Abiraterone Acetate, Olaparib, and Prednisone in Treating Patients with Metastatic Castration-Resistant Prostate Cancer with DNA Repair Defects
- Ability to understand and the willingness to sign a written informed consent document that is approved by the local institutional review board and Health Insurance Portability and Accountability Act (HIPAA) authorization for the release of personal health information
- Histological or cytological proof of prostate adenocarcinoma (Note: small-cell carcinoma of the prostate is not permitted)
- Documented progressive mCRPC based on at least one of the following criteria: * PSA progression defined as 25% increase over baseline value with an increase in the absolute value of at least 2.0 ng/mL that is confirmed by another PSA level with a minimum of a 1 week interval and a minimum PSA of 2.0 ng/mL * Progression of bidimensionally measurable soft tissue or nodal metastasis assessed within 42 days prior to registration by a computed tomography (CT) scan or magnetic resonance imaging (MRI) * Progression of bone disease (evaluable disease) (new bone lesion[s]) by bone scan
- Agree to undergo a biopsy of at least one metastatic site (fresh biopsy of primary prostate only allowed if there is clear local disease and no other measurable disease site or biopsiable bone lesion) to determine DNA repair defects; however: * Adequate archival metastatic or primary disease tumor tissue can be used if available in lieu of a new biopsy; these patients will only be eligible for protocol therapy if the biopsy has tumor that is positive for DNA repair defects * Patients with known DNA damage repair defects based on prior appropriately validated metastatic or prostate tissue analysis may be used in lieu of new biopsy/analysis based on central site evaluation of quality of the biopsy and analysis * Patients with known germline DNA repair defects are eligible without a biopsy; however it will be highly desirable that they undergo a metastatic (or fresh prostate biopsy if there is clear local disease and no other measurable disease site or biopsiable bone lesion) disease biopsy to better define the scope of the DNA repair defects in the current disease context
- Eastern Cooperative Oncology Group (ECOG) status of 0-2
- Within 14 days of registration: Absolute neutrophil count (ANC) >= 1500/ul
- Within 14 days of registration: Hemoglobin >= 10.0 g/dL
- Within 14 days of registration: White blood cell (WBC) > 3 x 10^9/L
- Within 14 days of registration: Platelet count >= 100,000/ul
- Within 14 days of registration: Creatinine >= 51 mL/min estimated using the Cockcroft-Gault equation
- Within 14 days of registration: Potassium >= 3.5 mmol/L (within institutional normal range)
- Within 14 days of registration: Total bilirubin within normal institutional limits (or < 2 X the upper limit of normal [ULN] in those with Gilbert’s disease)
- Within 14 days of registration: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional ULN unless liver metastases are present in which case it must be =< 5 x ULN
- Men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for at least 3 months thereafter
- Patients must discontinue antiandrogen therapy (i.e., flutamide, bicalutamide, nilutamide) for at least 4 weeks prior to registration with no evidence of a falling PSA after washout
- Serum testosterone < 50 ng/dL; patients must continue primary anti-androgen therapy (ADT) with a luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist) if they have not undergone orchiectomy
- Able to take oral medication without crushing, dissolving or chewing tablets
- Patients must have a life expectancy >= 6 months
- Patients may have received prior radiation therapy or surgery; however, at least 14 days must have elapsed since completion of radiation therapy or surgery and patient must have recovered from all side effects at the time of registration (e.g. back to baseline or grade 1)
- Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
- Prior exposure to CYP17 (other than ketoconazole) or PARP inhibitors for prostate cancer; patients with prior exposure to ketoconazole are eligible
- Prior chemotherapy for castration resistant disease; chemotherapy given in the hormone-sensitive setting is permissible if stopped at least 4 weeks prior to registration * Note: Patients can receive a stable dose of bisphosphonates for bone metastases, including zoledronic acid, or denosumab before and during the study as deemed appropriate by the treating physician
- Prior exposure to enzalutamide, androgen receptor antagonist ARN-509 (ARN-509) or other investigational AR-directed therapy in the setting of mCRPC
- Patients with a currently active second malignancy excluding non-melanomatous skin cancer or superficial transitional cell carcinoma * Note: Patients are not considered to have a "currently active" malignancy if they have completed all therapy and are now considered without evidence of disease for 1 year
- Patients receiving any other investigational agents; any prior investigational agents must be stopped at least 14 days (2 week washout) prior to registration
- Patients who have received itraconazole or fluconazole within 3 weeks prior to registration or those who have not recovered (i.e., back to baseline or grade 1) from adverse events (AEs) due to agents administered more than 3 weeks earlier
- Patients with a history of active seizures (or a single confirmed seizure event) in the last 2 years from the time of registration
- Patients with a history of pituitary or adrenal dysfunction or active or symptomatic viral hepatitis or chronic liver disease are not eligible
- Patients with active brain metastases; a scan to confirm the absence of brain metastases is not required for asymptomatic patients
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib or abiraterone
- 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, unstable spinal cord compression (untreated or unstable within at least 28 days prior to registration), superior vena cava syndrome, extensive bilateral lung disease on high-resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent
- Patients with prolonged pre-existing hematological toxicities including known indicators of bone marrow failure or abnormality
- Patients with myelodysplastic syndrome/acute myeloid leukemia
- Patients may continue on a daily multi-vitamin, calcium and vitamin D, but all other herbal, alternative and food supplements (i.e. prostate cancer [PC]- hope [spes (Latin)], saw palmetto, St John’s wort, etc.) must be discontinued before starting protocol treatment; hormonal-acting agents such as diethylstilbestrol (DES) are forbidden during the trial and must be stopped starting protocol treatment; no washout period will be required; patients on megestrol acetate for hot flashes are allowed to continue therapy
- Patients must stop taking ritonavir, idinavir, saquinavir, telithromycin, clarithromycin and nelfinavir 1 week prior to registration; Note: topical ketoconazole is permitted
- Patients must stop taking phenytoin, rifampicin, rifapentine, rifabutin, carbamazepine, nevirapine, modafinil and St John’s wort (hypericum perforatum) 3 weeks prior to registration; patients must stop taking phenobarbitone 5 weeks prior to registration; patients must stop taking all strong CYP3A4 inhibitors, including clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, prior to registration
- Patients must not be planning to receive any concurrent cytotoxic chemotherapy, surgery or radiation therapy during protocol treatment
- Use of any prohibited concomitant medications within 7 days of registration
- Patients who are human immunodeficiency virus (HIV)-positive on combination antiretroviral therapy
- Patients with known active hepatitis B or hepatitis C
- Patients with baseline moderate to severe hepatic impairment (Child-Pugh class B and C)
- Persistent toxicities (>= Common Terminology Criteria for Adverse Events [CTCAE] grade 2), with the exception of alopecia, caused by previous cancer therapy
- Resting electrocardiogram (ECG) with corrected QT (QTc) > 470 msec on 2 or more time points within a 24 hour period or of long QT syndrome
- Patients with significant cardiac history including: * Severe or unstable angina pectoris * Uncontrolled hypertension (defined as systolic blood pressure [BP] >= 160 mmHg or diastolic BP >= 95 mmHg;. Note - patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment * Atrial fibrillation or other cardiac arrhythmia requiring therapy. * Heart disease as evidenced by myocardial infarction, or aterial thrombotic events in the past 6 months * Class II-IV heart failure (as defined by New York Heart Association) or a cardiac ejection fraction measurement of less than 50% at baseline
- Blood transfusion within 30 days of consent
- Previous allogeneic bone marrow transplant
- Major surgery within 14 days of registration and patients must have recovered from any effects of any major surgery
- Patients with any condition likely to interfere with absorption of the study medication
- No other condition which, in the opinion of the Investigator, would preclude participation in this trial
- Patients who have noncanonical DNA repair defects and extensive visceral disease or symptomatic bone disease requiring urgent tumor response
Salt Lake City
I. Evaluate the objective progression-free survival (PFS) of abiraterone acetate (abiraterone)/prednisone, olaparib or the combination abiraterone/prednisone + olaparib in metastatic castration-resistant prostate cancer (mCRPC) patients with DNA repair defects in BRCA1, BRCA2, or ATM.
I. Measurable disease response rate by Response Evaluation Criteria in Solid Tumors (RECIST).
II. Prostate specific antigen (PSA) response rate and rate of undetectable PSA (=< 0.2 ng/ml).
III. Whether non-canonical DNA repair defects in FANCA, PALB2, RAD51, ERCC3, MRE11, NBN,
CDK12, CHEK2, HDAC2, ATR, GEN1, BRIP1, or FAM175A have clinical susceptibility to PARP inhibition alone.
IV. The safety of the combination of abiraterone/prednisone and olaparib combination therapy.
V. The response rate and PFS with cross over to olaparib or abiraterone post progression on therapy with abiraterone or olaparib respectively.
VI. The qualitative and quantitative toxicities.
I. Circulating tumor cell (CTC) number, morphology and possible DNA, ribonucleic acid (RNA) analyses will assess for heterogeneity, mutational load, DNA repair defects, and expression of key prostate cancer-related genes for potential use as biomarkers of response or failure and also as a potential surrogate for the metastatic biopsy.
II. Circulating tumor-derived DNA (ctDNA) will be assessed for mutational load as a biomarker of response or failure and also as a means to identify DNA repair defects for use as a potential surrogate for the metastatic biopsy.
III. Correlation of mutational data, copy number alterations, and transcriptome profiling between liquid assays and tissue-based analyses.
IV. Within the above data sets and also the sequencing of the metastatic biopsy, the predictive and prognostic role of androgen receptor (AR) mutations, amplifications, splice variants, expression regulation, and other androgen signaling pathway modulation.
V. Immunohistochemistry (IHC) or other genetic/proteomic/methylomic analyses in the future may be pursued as excess samples will be banked.
OUTLINE: Patients are randomized or assigned into 1 of 4 arms based on gene mutations.
ARM I: Patients receive abiraterone acetate orally (PO) once daily (QD) and prednisone PO twice daily (BID) on days 1-28. Patients who develop objective progression may crossover to Arm II.
ARM II: Patients receive olaparib PO BID on days 1-28. Patients who develop objective progression may crossover to Arm I.
ARM III: Patients receive abiraterone acetate PO QD, prednisone PO BID, and olaparib PO BID on days 1-28.
ARM IV: Patients with mutations in noncanonical DNA repair genes receive olaparib PO BID on days 1-28. Patients who develop objective progression may crossover to Arm I.
In all arms, 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 and every 4 weeks and every 6 months for up to 2 years.
Trial Phase Phase II
Trial Type Treatment
Maha H. A. Hussain
- Primary ID NU 16U05
- Secondary IDs NCI-2016-01834, STU00203960
- Clinicaltrials.gov ID NCT03012321