Olaparib as Adjuvant Treatment in Patients With Germline BRCA Mutated High Risk HER2 Negative Primary Breast Cancer (OlympiA)

• ClinicalTrials.gov Identifier: NCT02032823
• Recruitment Status: Active, not recruiting
• First Posted: January 10, 2014
• Last Update Posted: May 5, 2020
• Sponsor: AstraZeneca
• Collaborators: Breast International Group; Frontier Science & Technology Research Foundation, Inc.; NRG Oncology; Myriad Genetic Laboratories, Inc.; Br.E.A.S.T. -Data Center & Operational Office Institut Jules Bordet; Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: January 3, 2014
• First Posted Date: January 10, 2014
• Last Update Posted Date: May 5, 2020
• Actual Study Start Date: April 22, 2014
• Estimated Primary Completion Date: November 18, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 27, 2015)

Invasive Disease Free Survival (IDFS) [ Time Frame: Up to 10 years ]

Time from randomisation to date of first treatment failure that is loco-regional or distant recurrence or new cancer or death from any cause

Original Primary Outcome Measures (submitted: January 9, 2014)

Efficacy of adjuvant treatment with olaparib on Invasive Disease Free Survival (IDFS). [ Time Frame: Patients will be followed for disease recurrence and new cancers for approximately 10 years following randomisation ]

Recurrence assessments on a 3 monthly basis during the first 2 years and on a 6 monthly basis in year 3, 4, 5 and annually from year 6 to 10. MRI performed every 12 months beginning 6 months after randomization

Current Secondary Outcome Measures (submitted: November 27, 2015)

• Overall survival (OS) [ Time Frame: Until 10 years after the last patient is randomised ]
  Efficacy by assessment of OS (time from randomisation to death by any cause).
• Distant Disease Free Survival (DDFS) [ Time Frame: Up to 10 years ]
  Time from randomisation until documented evidence of first distant recurrence of breast cancer
• Effect on the incidence of new primary contralateral breast cancers, new primary ovarian cancer, new primary fallopian tube cancer and new primary peritoneal cancer [ Time Frame: Up to 10 years ]
  Time from randomisation until documented incidence of new primary contralateral breast cancers, new primary ovarian cancer, new primary fallopian tube cancer and new primary peritoneal cancer
• Effect in patients identified as having a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays. [ Time Frame: Up to LSLV & 15 years thereafter ]
  Retrospective analysis of samples
• Exposure to Olaparib (in plasma) in patients receiving Olaparib as adjuvant therapy [ Time Frame: Visit 4, day 29 ]
  Pharmacokinetic analysis
• FACIT-Fatiure symptoms and EORTC QLQ-C30 Questionnaires [ Time Frame: Up to 2 years ]
  Assess weather olaparib arm patients may experience greater fatigue (FACIT-Fatigue), greater GI symptoms and no difference in Quality of Life (EORTC QLQ-C30)

Original Secondary Outcome Measures (submitted: January 9, 2014)

• Efficacy of adjuvant treatment with olaparib on overall survival (OS). [ Time Frame: OS follow up will be done every 12 months following completion of 10 year new cancer/recurrence follow up. ]
• Efficacy of adjuvant treatment with olaparib on Distant Disease Free Survival (DDFS) [ Time Frame: Physical examination will be performed at weeks 12, 24, 38, 52. In follow-up period in year 2 every 3 months, in year 3, 4,5 every 6 months and year 6 to 10 every 12 months. MRI to be performed every 12 months after the 6 months scan. ]
• Efficacy of adjuvant treatment with olaparib on the incidence of new invasive breast primary cancer and/or new epithelial ovarian cancer. [ Time Frame: New cancer assessments will be performed at day 1, weeks 12, 24, 38, 52. In follow-up period in year 2 every 3 months, in year 3, 4,5 every 6 months and year 6 to 10 every 12 months. MRI to be performed every 12 months after the 6 months scan. ]
• Efficacy of olaparib on patient reported outcomes using the FACIT fatigue scale and EORTC QLQ-C30 QoL scale. [ Time Frame: Baseline assessmnet prior to day 1 and then at week 24, 52 and month 18 and 24 following randomisation. ]
• Efficacy of olaparib in patients identified as having a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (gene sequencing and large rearrangement analysis). [ Time Frame: Within 15 years from last subject last visit. ]

Current Other Pre-specified Outcome Measures (submitted: November 27, 2015)

Safety and tolerability of olaparib [ Time Frame: 12 months of study treatment + 30 days after treatment discontinuation ]

Assessment of Adverse Events (AE), physical examination, vital signs including blood pressure (BP), pulse, and laboratory findings including clinical chemistry and haematology

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Olaparib as Adjuvant Treatment in Patients With Germline BRCA Mutated High Risk HER2 Negative Primary Breast Cancer
• Official Title: A Randomised, Double-blind, Parallel Group, Placebo-controlled Multi-centre Phase III Study to Assess the Efficacy and Safety of Olaparib Versus Placebo as Adjuvant Treatment in Patients With gBRCA1/2 Mutations and High Risk HER2 Negative Primary Breast Cancer Who Have Completed Definitive Local Treatment and Neoadjuvant or Adjuvant Chemotherapy
• Brief Summary: Olaparib treatment in patients with germline BRCA1/2 mutations and high risk HER2 negative primary breast cancer who have completed definitive local treatment and neoadjuvant or adjuvant chemotherapy

Detailed Description

Patients will be randomised in 1:1 ratio to either olaparib or placebo. Randomisation will be stratified by Hormone receptor status (ER and/or PgR positive/HER2 negative versus TNBC), prior neoadjuvant versus adjuvant chemotherapy and prior platinum use for breast cancer.

