Olaparib and Ceralasertib in Treating Patients with Metastatic Castration-Resistant Prostate Cancer

Inclusion Criteria

• Provision of informed consent prior to any study specific procedures
• Male ages 18 years and older at time of signing the informed consent form
• 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
• 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• Patients must be withdrawn from prior therapy for 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 labor known germline loss of BRCA1, BRCA2 or ATM. If no site is reachable, or first biopsy insufficient/unsuccessful, circulating tumor DNA may be obtained
• 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). A stable dose of bisphosphonate or denosumab for bone metastases should be continued as long as started at least 5 days prior to C1D1 planned start day
• At the time of planned treatment start (C1D1), at least 21 or more days will have elapsed from palliative radiation (with the exception of radiation to >30% of bone marrow or with a wide field of radiation, this requires 28 or more days)
• 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
• Male patients who are sexually active must be willing to use barrier contraception for the duration of the study and for 1 week after the last study drug administration, with all sexual partners. Male patients must use a condom during treatment and for 6 months after the last dose of study drug(s) when having sexual intercourse with a pregnant woman or with a woman of childbearing potential and must not donate sperm for 6 months after the last dose of study drug. Female partners of male patients should also use a highly effective form of contraception for 6 months after the last dose of study drug(s) if they are of childbearing potential. True abstinence is an acceptable form of contraception and must be documented as such
• 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

Exclusion Criteria

• A diagnosis of ataxia telangiectasia
• Prior treatment with a PARP inhibitor (e.g. olaparib, veliparib, niraparib, rucaparib), AZD6738 or other DNA-damage response agents (e.g. cisplatin or carboplatin)
• 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) of planned treatment start. For clarity, enzalutamide requires 5 weeks washout
• 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 or moderate cytochrome P (CYP) 3A inhibitors (e.g. itraconazole, ciprofloxacin, diltiazem) require 2-week washout prior to planned C1D1. Concomitant use of strong or moderate CYP3A inducers (e.g. phenobarbital, enzalutamide, modafinil require 5-week washout for enzalutamide or phenobarbital and 3 week washout for all others
• 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