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Prostatic Neoplasms

Adenocarcinoma

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

All Drugs and Chemicals

Antineoplastic Agents

Anti-Inflammatory Agents

Anti-Infective Agents

Dermatologic Agents

Reproductive Control Agents

Psychotropic Drugs

Amino Acids

Hormones

Docetaxel

Prednisone

Salicylic Acid

Leuprolide

Goserelin

Cortisone

Triptorelin Pamoate

Tryptophan

Bicalutamide

Flutamide

Nilutamide

Tubulin Modulators

Antimitotic Agents

Glucocorticoids

Hormone Antagonists

Antineoplastic Agents, Hormonal

Androgens

Androgen Antagonists

Contraceptive Agents

Contraceptive Agents, Female

Contraceptive Agents, Hormonal

Antidepressive Agents

Participants receive 1 acceptable form of SST as in Induction except for treatment with docetaxel and prednisone.

Participants receive 1 acceptable form of SST as in Induction except for treatment with docetaxel and prednisone. Participants undergo prostatectomy within 8 weeks after randomization or radiation therapy within 4 weeks of randomization.

Standard treatment data collection prior to randomization

Abiraterone

Degarelix

Goserelin Acetate

Histrelin Acetate

Leuprolide Acetate

Orchiectomy

Quality-of-Life Assessment

Radiation Therapy

Radical Prostatectomy

Triptorelin

Dana Sparks, MAT

Site Public Contact

Chinedu Mmeje

Shahzad Siddique

Juan Chipollini

Shi-Ming Tu

Andrea L. Harzstark

Uzair B. Chaudhary

Tanya B. Dorff

Aditya Bagrodia

Greg Gin

Siamak Daneshmand

Richard K. Valicenti

Amir Lavaf

Geoffrey A. Sonn

Paul D. Maroni

Nicholas DiBella

Patricia H. Hardenbergh

Supriya Jain

Preston C. Sprenkle

Anthony P. Gulati

Gregory A. Masters

Michael J. Whalen

Michael A. Schwartz

Chad R. Ritch

Jonathan J. Melquist

Shreyas Joshi

Sharad A. Ghamande

Wayne B. Harris

John M. Schallenkamp

Sinisa Stanic

Bryan A. Faller

Srinivas Vourganti

Daniel Moreira

Brian Chapin

This phase III trial studies how well standard systemic therapy with or without definitive treatment (prostate removal surgery or radiation therapy) works in treating participants with prostate cancer that has spread to other places in the body. Addition of prostate removal surgery or radiation therapy to standard systemic therapy for prostate cancer may lower the chance of the cancer growing or spreading.

PRIMARY OBJECTIVES:

I. To compare overall survival in metastatic prostate cancer patients who are randomized to standard systemic therapy (SST) plus definitive treatment of the primary tumor versus standard systemic therapy alone.

SECONDARY OBJECTIVES:

I. To compare overall survival in metastatic prostate cancer patients who received SST plus surgical excision of the primary tumor versus SST alone in the subset who specify the surgical intent stratification factor.

II. To compare the rate of symptomatic local progression between the treatment arms.

III. To compare progression-free survival (PFS) between the two treatment arms. IV. To compare rates of progression-free survival between arms for the subsets of patients with and without metastasis directed therapy (MDT) to oligometastatic sites.

QUALITY OF LIFE OBJECTIVES:

I. To compare between arms patient-reported urinary function and urinary bother over time (after initiation of SST at 6 months, 1, 2, and 3 years) using the Expanded Prostate Cancer Index Composite (EPIC) and patient-reported pain and physical functioning using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) between patients receiving standard systemic therapy and those receiving systemic therapy and definitive management of the primary prostate cancer.

OTHER OBJECTIVES:

I. To bank tissue and whole blood specimens for future use.

OUTLINE:

INDUCTION: Participants receive 1 of 6 acceptable forms of SST for 22-28 weeks. I. Participants undergo a bilateral orchiectomy. II. Participants receive goserelin acetate subcutaneously (SC) every 28 days or 12 weeks, histrelin acetate SC every 12 months, leuprolide acetate SC or intramuscularly (IM) every 1, 3, 4, or 6 months, and triptorelin every 1, 3, or 6 months.

