Genetic and Molecular Mechanisms in Assessing Response in Patients With Prostate Cancer Receiving Enzalutamide Therapy

Molecular Mechanisms Underlying Tumor Progression Despite Enzalutamide Treatment

This phase II trial studies genetic and molecular mechanisms in assessing response in patients with prostate cancer receiving enzalutamide therapy. Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as enzalutamide, may lessen the amount of androgens made by the body. Studying samples of tissue and blood in the laboratory from patients with prostate cancer may help doctors better understand castration-resistant prostate cancer. It may also help doctors make improvements in prostate cancer treatment.

Study Overview

• Status: Active, not recruiting
• Conditions: Castration-Resistant Prostate Carcinoma; Metastatic Malignant Neoplasm in the Bone; Metastatic Malignant Neoplasm in the Soft Tissues; Recurrent Prostate Carcinoma; Metastatic Prostate Adenocarcinoma; Stage III Prostate Adenocarcinoma AJCC v7; Stage IV Prostate Adenocarcinoma AJCC v7
• Intervention / Treatment: Drug: Enzalutamide

Detailed Description

PRIMARY OBJECTIVE:

I. To assess the correlations between baseline molecular features and pathways and prostate-specific antigen (PSA) change (</>= 50% decline) at 12 weeks versus (vs.) baseline.

SECONDARY OBJECTIVES:

I. To measure PSA change at 12 weeks and at each study visit vs. baseline after enzalutamide treatment.

II. To measure objective response after enzalutamide treatment. III. To assess the correlations between the baseline molecular features and pathways and progression-free survival, disease-specific survival, and overall survival.

IV. To assess the correlations between the baseline molecular features and pathways and time to PSA progression.

V. To identify molecular features and cellular pathways present in tumors from men with metastatic castrate-resistant prostate cancer (CRPC) that are progressing despite enzalutamide treatment.

VI. To explore correlation between baseline molecular features and pathways and changes in circulating tumor cells (CTCs) counts.

VII. To explore correlation between baseline molecular features and pathways and objective response.

VIII. To assess the correlations between the baseline molecular features and pathways and degree of PSA decline at 12 weeks and maximal PSA decline observed while on study.

IX. To assess the correlations between the baseline molecular features and time on treatment.

EXPLORATORY OBJECTIVES:

I. To assess correlations between cell-free deoxyribonucleic acid (DNA) (cfDNA) molecular features from blood and molecular features and pathways from the biopsy samples.

II. To assess correlations between cfDNA molecular features and endpoints in the primary and secondary objectives listed above.

III. To assess correlations between cell-free DNA and tumor molecular features and changes in PSA after discontinuing enzalutamide.

IV. To explore correlations with baseline molecular features and tissue histology.

V. To explore correlations with baseline tissue histology and PSA change, time to PSA progression, time on treatment, progression-free survival, and overall survival.

OUTLINE:

Patients receive enzalutamide orally (PO) once daily (QD) in the absence of disease progression or unacceptable toxicity. Patients undergo a tumor biopsy of a metastatic site at study entry (prior to initiation of enzalutamide) and after the time of progression. Patients may continue treatment beyond progression at the investigator's discretion.

After completion of study treatment, patients are followed up at 2-3 or 6 weeks and then every 12 weeks thereafter.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94115
      • UCSF Medical Center-Mount Zion
  • Oregon
    • Portland, Oregon, United States, 97239
      • OHSU Knight Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the prostate without pure small cell carcinoma; patients without histologically confirmed adenocarcinoma may be eligible if both the treating physician and the study principal investigator (PI) agree that the patient's history is unambiguously indicative of advanced adenocarcinoma
• Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) analogue or orchiectomy (i.e., surgical or medical castration); patients who have not had an orchiectomy must maintain effective GnRH-analogue therapy for the duration of the trial
• Radiographic evidence of regional or distant metastases with suspected tumor in an area that is safe to biopsy
• Willingness to undergo a tumor biopsy at baseline and at disease progression
• Serum testosterone level < 50 ng/dL at screening

