Olaparib and Ceralasertib in Treating Patients with Metastatic Castration-Resistant Prostate Cancer
This phase II trial studies how well olaparib and ceralasertib work in treating patients with castration-resistant prostate cancer that has spread to other places in the body (metastatic). Olaparib and ceralasertib work by blocking proteins important for repairing damage to deoxyribonucleic acid (DNA). When this damage cannot be repaired, tumor cells die. This trial is being done to test the effectiveness of olaparib and ceralasertib in treating patients with metastatic castration-resistant prostate cancer.
- Provision of informed consent prior to any study specific procedures
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 within 42 days prior to registration
- Histologic or cytologic proof of prostate adenocarcinoma (excluding small-cell or neuroendocrine pathologies)
- Metastatic prostate cancer on computed tomography (CT), magnetic resonance imaging (MRI) or bone scan
- Must have disease progression (while testosterone level is under 50 ng/dl) on prior therapy prior to study entry defined as one (or more) of the following: * PSA progression defined as continuously rising PSA values measured a minimum of 1 week apart with a minimal starting value of 1.0 ng/mL * Progression of bidimensionally measurable soft tissue or nodal metastasis by CT or MRI based on Response Evaluation Criteria in Solid Tumors (RECIST), version (v)1.1 * Progression of bone disease on bone scan as defined by two new lesions per Prostate Cancer Working Group 3 (PCWG3)
- Prior treatment with at least one of the following: * One line of therapy in mCRPC * Second generation anti-androgen (e.g. abiraterone, enzalutamide or apalutamide) within the hormone-sensitive phase of disease AND progression occurs while on therapy
- Patients must be withdrawn from prior therapy for >= 3 weeks without PSA decline (patients may remain on prior prednisone up to 10 mg total daily exposure at provider’s discretion)
- Agree to undergo a biopsy of at least one metastatic site (if feasible) to determine DNA repair status, unless prior metastatic tissue underwent next-generation sequencing in a Clinical Laboratory Improvement Amendments (CLIA) certified lab. If no site is reachable, or first biopsy insufficient/unsuccessful, circulating analysis by Guardant360 panel will be done
- Treated with continuous androgen deprivation therapy (either surgical castration or luteinizing hormone-releasing hormone [LHRH] agonist/antagonist) with documented castrate level of serum testosterone (< 50 ng/dL)
- At least 2 weeks since prior palliative radiation or 4 weeks for radiation to > 30% of the bone marrow or with a wide field of radiation
- Hemoglobin >= 10 g/dL (with no blood transfusion or erythropoietin use within the past 42 days) (within 42 days prior to registration)
- Absolute neutrophil count >= 1.5 x 10^9/L (within 42 days prior to registration)
- Platelet count >= 100 x 10^9/L (with no platelet transfusions within last 42 days) (within 42 days prior to registration)
- Total bilirubin < 1.5 x upper limit of normal (ULN) (unless the patient has documented Gilbert’s disease and < 2.0 x ULN should be used) (within 42 days prior to registration)
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x ULN, unless liver metastases are present in which case they cannot be >= 5 x ULN (within 42 days prior to registration)
- Glomerular filtration rate (GFR) >= 51 mL/min, as assessed using the Cockcroft-Gault equation (within 42 days prior to registration)
- Estimated life expectancy >= 12 weeks
- Subjects must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) for the duration of the study (from the time they sign consent) and for 6 months after the last dose of either drug to prevent pregnancy in a partner. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential. Male patients should not donate sperm throughout the period of taking olaparib and for 6 months following the last dose of olaparib
- Patient is willing and able to comply with the protocol for the duration of the study, including undergoing biopsy (if warranted), treatment, scheduled visits and examinations
- A diagnosis of ataxia telangiectasia
- Prior treatment with a PARP inhibitor (e.g. olaparib, veliparib, niraparib, rucaparib), AZD6738 or other DNA-damage response agents
- Cytotoxic chemotherapy, first- or second-generation antiandrogen or CYP17 inhibitors are not permitted within 21 days or 5 half-lives of registration (whichever is longest)
- Major surgery < 2 weeks prior to enrolment; patients must have recovered from any effects of major surgery
- Persistent toxicities (>= Common Terminology Criteria for Adverse Events [CTCAE] grade 2) caused by previous cancer therapy, besides grade 2 alopecia and grade 2 neuropathy (these are allowed)
- Patients with current or prior myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML
- Any other malignancy which has been active or treated within the past 3 years, with the exception of non-melanomatous skin cancer, or Ta bladder cancer
- Patients with active brain metastases are excluded because of unknown penetration into the central nervous system (CNS). A confirmatory scan for asymptomatic patients is not required. Patients with a history of treated central nervous system (CNS) metastases are eligible provided they meet all of the following criteria: disease outside the CNS is present, no clinical evidence of progression since completion of CNS-directed therapy, minimum 3 weeks between completion of radiotherapy and registration and recovery from significant (grade >= 3) acute toxicity with no ongoing requirement for > 10 mg of prednisone per day or an equivalent dose of other corticosteroid. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
