This is a multicenter single-arm phase II clinical trial to evaluate the efficacy and safety
of olaparib in patients diagnosed of advanced triple negative breast cancer (TNBC) with
methylation of BRCA1 and/or BRCA2 promoters assessed in DNA from metastatic lesions and
absence of BRCA1 and 2 germline mutations.
Inclusion Criteria: (Any asterisked* are applicable as an inclusion criteria prior to
perform the BRCA methylation testing via central testing)
1. *The patient has signed and dated the informed consent document and it has been
obtained before conducting any procedure specifically for the study.
2. Female ≥ 18 years of age on day of signing informed consent.
3. Patient with histological confirmation of breast cancer with evidence of advanced
disease not amenable to resection or radiation therapy with curative intent.
4. Documented Triple Negative (TN) disease by immunohistochemistry (IHC) and/or in situ
hybridization based on local testing (preferably assessed on the most recent tumour
biopsy available). TN is defined as negative hormone receptor status (< 1% of tumour
cells with Estrogen Receptor (ER) and Progesterone Receptor (PgR) expression) and
Human Epidermal growth factor Receptor 2 (HER2) negative status (defined as IHC score
0/1+ or negative by in situ hybridization defined according to local criteria).
5. Patient must have received at least one previous regimen in the advance disease
6. Absence of deleterious or suspected deleterious germline mutations in BRCA1 and BRCA2.
Germinal BRCA mutational status will be centrally assessed in Myriad laboratories to
check eligibility unless the test has been previously performed at Myriad and absence
of mutations has been determined.
7. Availability of a tumour tissue sample from the metastatic lesions (every effort
should be done to obtain the sample after the previous therapeutic regimen for
advanced disease) for central testing.
8. Documented methylation of BRCA1 and/or 2 promoters based on central testing by
analysis on the most recent tumour from metastatic lesions available.
9. At least one lesion measurable not previously irradiated, that can be accurately
measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must
have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging
(MRI) or clinical examination and which is suitable for accurate repeated measurements
according to RECIST v.1.1.
10. Patient must have normal organ and bone marrow function measured within 28 days prior
to administration of study treatment 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 ≤ 1.5 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase, SGOT)
/Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase, SGPT) ] ≤
2.5 x institutional upper limit of normal unless liver metastases are present in
which case they must be ≤ 5 x ULN
- Patients must have creatinine clearance estimated using the Cockcroft-Gault
equation of ≥51 mL/min:
Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)/ serum
creatinine (mg/dL) x 72; where F=0.85 for females.
11. *Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (see protocol
12. *Patient must have a life expectancy ≥ 16 weeks
13. *Postmenopausal or evidence of non-childbearing status for women of childbearing
potential: negative urine or serum pregnancy test within 28 days of study treatment
and confirmed prior to treatment on day 1.
Postmenopausal patient is defined as a woman fulfilling any one of the following
criteria (based on the National Comprehensive Cancer Network (NCCN) definition of
- Prior bilateral oophorectomy.
- Age > 60 years.
- Age ≤ 60 years and with amenorrhea for 12 or more months in the absence of
chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle
stimulating hormone and estradiol in the postmenopausal range.
14. Olaparib is regarded as a compound with medium/high foetal risk, patients of
childbearing potential and their partners, who are sexually active, must agree to the
use of 2 highly effective forms of contraception in combination as listed below. This
should be started from the signing of the informed consent and continue throughout
period of taking study treatment and for at least 1 month after last dose of study
drug or they must totally/truly abstain from any form of sexual intercourse (see
Acceptable non-hormonal birth control methods include:
- Total sexual abstinence. Abstinence must continue for the total duration of the
study treatment and for at least 1 month after one dose. Periodic abstinence
(e.g., calendar ovulation, symptothermal, post-ovulation methods) and withdrawal
are not acceptable methods of contraception.
- Vasectomised sexual partner plus male condom. With participant assurance that
partner received post-vasectomy confirmation of azoospermia.
- Tubal occlusion plus male condom.
- Intrauterine Device (IUD) plus male condom. Provided coils are copper-banded.