• Progressive disease by PSA or imaging in the setting of medical or surgical castration; disease progression for study entry is defined as one or more of the following three criteria:

  • PSA evidence for progressive prostate cancer which consists of a PSA level of at least 2 ng/ml which has risen on at least 2 successive occasions, at least 1 week apart; if the confirmatory PSA value is less than the screening value, then an additional PSA value greater than #2 will be required to document progression of >= 1 week

    • PSA values to be obtained >= 1 week apart
  • Soft tissue disease progression defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Bone disease progression defined by two or more new lesions on bone scan
• Patient's physician has already recommended enzalutamide for treatment of progression
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Willing and able to give informed consent
• Estimated life expectancy >= 6 months
• Subjects who have partners of childbearing potential must be willing to use a method of birth control with adequate barrier protection as determined to be acceptable by the principal investigator and sponsor during the study and for 1 week after last study drug administration
• A minimum of 4 weeks elapsed off of anti-androgen therapy prior to enrollment for flutamide and 6 weeks for bicalutamide and nilutamide without evidence of an anti-androgen withdrawal response; patients who NEVER HAD A PSA decline with the most recent anti-androgen therapy or in whom the response to the most recent anti-androgen was for < 3 months require only a 2 week washout period prior to first dose of study drug
• A minimum of 4 weeks from prior systemic anti-cancer therapies or 3 weeks for radiation treatment prior to enrollment is required

Exclusion Criteria:

• Severe, concurrent disease, infection, or co-morbidity that, in the judgment of the investigator, would make the patient inappropriate for enrollment
• Previous treatment with docetaxel for metastatic prostate cancer
• Known metastases in the brain or active epidural disease (NOTE: patients with treated epidural disease are allowed)
• Absolute neutrophil count < 1,000/uL
• Platelet count < 75,000/uL
• Hemoglobin < 9 g/dL at the screening visit; (NOTE: subject may not have received any growth factors or blood transfusions within seven days of the hematologic laboratory values obtained at the screening visit)
• Total bilirubin (TBL) > 2.5 times the upper limit of normal at the screening visit
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal at the screening visit
• Creatinine (Cr) > 2 mg/dL at the screening visit
• Prothrombin time (PT) or international normalized ratio (INR) and a partial thromboplastin time (PTT) > 1.5 times the upper limit of normal
• Previous treatment with an agent that blocks adrenal androgen synthesis (e.g. abiraterone acetate, TAK-700, TOK-001, ketoconazole) or second generation androgen receptor (AR) antagonists (e.g., BMS 641988, ARN-509,TOK-001)
• Systemic corticosteroids greater than the equivalent of 10 mg of prednisone per day within 4 weeks of study drug administration are prohibited
• Structurally unstable bone lesions suggesting impending fracture
• Previous treatment with enzalutamide (MDV3100)
• Medical contraindications to stopping aspirin, Coumadin or other anticoagulants prior to image-guided tumor biopsies; follow institutional guidelines when determining drugs to avoid and length of washout
• Plans to initiate treatment with an investigational agent during the study
• History of seizure or condition that may predispose to seizure; also, history of loss of consciousness or transient ischemic attack within 12 months of (day 1 visit)
• Concomitant use of the strong CYP2C8 inhibitors gemfibrozil or trimethoprim (Bactrim)
• History of known malabsorption syndrome or prior surgery(ies) that may lead to malabsorption
• Use of herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (e.g., saw palmetto) within 4 weeks of study drug administration (day 1)
• Use of the following drugs within 4 weeks of study drug administration: 5 alpha-reductase inhibitors (finasteride, dutasteride), estrogens, Cyproterone acetate, biologic, or other agents with anti-tumor activity against prostate cancer, and androgens (testosterone, dihydroepiandrosterone [DHEA], etc.)
• A second active malignancy except adequately treated non-melanoma skin cancer or other non-invasive or in situ neoplasm