- Any of the following cardiac disease currently or within the last 6 months: * Unstable angina pectoris * Congestive heart failure (by New York Heart Association >= class 2) or known reduced left ventricular ejection fraction (LVEF) < 55% * Acute myocardial infarction * Conduction abnormality not controlled with pacemaker or medication (e.g. complete left bundle branch block or third-degree heart block) * Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible) * Uncontrolled hypertension (grade 2 or above) requiring clinical intervention * Patients at risk of brain perfusion problems, e.g. transient ischemic attacks (TIAs) or history of presyncope or syncopal episodes unexplained by reversible causes
- Mean resting corrected QT interval > 470 msec for females and > 450 for men, obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart using the Fridericia formula. Absence of any factors that increase the risk of corrected QT (QTc) prolongation or risk of arrhythmic such as congenital long QT syndrome, immediate family history of long QT syndrome or unexplained sudden death under 40 year of age. Patients with relative hypotension (< 90/60 mmHg) or previously known clinically relevant orthostatic hypotension defined as a postural hypotension >= 20 mmHg
- Concomitant use of known potent cytochrome P (CYP) 3A inhibitors or inducers. The required washout period prior to starting study treatment is five half-lives except for St-Johns’ wort, which is 3 weeks * Patient has had prescription or non-prescription drugs or other products known to be CYP3A4 and/or CYP2B6 substrates or CYP3A4 and/or CYP2B6 substrates with a narrow therapeutic index. Exposure of other drugs metabolized by CYP3A4 and/or CYP2B6 may be reduced and additional monitoring may be required * The use of herbal supplements or ‘folk remedies’ (and medications and foods that significantly modulate CYP3A activity) should be discouraged. If deemed necessary, such products may be administered with caution and the reason for use documented in the case report form (CRF)
- As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases that places the patient at unacceptable risk of toxicity or non-compliance. Examples include, but are not limited to, active bleeding diatheses, renal transplant, uncontrolled major seizure disorder, severe chronic obstructive pulmonary disease (COPD), superior vena cava syndrome, extensive bilateral lung disease on high resolution CT scan, severe Parkinson’s disease, active inflammatory bowel disease, psychiatric condition, immunocompromised patients or active infection including any patient known to have hepatitis B, hepatitis C and human immunodeficiency virus (HIV) or requiring systemic antibiotics, antifungals or antiviral drugs. Screening for chronic conditions is not required
- A known hypersensitivity to olaparib, AZD6738 or any excipient of the product or any contraindication to the combination anti-cancer agent as per local prescribing information
- Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with the absorption of the study medication, refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant bowel resection, with clinically significant sequelae that would preclude adequate absorption of AZD6738
- Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
- Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable)
- Involvement in the planning and/or conduct of the study
- Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
- Previous enrollment in the present study
- Has received a live vaccination with 2 weeks of enrollment
Locations & Contacts
Contact: Zachery Roger Reichert
Trial Objectives and Outline
I. To determine the response rate of the combination of olaparib and ceralasertib (AZD6738) in metastatic castration-resistant prostate cancer (mCRPC) patients who are deoxyribonucleic acid (DNA) repair proficient (DNA repair defect negative [DRPro], e.g. intact ATM, BRCA1 or BRCA2).
I. To determine the response rate of the combination of olaparib and AZD6738 in mCRPC patients who are DNA repair deficient (mono or biallelic loss of ATM or biallelic loss of BRCA1 or BRCA2).
II. Objective progression-free survival (combined radiographic and clinical progression-free survival).
III. Objective radiographic disease response rate.
IV. Prostate-specific antigen (PSA) progression-free survival.
V. PSA response rate for =< 0.2 ng/ml, 50% decline, 90% decline from entry PSA and confirmed 4 weeks later.
VI. Duration of combined radiographic and PSA response.
I. To evaluate the quantitative and qualitative tolerability of the combination within the combined, DRPro and DNA repair defect positive (DRDef) patients.
I. To evaluate the predictive capacity of circulating analytes within both genetic cohorts.
Patients receive olaparib orally (PO) twice daily (BID) on days 1-28 and ceralasertib PO once daily (QD) on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, then up to 5 years.
Trial Phase & Type
University of Michigan Comprehensive Cancer Center
Zachery Roger Reichert
Secondary IDs NCI-2019-04531
Clinicaltrials.gov ID NCT03787680