Randomised patients will receive study treatment for up to a maximum of 12 months. All patients will have safety assessments every 2 weeks during the first month, every 4 weeks for the following 5 months and 3 monthly for the remaining 6 months of study treatment plus 30 days after its discontinuation. Following randomisation, all patients will be assessed regularly for signs, symptoms and evidence of disease recurrence by taking medical history, physical examination and mammogram/breast MRI. Efficacy assessments will be performed on a 3 monthly basis during the first 2 years, followed by 6 monthly assessments for years 3, 4 and 5 and annually thereafter. All patients (except those with bilateral mastectomy) will have mammogram / breast MRI annually for 10 years beginning 6 months after randomisation.

All randomised patients will have clinical assessment visits for 10 years following their randomisation into the study. Once a patient completes 10 years of clinical assessment they will enter the survival follow up phase of the trial which will continue until 10 years after the last patient is randomised.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: Olaparib
  Patients will be administred olaparib orally twice daily (b.i.d.) at 300 mg. Two (2) x 150 mg olaparib tablets should be taken at the same times each morning and evening of each day, approximately 12 hours apart with approximately 240 ml of water.
  Other Name: Lynparza
• Drug: Placebo
  Patients will be administred matching placebo. Two (2) tablets should be taken at the same times each morning and evening of each day, approximately 12 hours apart with approximately 240 ml of water.

Study Arms

• Experimental: Olaparib
  Olaparib tablets 300mg b.i.d. p.o.
  Intervention: Drug: Olaparib
• Placebo Comparator: Placebo
  Placebo tablets b.i.d. p.o.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 31, 2020): 1836
• Original Estimated Enrollment (submitted: January 9, 2014): 1320
• Estimated Study Completion Date: November 27, 2028
• Estimated Primary Completion Date: November 18, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast that is one of the following phenotypes:

  1. Triple negative breast cancer defined as: ER and PgR negative AND HER2 negative (not eligible for anti-HER2 therapy)
  2. ER and/or PgR positive, HER2 negative
• Documented germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function).
• Completed adequate breast and axilla surgery.
• Completed at least 6 cycles neoadjuvant or adjuvant chemotherapy containing anthracyclines, taxanes or the combination of both. Prior platinum as potentially curative treatment for prior cancer (e.g. ovarian) or as adjuvant or neoadjuvant treatment for breast cancer is allowed.
• ECOG 0-1.

Exclusion criteria:

• Any previous treatment with a PARP inhibitor, including olaparib and/or known hypersensitivity to any of the excipients of study treatment.

• Patients with second primary malignancy. EXCEPTIONS are:

  1. adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, Ductal Carcinoma in situ (DCIS) of the breast, stage 1 grade 1 endometrial carcinoma
  2. other solid tumours and lymphomas (without bone marrow involvement) diagnosed ≥ 5 years prior to randomisation and treated with no evidence of disease recurrence and for whom no more than one line of chemotherapy was applied.
• Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting study treatment is 2 weeks. Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
• Evidence of metastatic breast cancer

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Canada, China, France, Germany, Hungary, Iceland, Israel, Italy, Japan, Korea, Republic of, Netherlands, Poland, Portugal, Puerto Rico, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT02032823
• Other Study ID Numbers: D081CC00006; NSABP B-55 ( Other Identifier: NSABP ); BIG 6-13 ( Other Identifier: Breast International Group )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• 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.
• 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.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Responsible Party: AstraZeneca
• Study Sponsor: AstraZeneca

Collaborators

• Breast International Group
• Frontier Science & Technology Research Foundation, Inc.
• NRG Oncology
• Myriad Genetic Laboratories, Inc.
• Br.E.A.S.T. -Data Center & Operational Office Institut Jules Bordet
• Merck Sharp & Dohme Corp.

Investigators

• Principal Investigator: Andrew Tutt, Doctor of Medicine; Integrated Cancer Centre Guy's Hospital, King's College, London School of Medicine, London, UK
• Principal Investigator: Bella Kaufman, Doctor of Medicine; Sheba Medical Center, Breast Cancer Unit, 52621 Tel Hashomer, Israel
• Principal Investigator: Judy Garber, Doctor of Medicine; Harvard Medical School, Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Susan F. Smither Center for Women's Cancers, 450 Brookline Avenue, Boston; MA 02215, US
• Principal Investigator: Charles Geyer, Doctor of Medicine; Virginia Commonwealth University Massey Cancer Center, McGlothlin Medical Education Center, Room 12-217, 1201 East Marshall St., PO Box 980070, Richmond, VA 23298-0070, USA

• PRS Account: AstraZeneca
• Verification Date: April 2020