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (Enzalutamide); Patients receive enzalutamide PO QD in the absence of disease progression or unacceptable toxicity. Patients undergo a tumor biopsy of a metastatic site at study entry (prior to initiation of enzalutamide) and after the time of progression. Per the investigator, patients may continue treatment beyond progression.	Drug: Enzalutamide; Given PO; Other Names: Xtandi; MDV3100; ASP9785

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With a >= 50% Decline in Prostate-specific Antigen (PSA) Value	The percentage of participants with a >= 50% decline in PSA values will be reported with 95% exact confidence interval. For each participant, percentage decline in PSA values are calculated as 100% times the difference between PSA values taken at baseline and 12 weeks divided by PSA values at baseline. Percentage of participants determined as 100% times the number of participants with >= 50% decline divided by overall number of participants.	Baseline to 12 weeks
Percentage of Participants With Tumor Protein 53 Gene (TP53) Copy Number Alterations and Mutations	Evaluate the association between PSA response at 12 weeks after initiating therapy, and TP53 copy number alterations and mutations at baseline. Simple Logistic regression was planned but due to sample size we used Fisher's Exact test. Percentage of patients in each arm with TP53 copy number alterations and mutations will be reported and odds ratio with two-sided 95% confidence interval will be calculated.	Baseline to 12 weeks
Percentage of Participants With Phosphatase and Tensin Homologue Gene (PTEN) Copy Number Alterations and Mutations	Evaluate the association between PSA response at 12 weeks after initiating therapy, and PTEN copy number alterations and mutations at baseline. Simple Logistic regression was planned but due to sample size we used Fisher's Exact test. Percentage of patients in each arm with PTEN copy number alterations and mutations will be reported and odds ratio with two-sided 95% confidence interval will be calculated.	Baseline to 12 weeks
Percentage of Participants With Retinoblastoma Gene (RB1) Copy Number Alterations and Mutations	Evaluate the association between PSA response at 12 weeks after initiating therapy, and RB1 copy number alterations and mutations at baseline. Simple Logistic regression was planned but due to sample size we used Fisher's Exact test. Percentage of patients in each arm with RB1 copy number alterations and mutations will be reported and odds ratio with two-sided 95% confidence interval will be calculated.	Baseline to 12 weeks
Androgen Receptor (AR) Messenger RNA (mRNA) Expression	Median AR mRNA expression between responders and non-responders.	Baseline to 12 weeks
Androgen Receptor Variant 7 (AR-V7) Expression	Median AR-V7 expression between responders and non-responders.	Baseline to 12 weeks
Percentage of Participants With Androgen Receptor (AR) Copy Number Alterations and Mutations	Evaluate the association between PSA response at 12 weeks after initiating therapy, and AR copy number alterations and mutations at baseline. Simple Logistic regression was planned but due to sample size we used Fisher's Exact test. Percentage of patients in each arm with AR copy number alterations and mutations will be reported and odds ratio with two-sided 95% confidence interval will be calculated.	Baseline to 12 weeks
Number of Participants With Protein Expression of AR	The number of participants, responders and non-responders, that were found to have protein expression of AR.	Baseline to 12 weeks
Androgen Receptor (AR) Activity Level	Median Normalized Enrichment Score (NES) AR activity levels of responders and non-responders. Gene Set Enrichment Analysis (GSEA) is used to interpret gene expression data. GSEA enrichment score (ES) reflects the degree to which a gene set (GS) is overrepresented at the top or bottom of a ranked list of genes. ES is calculated by walking down the list, increasing a running-sum statistic when a gene is in the GS and decreasing when it's not. Magnitude of increment depends on correlation of the gene with the phenotype. ES is the max deviation from zero encountered in walking the list. Positive ES indicates GS enrichment at the top of the list; negative indicates GS enrichment at the bottom. GSEA calculates NES as actual ES divided by mean (ESs against all permutations of the dataset). Low AR activity has been linked to stemness and lineage plasticity that are recognized as a cause of acquired resistance to AR-targeting therapies.	Baseline to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prostate-specific Antigen (PSA) Changes	Will be evaluated.	Baseline to up to 5 years
