Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

All Drugs and Chemicals

Antineoplastic Agents

Androgens

Testosterone

Goserelin

Antineoplastic Agents, Hormonal

Patients will have an multi-parametric magnetic resonance imaging (mpMRI) guided biopsy, then receive enzalutamide and goserelin subcutaneous (SC) treatment for 6 months followed by a second mpMRI examination.

10.8mg administered subcutaneously every 12 weeks (2 doses)

Enzalutamide

Multiparametric MRI - One at baseline and after 6 months of treatment

mpMRI

Fatima Karzai, M.D.

Background:

* There are several ways to treat prostate cancer. Researchers want to see how well a certain kind of imaging helps detect prostate cancer. They also want to see if a particular drug combination used before surgery will benefit people with prostate cancer that hasn't spread in the body (non-metastatic). The combination will be androgen deprivation therapy and enzalutamide.
* The combination of androgen deprivation therapy and enzalutamide has been shown to make patients with advanced (metastatic disease) live longer. The investigators want to see if using it earlier can increase cure rate of surgery and identify genetic or molecular characteristics that are associated with better outcomes.

Objectives:

- To develop better ways of detecting prostate cancer before and after pre-operative treatment.

Eligibility:

- Men at least 18 years old with non-metastatic prostate cancer. They must be candidates for a radical prostatectomy.

Design:

* Participants will be screened with medical history, physical exam, and blood tests. They will have scans and X-rays.
* Before starting the study drugs, participants will have:
* Vital signs taken, medical history, and blood tests.
* Electrocardiogram (ECG) heart test, with patches stuck on the skin.
* Small piece of tumor removed (biopsy) using image guidance from magnetic resonance imaging (MRI) and ultrasound.
* 3T multi-parametric magnetic resonance imaging (mpMRI). Participants will lie on a table that slides into a metal cylinder. A probe will be inserted in the rectum. They will be in the scanner for about 60 minutes, lying still. The scanner makes loud knocking sounds. Participants will get earplugs.
* Participants will take the 2 study drugs for 6 months.
* Enzalutamide is taken as 4 pills once a day.
* Androgen deprivation therapy is given by injection 2 times over 6 months.
* During these 6 months, participants will visit the clinic monthly. They will have physical exam, vital signs, and blood drawn.
* After finishing the study drugs, participants will have another 3T mpMRI. Then they will have prostate removal surgery.

Background:

* Most men diagnosed with prostate cancer will present with intermediate or high-risk disease
* Many develop castrate resistant prostate cancer (CRPC) as curative strategies are often unsuccessful
* Treatment options typically involve radical prostatectomy (RP) or radiation therapy (RT) in combination with androgen deprivation therapy (ADT)
* Even when cancers are initially sensitive to ADT, resistance ultimately emerges either through clonal selection or through a variety of adaptive mechanisms (secondary resistance).
* The recent introduction of novel androgen pathway inhibitors offers an opportunity to potentially improve the cure rate of men with intermediate and high risk localized prostate cancer
* There remains a great need for improved techniques to determine mechanisms of treatment response and resistance.

Objectives:

-To test the feasibility of multi parametric magnetic resonance imaging (mpMRI) for the localization and detection of focal prostate cancer both before and after pre-operative treatment with ADT and enzalutamide.

Eligibility:

* Patients with nonmetastatic castration sensitive prostate cancer with intermediate or high-risk features
* Patients with testosterone levels greater than or equal to 100 ng/dL.
* Eastern Cooperative Oncology Group (ECOG) 0-1.

Design:

* Patients will be treated with ADT and enzalutamide for 6 months
* Two 3T mpMRI endorectal examinations (One at screening and after 6 month of treatment)
* Screening biopsy (magnetic resonance (MR)/ultrasound (US) guided) samples
* Standard of care prostatectomy (RP) following post treatment mpMRI
* All tumor specimens will undergo genomic analysis

Using Multiparametric MRI to Evaluate Intraprostatic Tumor Responses and Androgen Resistance Patterns in Newly Diagnosed Prostate Cancer

Neoadjuvant Androgen Deprivation and Enzalutamide: Using Multiparametric MRI to Evaluate Intraprostatic Tumor Responses and Androgen Resistance Patterns in Newly Diagnosed Prostate Cancer

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).

Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event (i.e., Grade 1) is any untoward medical occurrence. A serious adverse event (i.e., Grade 2-3) is an adverse event or suspected adverse reaction that results in an adverse drug experience, and/or disruption of the ability to conduct normal life functions attributable to the research.

The prostate lesion is contoured manually by an expert radiologist. Research software (mim-vista) calculates the volume. Greater tumor volumes may indicate higher prostate tumor growth.

The effect of intense androgen suppression and inhibition was measured on tumors using anti-AR immunostains of biopsy and surgical specimens. Detection of tumor nuclear AR was quantified on a per-nucleus basis using computer-aided image analysis with Definiens Developer XD 64, grouping nuclei into high, medium, low, and absent bins, a histology score was assigned to each sample.

Nucleus classification is low vs. med. at 0.7; med. vs. high at 0.95. Definiens reported the total # of positively stained nuclei or cells, along with the distribution of low-, med.-, and high-intensity stained nuclei/cells for ea. tumor focus. A %positive index score was calculated using a weighted avg. divided by the total # of objects, where index = \[ (1 × nuclei/cells stained low) + (2 × nuclei/cells stained med.) + (3 × nuclei/cells stained high) \](3 × total nuclei).

Prostate lesion volumes on baseline and post-treatment multiparametric magnetic resonance imaging (mpMRI) were calculated from T2W-MRI sequences using software embedded in the PACS after manual contouring by the same radiologist. Lesion volume scores were categorized as low (2 or fewer positive sequences), moderate (3 positive sequences) and high (4 positive sequences). Lesion volume values are in cubic centimeters (cc's).

Complete response was evaluated after neoadjuvant treatment with androgen deprivation therapy (ADT) and enzalutamide and assessed by pathologic exam. Pathologic complete response: the absence of residual invasive cancer confirmed by immunohistochemistry (IHC).

Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Prostate lesion volumes on baseline and post-treatment mpMRI were calculated from T2W-MRI sequences using software embedded in the PACS after manual contouring by the same radiologist.

The Youden index was used as a measure for evaluating biomarker effectiveness and was calculated to determine the cutoffs that gave the optimal combination of sensitivity and speciﬁcity for patient response to treatment. The index is: J=sensitivity + specificity -1. Its value ranges from 0 through 1 (inclusive). A value of 1 indicates that there are no false positives or false negatives, i.e. the test is perfect. The index gives equal weight to false positive and false negative values, so all tests with the same value of the index give the same proportion of total misclassified results. Sensitivity and specificity are the probability of truly identifying relative tumor burden on multiparametric magnetic resonance imaging (mpMRI) respectively at a statistically established cut point.

PTEN level reduction was evaluated using immunohistochemistry in post treatment specimens. For anti-PTEN immunohistochemistry, a case was considered PTEN-reduced (abnormal) if at least 5% of tumor cells demonstrated reduced PTEN intensity relative to PTEN in benign cells (lower than 5%, then abnormal).

ERG protein overexpression was evaluated using immunohistochemistry in post treatment specimens. A positive ETS-related ERG overexpression is a bad outcome.

National Cancer Institute (NCI)

Principal Investigator

Patients will have an multi-parametric magnetic resonance imaging (mpMRI) guided biopsy, then receive enzalutamide and goserelin subcutaneous (SC) treatment for 6 months followed by a second mpMRI examination.

Goserelin: 10.8mg administered subcutaneously every 12 weeks (2 doses)

Enzalutamide: 160mg orally, daily for 24 weeks

mpMRI: Multiparametric MRI - One at baseline and after 6 months of treatment

1/Arm 1- Enzalutamide and Goserelin

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Normal PSA is 0 to 4 ng/ml. Above 4ng/ml indicates cancer of the prostate.

Median Prostate-Specific Antigen (PSA) at Baseline

Prostate Cancer Staging TNM system. T = tumor, N = nodes, M = metastasized.

Stages of cancer is numbered from 1-4. A lower number (i.e. 1) means less cancer spread and a higher number (i.e. 4) means more cancer spread. Also, alphabetical letters a, b, and c can be used to denote lower or higher stages of the disease. A lower letter = lower stage of disease and a higher number = higher stage of disease.

Number of Participants Pre-Treatment Clinical Stage at Baseline

Prostate volume on magnetic resonance imaging (MRI) is calculated by 0.52 x length x width x height. Normal volume should be less than 25 cc's. Greater than 25 cc's is an enlarged prostate (bad) as it can cause symptoms (i.e.: nocturia, difficulty emptying, etc.)