III. Participants receive goserelin acetate SC every 28 days or 12 weeks, histrelin acetate SC every 12 months, leuprolide acetate SC or IM every 1, 3, 4, or 6 months, and triptorelin every 1, 3, or 6 months. Participants also receive nilutamide orally (PO) daily, flutamide PO every 8 hours, and bicalutamide PO daily.

IV. Participants receive degarelix via injection for 2 doses and then every 28 days.

V. Participants receive nilutamide PO daily, flutamide PO every 8 hours, and bicalutamide PO daily. Participants also receive docetaxel over 1 hour every 3 weeks with or without prednisone PO every 12 hours.

VI. Participants receive nilutamide PO daily, flutamide PO every 8 hours, and bicalutamide PO daily. Participants also receive abiraterone PO daily or prednisone PO every 12 hours.

After completion of 22-28 weeks of SST, participants are then randomized to 1 of 2 arms.

ARM I: Participants receive 1 acceptable form of SST as in Induction except for treatment with docetaxel and prednisone.

ARM II: Participants receive 1 acceptable form of SST as in Induction except for treatment with docetaxel and prednisone. Participants undergo prostatectomy within 8 weeks after randomization or radiation therapy within 4 weeks of randomization.

After completion of study treatment, participants are followed up for 8 years.

Standard Systemic Therapy With or Without Definitive Treatment in Treating Participants With Metastatic Prostate Cancer

Phase III Randomized Trial of Standard Systemic Therapy (SST) Versus Standard Systemic Therapy Plus Definitive Treatment (Surgery or Radiation) of the Primary Tumor in Metastatic Prostate Cancer

Will compare OS in metastatic prostate cancer patients who received standard systemic therapy (SST) plus surgical excision of the primary tumor versus SST alone in the subset who specify the surgical intent stratification factor.

Defined as any of the following events post-randomization: Common Terminology Criteria for Adverse Events version 5 grade \>= 2 hematuria, urinary retention, urinary tract obstruction, urinary tract pain, pelvic pain, renal and urinary disorders-other. Will be compared between the treatment arms. A proportional hazards model will be fit to each of these endpoints where the time interval starts at date of randomization to (i) time of first symptomatic local progression or ii) progression or death due to any cause, where those without the event are censored at their last contact date. Stratification factors will be adjusted for as covariates.

Will be compared between for the subsets of patients with and without metastasis directed therapy (MDT) to oligometastatic sites. A proportional hazards model will be fit to each of these endpoints where the time interval starts at date of randomization to (i) time of first symptomatic local progression or ii) progression or death due to any cause, where those without the event are censored at their last contact date. Stratification factors will be adjusted for as covariates.

National Cancer Institute (NCI)

SWOG Cancer Research Network

Symptoms and General Pathology

Immune System Diseases

Recurrence

Hypersensitivity

Patients receive enzalutamide PO QD for 12 months in the absence of disease progression or unacceptable toxicity.

Patients receive standard of care ADT comprising one of the following at the discretion of the treating physician: leuprolide acetate, goserelin acetate, histrelin acetate, triptorelin, or degarelix SC or IM for 12 months in the absence of disease progression or unacceptable toxicity. Patients may also choose to undergo surgical castration as an alternative form of ADT.

Enzalutamide

leuprolide acetate

goserelin acetate

histrelin acetate

triptorelin

degarelix

Elizabeth Kessler, MD

This randomized phase II trial compares enzalutamide with standard androgen deprivation therapy in reducing incidence of metabolic syndrome in patients with prostate cancer that has spread to other places in the body. Metabolic syndrome is defined as changes in cholesterol, blood pressure, circulating sugar levels, and body weight. Previous studies have shown that patients with prostate cancer, who have been treated with standard medical therapy that lowers testosterone levels, have an increased risk of these changes. Hormone therapy using enzalutamide may fight prostate cancer by blocking the use of testosterone by the tumor cells instead of lowering testosterone levels. It is not yet known whether prostate cancer patients who receive enzalutamide will have reduced incidence of metabolic syndrome than patients who receive standard androgen deprivation therapy.

