A number of important systemic therapies have been developed to treat mCRPC and have received
regulatory approval and now comprise the current therapeutic landscape. Durable and complete
response following first-line chemotherapy in patients with advanced PC are uncommon. Most
patients will ultimately experience disease progression within 6-9 months after initial
response. Optimal Second line therapy in mCRPC is not well established and several options
Olaparib has demonstrated anti-tumour activity in non-comparative studies in patients with
germline BReast CAncer gene (gBRCA) mutated cancers including ovarian, breast, pancreas and
prostate. Olaparib is indicated as monotherapy for the maintenance treatment of adult
patients with platinum-sensitive relapsed Breast Cancer gene-mutated (germline and/or
somatic) high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer
who are in response (complete response or partial response) to platinum-based chemotherapy.
This phase II study is developed to assess the effect of maintenance treatment with olaparib
on radiologic progression free survival (rPFS) in patients with mCRPC who have received at
least 6 cycles of docetaxel and achieved partial or complete response or disease
stabilization according RECIST 1.1 criteria and PCWG3.
- Provision of informed consent prior to any study specific procedures. For inclusion in
the study patients must provide the informed consent also for genetic research.
Genetic counselling for patients with germline mutation in any of the Homologous
Recombination Repair genes should be performed.
- Male patients, who must be ≥18 years of age.
- Histologically confirmed prostate adenocarcinoma.
- Patients must have metastatic disease before starting treatment with docetaxel
(metastatic disease documented by positive bone scan or metastatic lesions on CT,
- No prior exposure to platinum, cyclophosphamide, mitoxantrone or Polyadenosine
5'diphosphoribose polymerisation (PARP) inhibitors.
- No cancer progression on the basis of Prostate Cancer Working Group (PCWG3) criteria
to docetaxel therapy.
- Completed at least six cycles and a maximum of ten cycles of chemotherapy containing
- Patients are allowed to have received up to two lines for mCRPC before chemotherapy
(abiraterone, enzalutamide or radium 223).
- Documented germline/somatic mutation in any of the Homologous Recombination Repair
genes, including among others, BRCA1 or BRCA2, ATM, Fanconi genes, CHEK2, mutL homolog
1 (MLH1), mutS homologue 2 (MSH2), mutS homolog 6 (MSH6), PMS2, PALB2, RAD51C, MRE11
that is predicted to be deleterious or suspected deleterious (known or predicted to be
detrimental/lead to loss of function).
- Patients 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 transfusion 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 ≤ 5x 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)^a) / serum
creatinine (mg/dL) x 72 F=1 for males.
- *Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
- Patients must be able to take oral medication.
- *Patients must have a life expectancy ≥ 16 weeks.
- Male patients and their partners, who are sexually active and of childbearing
potential, must agree to the use of two highly effective forms of contraception in
combination [see appendix A for acceptable methods], throughout the period of taking
study treatment and for 3 months after last dose of study drug(s) to prevent pregnancy
in a partner.
- 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 cancer must be
available for central testing. If there is not written confirmation of the
availability of an archived tumour sample prior to enrolment the patient is not
eligible for the study.
- Involvement in the planning and/or conduct of the study (applies to AstraZeneca or
sponsor staff and/or staff at the study site).
- Previous inclusion in the present study.
- Participation in another clinical study with an investigational product during the
- Any previous treatment with PARP inhibitor, including olaparib.
- Patients who do not have deleterious or suspected deleterious Homologous Recombination
Repair genes mutations and only have Homologous Recombination Repair genes 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.).
- Other malignancy within the last 5 years except: adequately treated non-melanoma skin
cancer, 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.
- 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.
- Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
reasons) within 3 weeks prior to study treatment.
- Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
period prior to starting olaparib is 2 weeks.
- Concomitant use of known strong (eg. 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.
- Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2)
caused by previous cancer therapy, excluding alopecia and nail toxicity.
- Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features
suggestive of MDS/AML.
- Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence
of brain metastases is not required. 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.
- Major surgery within 4 weeks of starting study treatment and 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, unstable spinal
cord compression, superior vena cava syndrome, extensive interstitial bilateral lung
disease on High Resolution Computed Tomography (HRCT) scan or any 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
- Immunocompromised patients, e.g., patients who are known to be serologically positive
for human immunodeficiency virus (HIV).
- Patients with a known hypersensitivity to olaparib or any of the excipients of the
- Patients with known active hepatitis (i.e. Hepatitis B or C) due to risk of
transmitting the infection through blood or other body fluids.
- Previous allogenic bone marrow transplant or double umbilical cord blood
- Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable).