ABCSG 41/OlympiA Details
A randomised, double-blind, parallel group, placebo-controlled multicentre Phase-III-study to assess the efficacy and safety of olaparib vs. placebo as adjuvant 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.
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The primary objective is to assess the effect of adjuvant treatment with olaparib on Invasive Disease Free Survival (IDFS).
- To assess the effect of adjuvant treatment with olaparib on overall survival (OS)
- To assess the effect of adjuvant treatment with olaparib on Distant Disease Free Survival (DDFS)
- To assess the effect of adjuvant treatment with olaparib on the incidence of new invasive breast primary cancer and/or new epithelial ovarian cancer
- To assess the effect of olaparib on patient reported outcomes using the FACIT fatigue scale and EORTC QLQ-C30 QoL scale
- To assess 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 germline BRCA mutation assays (gene sequencing and large rearrangement analysis)
- To explore methods for estimating overall survival (OS) adjusting for the impact of confounding by subsequent therapies, specifically the control arm receiving subsequent Polyadenosine 5’diphosphoribose [poly (ADP ribose)] polymerisation (PARP) inhibitors or platinum salts (to support reimbursement appraisals)
- To explore whether resistance mechanisms to olaparib can be identified through analysis of tumour and blood sample derivatives (cells, plasma and protein and nucleic acid derivatives) – archival primary and post neoadjuvant tumour (mandatory (if available)) and tumour biopsy at recurrence (optional) and blood samples at baseline, 30 days post study treatment and on disease recurrence (mandatory)
- To determine the frequency of and describe the nature of BRCA mutation/s in tumour samples and to compare this with germline BRCA mutation status
- Future exploratory research into factors that may influence development of cancer and/or response to treatment (where response is defined broadly to include efficacy, tolerability or safety) may be performed on the collected and stored tumour and blood samples
- To collect and store DNA according to each country’s local and ethical procedures for future exploratory research into genes/genetic variation that may influence response (i.e. distribution, safety, tolerability and efficacy) to study treatments and/or susceptibility to disease (optional)
- Provision of informed consent prior to any study specific procedures
- Female or male patients must be ≥18 years of age
- Histologically confirmed non-metastatic primary triple negative invasive adenocarcinoma of the breast that is at surgery:
either axillary node-positive (any tumour size) or axillary node-negative with primary tumour > 2cm for patients who received adjuvant chemotherapy or showing evidence of non pCR for patients who received neoadjuvant chemotherapy
- Invasive TNBC defined as:
- ER- and PR-negative (not eligible for endocrine therapy) defined as IHC nuclear staining <1% AND (*since May 3rd, 2016 after a protocol amendment also ER- and PR-positive patients)
- HER2-negative (not eligible for anti-HER2 therapy) defined as:
- IHC 0, 1+ without ISH or
- IHC 2+ and ISH non-amplified with ratio less than 2.0 and if reported average HER2 copy number < 6 signals/cells or
- ISH non-amplified with ratio less than 2.0 and if reported average HER2 copy number < 6 signals/cells without IHC)
- Documented 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 defined as:
- The inked margins of breast conservation surgery or mastectomy must be histologically free of invasive breast cancer and ductal carcinoma in situ with the exception of the posterior margin if this margin is the pectoralis major fascia or the anterior margin if this is the dermis. Patients with resection margins positive for lobular carcinoma in situ are eligible.
- Patients with breast conservation must have adjuvant radiotherapy. Patients having mastectomy should have adjuvant radiotherapy according to international guidelines (St Gallen/ASCO/ESTRO).
- Sentinel lymph node biopsy alone if negative or if lymph node(s) only contain micrometastases (≤2.0 mm) or positive sentinel lymph node biopsy followed by axillary node clearance or axillary nodal radiotherapy
- If sentinel lymph node biopsy before neoadjuvant chemotherapy: sentinel lymph node biopsy alone if negative or if lymph node(s) only contain micrometastases (≤2.0 mm) or positive sentinel lymph node biopsy followed by axillary node clearance or axillary nodal radiotherapy following completion of neoadjuvant chemotherapy
- If sentinel lymph node biopsy after neoadjuvant chemotherapy: Sentinel lymph node biopsy alone if negative or positive sentinel lymph node biopsy followed by axillary node clearance.
