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

Study Overview
=================
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.

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

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Olaparib
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast that is one of the following phenotypes: Triple negative breast cancer defined as: ER and PgR negative AND HER2 negative (not eligible for anti-HER2 therapy) 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: 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 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olaparib<br>Olaparib tablets 300mg b.i.d. p.o. | Drug: Olaparib<br>* 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.<br>* Other names: Lynparza;|
| Placebo Comparator: Placebo<br>Placebo tablets b.i.d. p.o. | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive Disease Free Survival (IDFS) | An IDFS event is defined as the first occurrence of loco-regional or distant recurrence or new cancer or death from any cause. | From date of randomisation to data cut off: 27 March 2020 (approximately 5 years 11 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distant Disease Free Survival (DDFS) | A DDFS event is defined as documented evidence of first distant recurrence of breast cancer or death from any cause | From date of randomisation to data cut off: 27 March 2020 (approximately 5 years 11 months) | 
| Overall Survival (OS) | An OS event is defined as death by any cause. | From date of randomisation to data cut off: 12 July 2021 (approximately 7 years 3 months) | 
| Number of Participants With Contralateral Invasive and Non-invasive Breast Cancer, New Primary Ovarian Cancer, New Primary Fallopian Tube Cancer and New Primary Peritoneal Cancer | Number of patients with contralateral invasive breast cancer, contralateral non-invasive breast cancer, new primary ovarian cancer, new primary fallopian tube cancer and new primary peritoneal cancer. Analysis of contralateral breast cancers exclude patients with a bilateral mastectomy prior to randomisation. Analysis of new primary ovarian cancers excludes male patients and patients with a bilateral oophorectomy prior to randomisation. Analysis of new primary fallopian tube cancer excludes male patients and patients with a bilateral salpingectomy prior to randomisation. Analysis of new primary peritoneal cancers excludes male patients. | From date of randomisation to data cut off: 12 July 2021 (approximately 7 years 3 months) | 
| Change From Baseline for FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) Score for Participants Who Completed Neoadjuvant Chemotherapy | Change from baseline for FACIT-Fatigue Score at 6, 12, 18 and 24 months for patients who completed neoadjuvant chemotherapy. Adjusted least-square mean changes and 95% Confidence Interval (CI) are obtained from mixed model for repeated measures (MMRM) analysis of the change from baseline. Only patients with evaluable baseline forms are included. FACIT-Fatigue score ranges from 0 to 52 with higher score indicating less fatigue. | 6, 12, 18 and 24 months after randomisation (data cut off: 12 July 2021) | 
| Change From Baseline for FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) Score for Participants Who Completed Adjuvant Chemotherapy | Change from baseline for FACIT-Fatigue Score at 6, 12, 18 and 24 months for patients who completed adjuvant chemotherapy. Adjusted least-square mean changes and 95% CI are obtained from mixed model for repeated measures (MMRM) analysis of the change from baseline. Only patients with evaluable baseline forms are included. FACIT-Fatigue score ranges from 0 to 52 with higher score indicating less fatigue. | 6, 12, 18 and 24 months after randomisation (data cut off: 12 July 2021) | 
| Change From Baseline for EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questions 30) Scores for Participants Who Completed Neoadjuvant Chemotherapy | Change from baseline for EORTC QLQ-C30 Global health status QOL (Quality of Life) Score at 6, 12, 18 and 24 months for patients who completed neoadjuvant chemotherapy. Adjusted least-square mean changes and 95% CI are obtained from mixed model for repeated measures (MMRM) analysis of the change from baseline. Only patients with evaluable baseline forms are included. EORTC QLQ-C30 scores range from 0 to 100 with higher score indicating better quality of life. | 6, 12, 18 and 24 months after randomisation (data cut off: 12 July 2021) | 
| Change From Baseline for EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questions 30) Scores for Participants Who Completed Adjuvant Chemotherapy | Change from baseline for EORTC QLQ-C30 Global health status QOL (Quality of Life) Score at 6, 12, 18 and 24 months for patients who completed adjuvant chemotherapy. Adjusted least-square mean changes and 95% CI are obtained from mixed model for repeated measures (MMRM) analysis of the change from baseline. Only patients with evaluable baseline forms are included. EORTC QLQ-C30 scores range from 0 to 100 with higher score indicating better quality of life. | 6, 12, 18 and 24 months after randomisation (data cut off: 12 July 2021) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Breast Cancer, Adjuvant, Olaparib, BRCA 1/2, HER2