ABCSG 45: A clinical trial that examines whether the treatment with the medication olaparib in combination with the chemotherapy carboplatin is more effective than treatment with a standard chemotherapy (anthracycline/taxane-based) against a specific type of breast cancer (triple-negative) with a biologic characteristic (homologous recombination deficiency)

Prior treatment

• Main study: 2. Previous randomization in the present study
• Main study: 21. Previous allogeneic bone marrow transplant
• Main study: 3. Participation in another clinical study with an investigational product during the last 6 months (i.e. 183 days) prior to randomization
• Main study: 4. Any previous treatment with a PARP inhibitor, including olaparib
• Main study: 5. Prior ipsilateral invasive breast cancer and/or ipsilateral Ductal Carcinoma in Situ (DCIS) and/or prior chemotherapy for any breast cancer • Patients with contralateral invasive breast cancer and/or contralateral DCIS diagnosed ≥5 years prior to randomization if curatively treated without chemotherapy are eligible
• Main study: 7. Patients with second primary malignancy are ineligible except for the following: • Adequately treated non-metastatic, non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, stage 1 grade 1 endometrial carcinoma or • Other curatively treated malignancies diagnosed ≥5 years prior to randomization with no evidence of disease for at least 5 years
• Main study: 9. Concomitant use of known strong or moderate Cytochrome P450 3A4 (CYP3A4) inducers. For further details refer to Appendix B
• Substudy: 1. Exposure to olaparib within 30 days prior to treatment start.
• Substudy: 3. Adjuvant radiotherapy within 2 weeks prior to treatment start
• Substudy: 4. Patients receiving or scheduled to receive adjuvant chemotherapy (e.g. capecitabine).
• Substudy: 5. Concomitant use of known strong or moderate Cytochrome P450 3A4 (CYP3A4) inhibitors and inducers.
• Main study: 12. Whole blood transfusions within 120 days prior to randomization
• Main study: 13. Major surgery within 14 days prior to randomization and/or patients with insufficient recovery from any major surgery per physician's assessment at the time of randomization
• Main study: 17. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) or patients who are receiving antiretroviral therapy

Other illness

• Main study: 18. Patients with known active hepatic disease (i.e. Hepatitis B or C)
• Main study: 19. Patients with a known hypersensitivity to olaparib, platins, taxanes, anthracyclines, or cyclophosphamide
• Main study: 20. Patients with uncontrolled seizures
• Main study: 6. Bilateral invasive breast cancer
• Substudy: 6. Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy.
• Main study: 14. Any medical condition rendering the patient unfit for pre-operative chemotherapy with TAC or carboplatin/olaparib
• Main study: 15. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the (N)IMP

Lab values

• Main study: 10. Resting ECG with QTc >470 msec and/ or family history of long QT syndrome • However, ECG measurement can be repeated within 24 hours and patient is ineligible if none of these repeated measurements demonstrate QTc ≤470 msec
• Main study: 8. Other severe acute and/or chronic medical and/or psychiatric condition and/or laboratory abnormality that would impart, in the judgment of the Investigator, risk associated with study participation or (N)IMP administration, or which, in the judgment of the Investigator, would make the patient inappropriate for participation in this study
• Main study: 11. Echocardiography (ECHO) and/or multigated acquisition (MUGA) scan with <50% Left Ventricular Ejection Fraction (LVEF)

Other

• Main study: 1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca/ABCSG staff and/or staff at the study site)
• Main study: 22. Known ≥ grade 2 peripheral neuropathy
• Substudy: 2. Known sensitivity or intolerance to olaparib
• Main study: 16. Pregnant or breast feeding women