Percentage of Participants With an Objective Response	The percentage of participants with an objective response will be reported with 95% exact confidence interval. Objective radiographic response is evaluated using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. For each participant, objective response is calculated as 100% times the difference between the sum of measurable target lesions at baseline and the smallest sum of measurable target lesions achieved after the initiation of therapy, divided by the sum of target lesions at baseline.	Baseline to date of first documented radiographic objective response, assessed up to 1 year
Progression-free Survival (PFS)	Correlations between baseline molecular features and pathways and PFS will be assessed using cox regression model. In addition, Kaplan-Meier plots will be used to graphically illustrate the survival distributions across the strata of categorical molecular predictors.	Time from day 1 of study drug treatment to date of first documented radiographic progression or clinical progression, assessed up to 5 years
Disease-specific Survival (DSS)	Correlations between baseline molecular features and pathways and DSS will be assessed using cox regression model. In addition, Kaplan-Meier plots will be used to graphically illustrate the survival distributions across the strata of categorical molecular predictors.	Time from day 1 of study drug treatment to date of death from prostate cancer, assessed up to 5 years
Overall Survival (OS)	Correlations between baseline molecular features and pathways and OS will be assessed using cox regression model. In addition, Kaplan-Meier plots will be used to graphically illustrate the survival distributions across the strata of categorical molecular predictors.	Time from day 1 of study drug treatment to date of death from any cause, assessed up to 5 years
Time to Prostate-specific Antigen (PSA) Progression	Correlations between baseline molecular features and pathways and time to PSA progression will be assessed.	Up to 5 years
Molecular Features and Cellular Pathways Present in Tumors That Are Progressing Despite Treatment With Enzalutamide	Random Forests classification will be used to identify molecular features and pathways present in patients with disease progression or who discontinue Enzalutamide treatment.	Up to 5 years
Changes in Circulating Tumor Cell (CTC) Counts	Linear regression model will be used to assess the association for changes in CTC counts from baseline and maximal prostate-specific antigen (PSA) observed while on study.	Baseline to up to 5 years
Degree of Prostate-specific Antigen (PSA) Decline	Degree of prostate-specific antigen (PSA) change from baseline to 12 weeks. PSA at week 12 minus PSA at baseline divided by PSA at baseline and multiplied by 100%. Decline shown as negative percent and incline shown as positive percent.	At 12 weeks
Maximal Prostate-specific Antigen (PSA) Decline Observed	Correlations between baseline molecular features and pathways and maximal PSA decline observed will be assessed. Linear regression model will be used to assess the association for changes in circulating tumor cells (CTC) counts from baseline and maximal PSA observed while on study.	Up to 5 years
Time on Treatment	The association between molecular predictors and survival outcomes (e.g., progression-free survival [PFS], disease-free survival [DSS] and overall survival [OS]) and time on treatment will be assessed using cox regression model.	Up to 5 years

Collaborators and Investigators

• Sponsor: OHSU Knight Cancer Institute
• Collaborators: Astellas Pharma US, Inc.; Oregon Health and Science University
• Investigators: Principal Investigator: Alexandra Sokolova, M.D., OHSU Knight Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2014
• Primary Completion (Actual): October 1, 2019
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: March 26, 2014
• First Submitted That Met QC Criteria: March 26, 2014
• First Posted (Estimated): March 31, 2014

Study Record Updates

• Last Update Posted (Actual): March 22, 2024
• Last Update Submitted That Met QC Criteria: March 20, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Urogenital Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Neoplasms; Prostatic Neoplasms; Carcinoma; Adenocarcinoma; Neoplasms, Second Primary
• Other Study ID Numbers: IRB00010241 (Other Identifier: OHSU Knight Cancer Institute); NCI-2014-00417 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); IIT000800; MR00045569

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No