- 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
- Patients must have normal organ and bone marrow function measured within 28 days prior to randomisation as defined below:
- Haemoglobin ≥ 10.0 g/dL with no blood transfusions in the past 28 days
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- Platelet count ≥ 100 x 109/L
- Total Bilirubin ≤ ULN (institutional upper limit of normal) except elevated total bilirubin
- AST (SGOT)/ALT (SGPT) ≤ 2.5 x ULN
- ALP ≤ 2.5 x ULN
Patients with screening ALT/AST or ALP above institutional upper limit of normal should have liver ultrasound or CT/ MRI prior to randomisation. Screening bone scan is required if ALP and/or corrected calcium level are above the institutional upper limit. (Note PET CT scan may be used as an alternative imaging techniques).
- Serum creatinine ≤ 1.5 x ULN
- ECOG performance status 0-1
- Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 7 days prior to randomisation
Postmenopausal is defined as:
- Age > 60 yrs
- Age < 60 and amenorrheic for 1 year or more in the absence of chemotherapy and/or hormonal treatment
- LH, FSH and plasma oestradiol levels in the post menopausal range for women under 60
- radiation-induced oophorectomy with last menses >1 year ago
- or surgical sterilisation (bilateral oophorectomy or hysterectomy)
- Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
- Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary tumor, if available.
For inclusion in
(a) the optional exploratory genetic research and
(b) the optional tumour biomarker research (tumour biopsy at disease recurrence)
patients must fulfil the following criteria:
- Provision of informed consent for genetic research
- Involvement in the planning and/or conduct of the study.
- BRCA 1 and/or BRCA2 mutations that are considered to be non detrimental (e.g., “Variants of uncertain clinical significance” or “Variant of unknown significance”or “Variant, favour polymorphism” or “benign polymorphism” etc.).
- Previous randomisation in the present study.
- Evidence of metastatic breast cancer. Patient considered at high risk of having disseminated disease (i.e those with clinical N2-3 or pathological N1-3 or locally advanced disease) must have a CT/MRI scan of the Thorax/Abdomen/Pelvis or any other area as clinically indicated and a bone scan at any point prior to randomisation. (Note PET CT scan may be used as an alternative imaging techniques and precludes the need for bone scan)
- Exposure to an investigational product within 30 days or five half lives (whichever is the longer) prior to randomisation.
- Any previous treatment with a PARP inhibitor, including olaparib and/or knownhypersensitivity to any of the excipients of study treatment.
- Patients with second primary cancer, EXCEPTIONS: adequately treated nonmelanoma skin cancer, curatively treated in situ cancer of the cervix, Ductal Carcinoma in situ (DCIS) of the breast, stage 1 grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥ 5 years prior to randomization.
More than one course of chemotherapy for previous malignancies (e.g: breast cancer or ovarian cancer > 5 years ago treated with adjuvant chemotherapy)
- Resting ECG with QTc > 470 msec detected on 2 or more time points within a 24 hour period or family history of long QT syndrome. If ECG demonstrates QTc>470 msec, patient will be eligible only if repeat ECG demonstrates QTc ≤470 msec.
- Patients receiving systemic chemotherapy within 3 weeks prior to start of study treatment.
- Patients receiving adjuvant radiotherapy within 2 weeks prior to start of study treatment
- Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.
- Persistent toxicities (≥CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy.
- Patients with myelodysplastic syndrome/ treatment related acute myeloid leukaemia (t-AML).
- Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery.
- Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, extensive bilateral lung disease on High Resolution Computed Tomography scan orany psychiatric disorder that prohibits obtaining informed consent.
- Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
- Pregnant or breastfeeding women.
- Patients with known active Hepatitis B or C or HIV
- Previous allogeneic bone marrow transplant.
- Whole blood transfusions in the last 120 days prior to entry to the study which may interfere with gBRCA testing (packed red blood cells and platelet transfusions are acceptable, for timing refer to inclusion criteria no.8)