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Apalutamide, Abiraterone Acetate, and Prednisone in Treating Patients with Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer

Trial Status: Active

This phase II trial studies how well apalutamide, abiraterone acetate, and prednisone work in treating patients with castration-resistant prostate cancer that has spread to other parts of the body and have not had prior treatment with chemotherapy. Androgens, or male sex hormones, can cause the growth of prostate cancer cells. It is believed apalutamide may help stop or slow the growth of prostate cancer cell growth by blocking the male sex hormones. Abiraterone acetate is a drug that blocks the remaining or residual male sex hormones in the body that may be helping prostate cancer to grow. Prednisone may help abiraterone acetate work better by making tumor cells more sensitive to the drug. Giving apalutamide, abiraterone acetate, and prednisone together may work better in treating patients with prostate cancer.

Inclusion Criteria

  • Karnofsky performance status >= 70
  • Life expectancy of >= 12 months as determined by treating investigator
  • Written Authorization for Use and Release of Health and Research Study Information (Health Insurance Portability and Accountability Act [HIPAA] authorization per institutional requirements)
  • Willing/able to adhere to the prohibitions and restrictions specified in this protocol
  • Willing to take abiraterone acetate on an empty stomach, and should be able to swallow tablets whole, without crushing/chewing tablets; must have the ability to swallow, retain, and absorb oral medication
  • Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to study entry
  • Agrees to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug; must also agree not to donate sperm during the study and for 3 months after receiving the last dose of study drug; abstinence is an acceptable method of birth control
  • Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
  • Platelets >= 100 x 10^9/L
  • Hemoglobin (Hb) >= 9 g/dL (independent of transfusion and/or growth factors within 3 months prior to cycle 1 day 1)
  • Serum potassium >= 3.5 mEq/L
  • Serum albumin of >= 3.0 g/dl
  • Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) < 2.5 x institutional upper limit of normal (ULN)
  • Serum total bilirubin =< 1.5 x institutional ULN (Note: In subjects with Gilbert’s syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is =< 1.5 x ULN, subject may be eligible)
  • Glomerular filtration rate (GFR) >= 45 mL/min
  • Histologically confirmed diagnosis of adenocarcinoma of the prostate; histologic variants of prostate cancer comprising of > 50% of the tumor including neuroendocrine features and small cell carcinoma of the prostate are excluded
  • Radiographic evidence of metastatic disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria OR by prostate cancer-specific positron emission tomography (PET) imaging; evaluable non-target lesions and/or bone only metastasis are permitted per RECIST 1.1 and Prostate Cancer Clinical Trials Working Group (PCWG3) guidelines; non-target, pathological lymph nodes >= 10 mm and less than 15 mm in the short axis are permitted
  • Ongoing androgen deprivation therapy (ADT) using a luteinizing hormone-releasing hormone (LHRH) agonist (e.g. leuprolide, goserelin) or antagonist (e.g. degarelix) must continue on therapy unless prior bilateral orchiectomy has been performed
  • PSA >= 2.0 ng/mL
  • Evidence of castration resistant disease in the setting of ongoing ADT (medical or surgical) as evidenced by at least one of the following: * Absolute rise in PSA of 2.0 ng/mL or an increase > 25% from the nadir, minimum 2 consecutive rising PSA levels with an interval of >= 1 week between each PSA level, OR * Computed tomography (CT) or magnetic resonance imaging (MRI) based evidence of disease progression (soft tissue, nodal or visceral disease progression) according to RECIST 1.1 criteria, OR * At least 1 new bone scan lesion as compared to the most immediate prior radiologic studies
  • A minimum of 2 weeks elapsed off of antiandrogen therapy prior to start of study drug (i.e. flutamide, nilutamide, bicalutamide)
  • A minimum of 2 weeks elapsed off of sipuleucel-T and radiation therapy prior to start of study drug
  • A minimum of 4 weeks from any major surgery prior to start of study drug
  • Self-reported race of either African American or Caucasian
  • Ability to understand and the willingness to sign a written informed consent document; if the subject is unable to understand the consent due to comorbidity, such as Alzheimer’s disease, consent by a legally authorized representative and assent by the subject will be obtained

Exclusion Criteria

  • Prior treatment with abiraterone acetate, enzalutamide, apalutamide, galeterone (TOK-001), orteronel (TAK-700), or similar agent
  • Active infection or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated
  • Active or symptomatic infection including human immunodeficiency virus (HIV), viral hepatitis or chronic liver disease
  • Any chronic medical condition requiring a higher dose of corticosteroid than 5 mg prednisone/prednisolone bid
  • Have known allergies, hypersensitivity, or intolerance to abiraterone acetate, apalutamide or prednisone or their excipients
  • Pathological finding consistent with small cell carcinoma of the prostate
  • Symptomatic liver or visceral organ metastasis
  • Have a history of gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of the study agents
  • Known brain metastasis
  • Prior cytotoxic chemotherapy or biologic therapy for the treatment of CRPC; Note: sipuleucel-T is permitted with a 2-week washout
  • Previously treated with ketoconazole for prostate cancer for greater than 7 days
  • Prior systemic treatment with an azole anti-fungal drug (e.g. fluconazole, itraconazole) within 4 weeks of cycle 1, day 1
  • Uncontrolled hypertension (systolic blood pressure [BP] >= 140 mmHg or diastolic BP >= 90 mmHg); patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment
  • Poorly controlled diabetes, fasting blood sugar (FBS) >= 200 mg/dL
  • History of pituitary or adrenal dysfunction
  • Symptomatic atrial fibrillation, or other symptomatic cardiac arrhythmia
  • Other malignancy, except non-melanoma skin cancer, with a >= 30% probability of recurrence within 24 months
  • History of any of the following: * Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 6 months of cycle 1 day 1, brain arteriovenous malformation, Schwannoma, meningioma, or other benign central nervous system [CNS] or meningeal disease which may require treatment with surgery or radiation therapy) * Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to first dose of study drug; venous thrombotic events within 6 months are permitted IF they are not attributed to prostate cancer (in the opinion of the treating physician)
  • Avoid concomitant strong CYP3A4 inducers during abiraterone acetate treatment
  • Avoid co-administration of abiraterone acetate with CYP2D6 substrates that have a narrow therapeutic index; if an alternative treatment cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate
  • Baseline moderate or severe hepatic impairment (Child Pugh class B & C)
  • Use of herbal products that may decrease PSA levels (i.e., saw palmetto) (no washout period required)
  • Administration of an investigational therapeutic within 30 days prior to cycle 1, day 1
  • Any condition which, in the opinion of the investigator, would preclude participation in this trial