Median Prostate Volume on Magnetic Resonance Imaging at Baseline

PSA density is defined as a calculation performed at diagnosis and is the serum prostate specific antigen (PSA) level (ng/mL) divided by the volume of the prostate gland (mL).

PSA density ≤0.08 is low risk for prostate cancer and ≥0.08 is high risk for prostate cancer.

Median Prostate Specific Antigen (PSA) Density

Relative tumor burden (RTB) volumes were calculated by dividing the combined volumes of each lesion divided by the prostate volume.

Median Magnetic Resonance Tumor Burden

There is a prostate cancer grading system, called the Grade Groups with groups 1 through 5 based on how much cancer cells look like normal prostate tissue under the microscope. If the cancerous tissue looks much like normal prostate tissue, a grade of 1 is assigned. If the cancer cells and their growth patterns look very abnormal, a grade of 5 is assigned. Grades 2 through 4 have features in between these extremes. The higher the grade, the more likely it is that the cancer will grow and spread quickly.

Number of Participants in a Gleason Group (biopsy)

Intermediate

High

Gleason score is calculated by adding the score of the most common grade (Gr) (primary Gr pattern) and the 2nd most common Gr (secondary Gr pattern) and ranges from 6-10. The individual primary and secondary Gr patterns range from 1-5. Higher Gleason scores = a higher Gr of prostate cancer, i.e., a more advanced or more aggressive type of cancer. Per protocol Intermediate risk is PSA10 and 20ng/ml or Gleason score 7 or Stage T2b (i.e. cancer in about 3/4 of the prostate) or T2c (i.e. cancer in entire prostate). High risk is Gleason score ≥8 or PSA\>20 at dx or seminal vesicle involvement.

Number of Participants in a Risk-Group

Dr. Fatima Karzai

Baseline

6 months

37 out of 39 patients completed treatment and underwent pre- and post- mpMRI. Two patients did not-one patient died on study from a recreational drug overdose. The other had progression of disease on study.

Median Tumor Volume Burden at Baseline Multi-parametric Magnetic Resonance Imaging (mpMRI) Before and After Surgery

biopsy specimen

residual tumor

Median Nuclear Androgen Receptor (AR) Level in Biopsy Specimens Versus Residual Tumors

Median Prostate Lesion Volume Before and After Treatment

Number of Participants With a Complete Response

Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

Number of Prostate Lesions Detected Within the Study Population at Baseline Multi-parametric Magnetic Resonance Imaging (mpMRI) and 6 Months After Enzalutamide Plus Androgen Deprivation Therapy (ADT)

Initial Multiparametric Magnetic Resonance Imaging (mpMRI) Percentage of Relative Tumor Volume Sensitivity

Number of Participants With Reduction in Phosphatase and Tensin Homolog (PTEN) Levels

Number of Participants With Positive Erythroblast Transformation-specific (ETS)-Related Gene (ERG) Protein Overexpression

Initial Multiparametric Magnetic Resonance Imaging (mpMRI) Percentage of Relative Tumor Volume Specificity

Fatigue

Edema, limbs

Erectile dysfunction

Gynecomastia

Hot flashes

Hypertension

Confusion

Libido decreased

Insomnia

Mood changes

Personality change

Restlessness

Headache

Dizziness

Memory impairment

Concentration impairment

Dysuria

Urinary incontinence

Dysgeusia

Dyspepsia

Nausea

Cough

Sore throat

Arthralgia

Back pain

Muscle weakness

Myalgia

Rash

Weight gain

Common Terminology Criteria for Adverse Events (CTCAE) v4

Grade 1 is Mild; asymptomatic or mild symptoms.

Grade 1

Common Terminology Criteria for Adverse Events (CTCAE) v4 Grade 2 is moderate, minimal.

Grade 2

Common Terminology Criteria for Adverse Events (CTCAE) v4 Grade 3 is severe or medically significant but not immediately life threatening,

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Using Multiparametric MRI to Evaluate Intraprostatic Tumor Responses and Androgen Resistance Patterns in Newly Diagnosed Prostate Cancer	NCT02430480	Prostate Cancer	Goserelin Enzalutamide mpMRI	18 Years -	National Institutes of Health Clinical Center (CC)
Using Multiparametric MRI to Evaluate Intraprostatic Tumor Responses and Androgen Resistance Patterns in Newly Diagnosed Prostate Cancer	NCT02430480	Prostate Cancer	Goserelin Enzalutamide mpMRI	18 Years -	National Institutes of Health Clinical Center (CC)

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