PRIMARY OBJECTIVES:

I. To determine the incidence of metabolic syndrome within 12 months, as defined by the Adult Treatment Panel III, in patients treated with enzalutamide compared to standard androgen deprivation therapy.

SECONDARY OBJECTIVES:

I. To determine the incidence of metabolic syndrome within 6 months, as defined by the Adult Treatment Panel III, in patients treated with enzalutamide compared to standard androgen deprivation therapy.

II. To assess bone health, as measured by a dual-energy x-ray absorptiometry (DXA) scanner.

III. To assess body composition (sarcopenic obesity), as measured by a DXA scanner.

IV. To assess quality of life (QOL), as measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Sexual Health Inventory in Men (SHIM).

V. To assess time to prostate-specific antigen (PSA) progression and time to radiographic progression.

VI. To assess the incidence of developing individual risk factors, or components, which comprise metabolic syndrome.

VII. To assess the change in high-sensitivity C-reactive protein (hs-CRP) as a marker of inflammation.

VIII. To assess the safety and tolerance of enzalutamide or androgen deprivation therapy (ADT).

IX. To assess the change in physical function as measured by the Short Physical Performance Battery (SPPB).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive enzalutamide orally (PO) once daily (QD) for 12 months in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive standard of care ADT comprising one of the following at the discretion of the treating physician: leuprolide acetate, goserelin acetate, histrelin acetate, triptorelin, or degarelix subcutaneously (SC) or intramuscularly (IM) for 12 months in the absence of disease progression or unacceptable toxicity. Patients may also choose to undergo surgical castration as an alternative form of ADT.

After completion of study treatment, patients are followed up at 30 days.

Enzalutamide Versus Standard Androgen Deprivation Therapy for the Treatment Hormone Sensitive Prostate Cancer

An Open Label, Randomized, Phase II Trial of Metabolic Complications in Patients Treated With Enzalutamide vs Standard ADT for the Treatment of Hormone Sensitive Prostate Cancer

Metabolic syndrome will be assessed at the beginning of each course and defined by the presence of 3 of the following five traits: abdominal obesity, defined as a waist circumference \> 102 cm (\> 40 in); serum triglycerides \>= 150 mg/dL (1.7 mmol/L) or drug treatment for elevated triglycerides; serum high density lipoprotein (HDL) cholesterol \< 40 mg/dL (1 mmol/L) or drug treatment for low HDL; blood pressure \>= 130/\>= 85 mmHg or drug treatment for elevated blood pressure; and fasting plasma glucose (FPG) \>= 100 mg/dL (5.6 mmol/L) or drug treatment for elevated blood glucose.

Metabolic syndrome will be assessed at the beginning of each course and defined by the presence of 3 of the following five traits: abdominal obesity, defined as a waist circumference \> 102 cm (\> 40 in); serum triglycerides \>= 150 mg/dL (1.7 mmol/L) or drug treatment for elevated triglycerides; serum HDL cholesterol \< 40 mg/dL (1 mmol/L) or drug treatment for low HDL; blood pressure \>= 130/\>= 85 mmHg or drug treatment for elevated blood pressure; and FPG \>= 100 mg/dL (5.6 mmol/L) or drug treatment for elevated blood glucose.

Will be assessed for each treatment group. Measurements will be taken at day 1 of each course. A paired t-test will test within an arm as to whether the change from baseline to 12 months is significantly different from zero.

We will measure bone density via a DXA scanner, Left Femur and Right femur T scores will be added to a composite score. A paired t-test will test within an arm as to whether the change from baseline to twelve months is significantly different from zero.

The T-score is the standard deviation of how much bone density differs from the bone mass of an average healthy 30 year old. A score of 0 indicates no deviation from average. The following ranges are used:

* T-score of -1.0 or above = normal bone density
* T-score between -1.0 and -2.5 = low bone density, or osteopenia
* T-score of -2.5 or lower = osteoporosis

A paired t-test will test within an arm as to whether the change from baseline to each time point is significantly different from zero.

These data are not able to be reported as the DXA did not measure free fat mass and thus we will be using cross sectional CT analysis.

A paired t-test will test within an arm as to whether the change from baseline to each time point is significantly different from zero.