• Main study: 1. Signed informed consent prior to any study specific assessments and procedures
• Main study: 7. Willingness to undergo adequate lymph node procedures (e.g., sentinel/ axillary lymph node dissection) acc. to institutional standards
• Main study: 8. Patients must have normal organ and bone marrow function measured within 28 days prior to randomization as defined below: • Haemoglobin (Hb) ≥10.0 g/dL • Absolute neutrophil count (ANC) ≥1.5 x 109/L • Absence of known Myelodysplastic Syndrome (MDS)/ Acute Myeloid Leukaemia (AML) and no features suggestive of MDS/ AML on *peripheral blood smear (*For patients randomized according to protocol version 2.0, peripheral blood smear only has to be performed if haematology assessment during screening shows abnormalities that require further clarification) • White blood cell (WBC) count ≥ 3.0 x 109/L • Platelet count ≥100 x 109/L • Total bilirubin ≤1.5 x institutional upper limit of normal (ULN) • AST (SGOT)/ ALT (SGPT) ≤2.5 x institutional ULN • Serum creatinine ≤1.5 x institutional ULN or creatinine clearance using the Cockcroft-Gault equation ≥51 mL/min
• Main study: 9. ECOG performance status 0-1
• Substudy: 1. Signed informed consent prior to any substudy specific assessments and procedures. Consent to substudy is optional.
• Substudy: 2. Completed at least 4 cycles neoadjuvant chemotherapy with TAC or neoadjuvant olaparib and carboplatin in the course of the ABCSG 45 main study.
• Substudy: 3. Completed locoregional therapy (i.e. adequate breast and axilla surgery with or without adjuvant radiotherapy). Patients must have recovered from any effects of any major surgery.
• Substudy: 4. Treatment with adjuvant olaparib starts ideally within 8 weeks after last treatment (surgery, or radiotherapy, whichever is last), but in no case longer than 12 weeks.
• Substudy: 5. Negative pregnancy test (serum or urine) max. 28 days prior to treatment start for women with childbearing potential
• Substudy: 6. Women of childbearing potential and male patients must use adequate contraception for the duration of protocol treatment and for 6 months after the last dose of olaparib for women and 3 months after the last dose of olaparib for men. Adequate contraception is defined as one highly effective form (i.e. total abstinence, (fe)male sterilization) OR two effective forms (e.g. non-hormonal intrauterine device (IUD) and condom/occlusive cap with spermicidal foam/gel/film/cream/suppository).
• Substudy: 7. Patient is willing and able to comply with the protocol for the duration of the substudy, including undergoing treatment, scheduled visits and examinations.
• Main study: 10. Negative pregnancy test (serum or urine) max. 28 days prior to randomization for women with childbearing potential: • Pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before randomization, as determined by local practice, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation
• Substudy: 8. Patients must have adequate organ and bone marrow function measured within 28 days prior to treatment start with no blood transfusions (packed red blood cells and/or platelet transfusions) in the past 28 days prior to testing for organ and bone marrow function
• Substudy: 9. ECOG performance status 0-1
• Main study: 11. Women of childbearing potential and male patients randomized into treatment Arm A or B must use adequate contraception for the duration of protocol treatment and for 6 months after the last dose of (N)IMP for women and 3 months for male patients. Adequate contraception is defined as one highly effective form (i.e. total abstinence, (fe)male sterilization) OR two effective forms (e.g. non-hormonal intrauterine device (IUD) and condom/occlusive cap with spermicidal foam/gel/film/cream/suppository)
• Main study: 12. Patient is willing and able to comply with the protocol for the duration of the study, incl. undergoing treatment, scheduled visits and examinations
• Main study: 2. Patients must be ≥ 18 years of age
• Main study: 3. Pre-menopausal (incl. peri-menopausal) and postmenopausal women and men with core-biopsied, early primary triple-negative (acc. to local standards) invasive breast cancer
• Main study: 4. Positive HRD status (centrally assessed) in core-biopsy sample of the breast
• Main study: 5. Absence of distant metastasis (M0) as assessed acc. to institutional standards within 90 days prior to randomization
• Main study: 6. Unilateral early invasive TNBC patients.