Acceptable hormonal methods:
- Normal and low dose combined oral pills plus male condom.
- Cerazette (desogestrel) plus male condom. Cerazette is currently the only highly
efficacious progesterone based pill.
- Hormonal shot or injection (e.g., Depo-Provera) plus male condom.
- Etonogestrel implants (e.g. Implanon or Norplan) plus male condom.
- Norelgestromin/ethinyl estradiol (EE) transdermal system plus male condom.
- Intrauterine system (IUS) device (e.g., levonorgestrel releasing IUS -Mirena®)
plus male condom.
- Intravaginal device plus male condom (e.g. EE and etonogestrel).
15. *Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits, laboratory tests and examinations
and other study procedures including follow up.
Exclusion Criteria: (Any asterisked* are applicable as an inclusion criteria prior to
perform the BRCA methylation testing via central testing)
1. Involvement in the planning and/or conduct of the study (applies to the sponsor and/or
study site staff).
2. Previous enrolment in the present study.
3. Participation in another clinical study with an investigational product during the
last 4 weeks.
4. *Any previous treatment with a Poly Adenosine diphosphate-Ribose Polymerase (PARP)
inhibitor, including olaparib.
5. *Patients with other malignancy within the last 5 years, except: adequately treated
non-melanoma skin cancer (basal cell or squamous cell carcinoma), curatively treated
in-situ cancer of the cervix, ductal carcinoma in situ (DCIS), 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
study inclusion. Patients with a history of localised breast cancer with a tumor
histology different to TN, with no evidence of disease for ≥ 5 years since they
completed their adjuvant treatment.
6. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
reasons), within 3 weeks prior to study treatment (or a longer period depending on the
defined characteristics of the agents used).
7. Resting ECG with corrected QT interval (QTc) > 470 msec on 2 or more time points
within a 24 hour period or family history of long QT syndrome.
8. *Concomitant use of known strong Cytochrome P3A (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 olaparib is 2 weeks. Please
refer to section 18.104.22.168 about strong and moderate CYP3A inhibitors.
9. *Concomitant use of known strong CYP3A inducers (e.g. phenobarbital, enzalutamide,
phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's
Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required
washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital
and 3 weeks for other agents. Please refer to section 22.214.171.124 about strong and
moderate CYP3A inducers.
10. *Persistent toxicities (> NCI-CTCAE grade 2) caused by previous cancer therapy (except
alopecia or other toxicities not considered a safety risk for the patient at
11. *Patients with myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) or with
features suggestive of MDS/AML.
12. *Patients with symptomatic uncontrolled brain metastases. A scan to confirm the
absence of brain metastases is not required. Patients with brain metastases may be
eligible for the study only if more than 4 weeks from treatment completion for these
metastases (including radiation and/or surgery), are clinically stable at the time of
study entry. The patient can receive a stable dose of corticosteroids before and
during the study as long as these were started at least 4 weeks prior to treatment.
Patients with spinal cord compression unless considered to have received definitive
treatment for this and evidence of clinically stable disease for 28 days.
13. Major surgery within 2 weeks of starting study treatment and patients must have
recovered from any effects of any major surgery.
14. *Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study
15. *Breast feeding women.
16. *Immunocompromised patients, e.g. patients who are known to be serologically positive
for human immunodeficiency virus (HIV).
17. *Patients with known active hepatitis (i.e., Hepatitis B or C) due to risk of
transmitting the infection through blood or other body fluids.
18. *Patients with a known hypersensitivity to olaparib or any of the excipients of the
19. *Patients considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled infection or
laboratory abnormality that may increase the risk associated with study participation
or may interfere with the interpretation of study results and, in the judgment of the
investigator, would make the patient inappropriate for entry into this study. Examples
include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3
months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal
cord compression, superior vena cava syndrome, moderate or severe hepatic impairment
(according to Child-Pugh classification), an extensive interstitial bilateral lung
disease on High Resolution Computed Tomography (HRCT) or any psychiatric disorder that
prohibits obtaining informed consent.
20. *Previous allogenic bone marrow transplant or double umbilical cord blood
21. *Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable, for timing refer to inclusion
criteria no 10).