New Orleans
Tulane University Health Sciences Center
Status: ACTIVE
Contact: Brian Edward Lewis


Owings Mills
Chesapeake Urology Associates-The Prostate Center
Status: ACTIVE
Contact: Ronald F. Tutrone
Phone: 443-231-1664


Wayne State University / Karmanos Cancer Institute
Status: ACTIVE
Contact: Elisabeth Iljas Heath

North Carolina

Chapel Hill
UNC Lineberger Comprehensive Cancer Center
Status: ACTIVE
Contact: Rachel Munoz
Phone: 919-445-4188
Novant Health Presbyterian Medical Center
Contact: Nasfat Shehadeh
Duke University Medical Center
Status: ACTIVE
Contact: Daniel James George
Phone: 919-668-4615
Maria Parham Hospital
Status: ACTIVE
Contact: Kim Ward
Phone: 919-419-5410
Scotland Memorial Hospital-Laurinburg Cancer Center
Status: ACTIVE
Contact: Kim Ward
Phone: 919-419-5410
Southeastern Regional Medical Center
Status: ACTIVE
Contact: Kim Ward
Phone: 919-419-5410
Johnston Memorial Hospital
Status: ACTIVE
Contact: Kim Ward
Phone: 919-419-5410

South Carolina

Gibbs Cancer Center & Research Institute
Status: ACTIVE
Contact: Michael Humeniuk
Phone: 864-560-6812
Spartanburg Medical Center
Status: ACTIVE
Contact: Amy Dawn Robertson
Phone: 910-291-7630


Virginia Oncology Associates - Lake Wright
Status: ACTIVE
Contact: Mark Tyrone Fleming
Phone: 757-827-9400


I. To estimate the radiographic progression free survival (PFS) distribution of African American and Caucasian men with metastatic castration-resistant prostate cancer (mCRPC) treated with apalutamide, abiraterone acetate, and prednisone.


I. To determine the duration of prostate-specific antigen (PSA) response, time to nadir, and percent of men who achieve a PSA < 0.1 ng/mL.

II. To estimate the rate of objective response and incidence of bone flares.

III. Safety (National Cancer Institute [NCI] Common Toxicity Criteria [CTC] version [v]4.0) and tolerability, particularly incidence and grade of hypertension in the two populations.

IV. Overall survival.


I. Perform ancestral genotyping to obtain genetically estimated indicators of race using deoxyribonucleic acid (DNA) isolated from whole blood at baseline.

II. Describe the baseline profile of serum hormone levels (including but not limited to testosterone, DHT, DHEA, DHEAS, estradiol) and lipids, the change in levels with subsequent therapy (cycle 4), and their correlation with response to abiraterone acetate plus apalutamide.

III. Abiraterone pharmacokinetics (PKs) drawn at cycle 1 day 1 (d1) at 1, 2, 4, 8 hours post dose and cycle 2 d1 at (24 hour trough), 1, 2, 4, 8 hours post dose.

IV. Describe the germline single nucleotide polymorphism (SNP) profiles of the androgen receptor gene, target genes involved in androgen metabolism and signaling and target genes that have been shown to be differentially expressed in African American versus Caucasian prostate cancer and their associations with response to abiraterone acetate plus apalutamide.

V. Describe the expression and splicing profiles of the androgen receptor gene, target genes involved in androgen metabolism and signaling and target genes that have been shown to be differentially expressed and/or spliced in African American versus Caucasian prostate cancer and their associations with response to abiraterone acetate plus apalutamide.

VI. Describe cell-free plasma DNA profiles and their associations with response to abiraterone acetate plus apalutamide.

VII. To explore the associations between baseline levels and treatment-related changes of plasma-based protein markers with response in patients treated with abiraterone acetate plus apalutamide.

VIII. Describe abiraterone metabolism by race with particular attention to active metabolites including D4A and 3-keto-5alpha-abiraterone.

IX. To assess the concordance between the genomic alterations identified in cell-free DNA (cfDNA) to the genomic alterations identified in the tumor-derived DNA.


Patients receive apalutamide orally (PO) once daily (QD) on days 1-28, abiraterone acetate PO QD on days 1-28, and prednisone PO twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 28 days, every 3 months for up to 24 months, and then every 6 months thereafter.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Duke University Medical Center

Principal Investigator
Daniel James George

  • Primary ID Pro00075097
  • Secondary IDs NCI-2017-01132
  • ID NCT03098836