The FACT-P is the Functional Assessment of Cancer Therapy - Prostate and measures physical/emotional quality of life in prostate cancer patients.

NUMBER OF ITEMS:39 PATIENT POPULATION:Prostate cancer patients 18 years and older RECALL PERIOD:Past 7 days RESPONSE SCALE:5 point Likert-type scale

SUBSCALE DOMAINS:

Physical Well-Being (PWB), Social/Family Well-Being (SWB), Emotional Well-Being (EWB), Functional Well-Being (FWB), Prostate Cancer Subscale (PCS)

SCORING:

Scores range from 0-158. In general, the higher the score, the better the quality of life.

Sexual Health in Men (SHIM). 5 item measure of erectile function. Total score is 1-25 with a higher score indicating better sexual health. Scores: no ED (SHIM total score, 22-25), mild (17-21), mild to moderate (12-16), moderate (8-11), and severe ED (1-7).

PSA progression as defined by an increase in \>= 50% from nadir and an absolute increase of at least 2 ng/mL above the nadir, occurring at least 12 weeks after start of therapy that is confirmed by two consecutive increases taken at least 2 weeks apart. Log rank test will be used to compare the distributions of above variables between the group treated with enzalutamide to the group on standard ADT.

Log rank test will be used to compare the distributions of above variables between the group treated with enzalutamide to the group on standard ADT.

Mean change in available samples from baseline to 12 months, presented in mg/dL

The incidence of adverse events has been reported in the adverse events log for clinicaltrials.gov

The Short SPPB incorporates 3 validated portions to assess a patient's balance and mobility. SPPB scores range from zero to 12 possible points. SPPB score of 3-9 points in persons with no mobility disability indicates frailty; SPPB score of 10 or greater for persons with no sarcopenia and no mobility disability indicates robustness. The higher the score, the better the physical function. Will be measured as a continuous outcome.

Will be assessed for each treatment group. Measurements will be taken at day 1 of each course. A paired t-test within an arm as to whether the change from baseline to 12 months is significantly different from zero. N-Telopeptide units - nM Bone Collagen Equivalent (BCE).

University of Colorado, Denver

There is no difference in our definition of an adverse event and that of clinicaltrials.gov

Patients receive enzalutamide PO QD for 12 months in the absence of disease progression or unacceptable toxicity.

Enzalutamide: Given PO

Arm I (Enzalutamide)

Patients receive standard of care ADT comprising one of the following at the discretion of the treating physician: leuprolide acetate, goserelin acetate, histrelin acetate, triptorelin, or degarelix SC or IM for 12 months in the absence of disease progression or unacceptable toxicity. Patients may also choose to undergo surgical castration as an alternative form of ADT.

leuprolide acetate: Given SC or IM

goserelin acetate: Given SC or IM

histrelin acetate: Given SC or IM

triptorelin: Given SC or IM

degarelix: Given SC or IM

Arm II (ADT)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

United States

Region of Enrollment

PSA value

Metastatic disease

This study was originally designed when ADT alone was SOC treatment for metastatic prostate cancer. In the years of opening and enrollment, the SOC changed thus affecting the population of potentially eligible patients.

Dr. Elizabeth R Kessler

The difference between metabolic syndrome and treatment were evaluated with the Chi-square test

This study did not meet it's target accrual goal and thus is underpowered to detect a statistically significant difference between the two groups.

Cohort characteristics for Metabolic Syndrome were summarized by event and arm using counts and percentages for categorical variables and the mean, standard deviation, median, and quartiles for continuous variables. The difference between metabolic syndrome and treatment were evaluated with the Chi-square test. P-values are reported based on a null hypothesis of no difference against a two-sided alternative. Analyses were performed using SAS 9.4 (SAS Inst

Cohort characteristics for Metabolic Syndrome, the SPPB, the SHIM/FACT-P, and PSA were summarized by event and arm using counts and percentages for categorical variables and the mean, standard deviation, median, and quartiles for continuous variables. The difference between metabolic syndrome and treatment were evaluated with the Chi-square test. The Wilcoxon signed-rank test was utilized to examine the difference between Month 1 and Month 12 SPPB scores. The Wilcoxon rank-sum test was used to assess the difference of SHIM/FACT-P scores and PSA between arms. These tests were chosen to account for the non-normal distributions of the continuous variables. The difference between PSA progression between arms was examined using the Fisher Exact Test. A heat map of scores ordered by the highest average score was also created. P-values are reported based on a null hypothesis of no difference against a two-sided alternative. Analyses were performed using SAS 9.4 (SAS Inst

