes HF, Costa-Cabral S, Johnson CD. Health-related quality of life scores of metastatic pancreatic cancer patients responsive to first line chemotherapy compared to newly derived EORTC QLQ-C30 reference values. BMC Cancer. 2022 May 20;22(1):563. doi: 10.1186/s12885-022-09661-7.
• Li N, Zheng H, Huang Y, Zheng B, Cai H, Liu M. Cost-Effectiveness Analysis of Olaparib Maintenance Treatment for Germline BRCA-Mutated Metastatic Pancreatic Cancer. Front Pharmacol. 2021 Apr 20;12:632818. doi: 10.3389/fphar.2021.632818. eCollection 2021.
• Zhan M, Zheng H, Yang Y, He Z, Xu T, Li Q. Cost-Effectiveness Analysis of Maintenance Olaparib in Patients with Metastatic Pancreatic Cancer and a Germline BRCA1/2 Mutation Based on the POLO Trial. Cancer Manag Res. 2020 Dec 16;12:12919-12926. doi: 10.2147/CMAR.S283169. eCollection 2020.
• Golan T, Kindler HL, Park JO, Reni M, Macarulla T, Hammel P, Van Cutsem E, Arnold D, Hochhauser D, McGuinness D, Locker GY, Goranova T, Schatz P, Liu YZ, Hall MJ. Geographic and Ethnic Heterogeneity of Germline BRCA1 or BRCA2 Mutation Prevalence Among Patients With Metastatic Pancreatic Cancer Screened for Entry Into the POLO Trial. J Clin Oncol. 2020 May 1;38(13):1442-1454. doi: 10.1200/JCO.19.01890. Epub 2020 Feb 19.
• Hammel P, Kindler HL, Reni M, Van Cutsem E, Macarulla T, Hall MJ, Park JO, Hochhauser D, Arnold D, Oh DY, Reinacher-Schick A, Tortora G, Algul H, O'Reilly EM, McGuinness D, Cui KY, Joo S, Yoo HK, Patel N, Golan T; POLO Investigators. Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib. Ann Oncol. 2019 Dec 1;30(12):1959-1968. doi: 10.1093/annonc/mdz406.

Helpful Links

• Related Info
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Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2014
• Primary Completion (Actual): January 15, 2019
• Study Completion (Actual): January 27, 2023

Study Registration Dates

• First Submitted: June 6, 2014
• First Submitted That Met QC Criteria: July 3, 2014
• First Posted (Estimated): July 9, 2014

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: August 18, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: BRCA, metastatic adenocarcinoma pancreas, maintenance olaparib monotherapy, first line platinum chemotherapy, pancreatic cancer, PARP inhibitor
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Adenocarcinoma; Pancreatic Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Olaparib
• Other Study ID Numbers: D081FC00001; 2014-001589-85 (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