Metabolic Syndrome Incidence, Summarized by the Number of Patients With at Least 3 of the 5 Pre-specified Criteria

Includes all patients still participating at this timepoint

Metabolic Syndrome Incidence, Summarized by the Proportion of Patients With at Least 3 of the 5 Pre-specified Criteria

Patients were compared to themselves as well as across groups. We reviewed difference from month 1 to 12 in order to gather adequate data. Below are the bone-specific alkaline phosphatase. Not all patients completed follow up for this measure.

Change in Bone Turnover Markers, as Measured by Bone-specific Alkaline Phosphatase

Patients exposed to androgen deprivation therapy

Androgen Deprivation Therapy

Not all patients completed follow-up for this measure.

Change in Bone Density

The DXA scanner was not able to analyze free fat mass, only bone density.

Change in Free Fat Mass, as Measured by a DXA Scanner

data cannot be reported as the dexa scanner used for the study only measured bone density and not lean body mass (this was realized part way through study).

Change in Fat Mass, as Measured by a DXA Scanner

SHIM

FACT-P

Patients were compared to themselves as well as across groups. We reviewed difference from month 1 to 7 in order to gather adequate data. Below is the SHIM.

Change in Quality of Life (QOL) Scores, as Measured by the Functional Assessment of Cancer Therapy - Prostate (FACT-P) and Sexual Health in Men (SHIM)

All patients were evaluated throughout the course of the study

Number of Patients With PSA Progression

Time to Radiographic Progression

Patients were compared to themselves as well as across groups. We reviewed difference from month 1 to 12 in order to gather adequate data. Some patients in the cohort were missing follow-up data.

Change in Markers of Inflammation, as Measured by Circulating Hs-CRP

adverse events reported in separate section

Incidence of Adverse Events, Using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.1

The results are presented in the following format: N Mean (Std Dev) Median (Q1, Q3). In all cases (Overall, Arm 1, and Arm 2) we fail to reject the null hypothesis that the samples come from the same population of scores at Month 1 versus Month 12 at the 0.05 significance level.

Change in Physical Function, as Measured by Short Physical Performance Battery (SPPB).

Patients were compared to themselves as well as across groups. We reviewed difference from month 1 to 12 to gather adequate data. Below are the N-telopeptide. Not all patients completed follow-up for this measure.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Standard Systemic Therapy With or Without Definitive Treatment in Treating Participants With Metastatic Prostate Cancer	NCT03678025	Castration Leve... Metastatic Pros... Stage IV Prosta... Stage IVA Prost... Stage IVB Prost...	Abiraterone Bicalutamide Degarelix Docetaxel Flutamide Goserelin Aceta... Histrelin Aceta... Leuprolide Acet... Nilutamide Orchiectomy Prednisone Quality-of-Life... Radiation Thera... Radical Prostat... Triptorelin	18 Years -	SWOG Cancer Research Network
Enzalutamide Versus Standard Androgen Deprivation Therapy for the Treatment Hormone Sensitive Prostate Cancer	NCT02278185	Adenocarcinoma ... Recurrent Prost... Stage III Prost... Stage IV Prosta...	Enzalutamide leuprolide acet... goserelin aceta... histrelin aceta... triptorelin degarelix	19 Years -	University of Colorado, Denver
Standard Systemic Therapy With or Without Definitive Treatment in Treating Participants With Metastatic Prostate Cancer	NCT03678025	Castration Leve... Metastatic Pros... Stage IV Prosta... Stage IVA Prost... Stage IVB Prost...	Abiraterone Bicalutamide Degarelix Docetaxel Flutamide Goserelin Aceta... Histrelin Aceta... Leuprolide Acet... Nilutamide Orchiectomy Prednisone Quality-of-Life... Radiation Thera... Radical Prostat... Triptorelin	18 Years -	SWOG Cancer Research Network

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