A Study of Salvage Radiotherapy With or Without Enzalutamide in Recurrent Prostate Cancer Following Surgery

Phase 2

Active, not recruiting

Conditions: Prostate Cancer

Interventions: Radiation: Radiation Therapy
Drug: Bicalutamide
Drug: Enzalutamide
Drug: GnRH analog

Registration Number: NCT03809000

Lead Sponsor: RTOG Foundation, Inc.

Brief Summary: Patients with post-prostatectomy PSA (Prostate Specific Antigen) recurrences with aggressive disease features will receive salvage radiation therapy and standard androgen deprivation therapy (ADT) or enhanced ADT to determine if there is any improvement in progression-free survival when enhanced ADT is used compared to standard ADT.

Detailed Description: PRIMARY OBJECTIVE:

To determine whether, in men with post-prostatectomy PSA (prostate specific antigen) recurrences with aggressive disease features, salvage radiotherapy (SRT) with enhanced androgen deprivation therapy (ADT), consisting of enzalutamide (MDV3100) and a GnRH analog, will improve progression-free survival compared to SRT with standard GnRH analog -based ADT.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: Male

Target Recruitment: 188

Inclusion Criteria

Pathologically (histologically) proven adenocarcinoma confirmed by prostatectomy performed within 10 years prior to registration and any type of radical prostatectomy is permitted, including retropubic, perineal, laparoscopic or robotically assisted.
Prostate-specific antigen (PSA) level (≥ 0.2 ng/mL) within 120 days prior to registration. Patients must have a PSA ≥ 0.2 ng/mL prior to starting ADT. For patients being followed by an ultrasensitive PSA assay, a serum PSA concentration of ≥ 0.10 ng/mL will be considered eligible.
GnRH analog may be started no more than 42 days prior study entry.
Hemoglobin ≥ 9.0 g/dL, independent of transfusion and/or growth factors within 90 days prior to registration.
Platelet count ≥ 75,000 x 10^9/µL independent of transfusion and/or growth factors within 90 days prior to registration.
At least 1 of the following aggressive features:
- Gleason score of 8-10 (note any Gleason score is eligible)
- Seminal vesicle invasion (SVI) (note any pT stage American Joint Committee on Cancer (AJCC) v8.0 is eligible but a pT stage
  
  ≥ pT3b is considered aggressive)
- Locoregional node involvement at radical prostatectomy (RP) (pN1)
- Persistently elevated PSA post-RP nadir (PEPP) defined as PSA > 0.1 ng/mL after radical prostatectomy
- PSA ≥ 0.7 ng/mL
Serum albumin ≥ 3.0 g/dL within 90 days prior to registration
Glomerular filtration rate (GFR) ≥35 mL/min estimated by Cockcroft-Gault or measured directly by 24 hour urine creatinine within 90 days prior to registration.
Serum total bilirubin ≤1.5 × upper limit of normal (ULN) (Note: In subjects with Gilbert's syndrome, if total bilirubin is >1.5 × ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤1.5 × ULN, subject is eligible) within 90 days prior to registration.
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <2.5 × ULN within 90 days prior to registration.
History and physical with Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 or within 90 days prior to registration.

Exclusion Criteria

Definitive clinical or radiologic evidence of metastatic disease with the exception of locoregional lymph nodes.
Prior invasive malignancy (except non-melanomatous skin cancer carcinoma in situ of the male breast, penis, oral cavity, or stage Ta of the bladder, or stage I completely resected melanoma) unless disease free for a minimum of 2 years).
Prior systemic chemotherapy for the study cancer. Note: prior chemotherapy for a different cancer is allowable.
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.
History of any of the following:
- Documented inflammatory bowel disease
- Transmural myocardial infarction within the last 4 months prior to registration.
- New York Heart Association Functional Classification III/IV within 4 months prior to registration.
- Unstable angina and/or congestive heart failure requiring hospitalization within the last 4 months prior to registration
- History of loss of consciousness or transient ischemic attack within 12 months prior to randomization
- History of seizure disorder or condition that may predispose to seizure (e.g. prior cortical stroke or significant brain trauma)
- History of uncontrolled hypertension defined as a sustained systolic blood pressure in excess of 150 mmHg or a sustained diastolic blood pressure in excess of 90 mmHg despite optimized antihypertensive therapy.
- History of repeated falls and fractures over the past 12 months that in the opinion of the treating investigator would put the patient at risk for poor bone outcomes from androgen receptor targeted therapy
Known gastrointestinal disorder affecting absorption of oral medications.
Active uncontrolled infection defined as an identified infectious condition that requires active therapy that has not yet been completed.
HIV positive patients with CD4 count < 200 cells/microliter within 30 days prior to registration OR HIV patients under treatment with highly active antiretroviral therapy (HAART) within 30 days prior to registration regardless of CD4 count. Note: HIV testing is not required for eligibility for this protocol as it is self-reported. This exclusion criterion is necessary because the treatments involved in this protocol may be immunosuppressive and/or interact with HAART.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Salvage Radiation Therapy + Enhanced ADT	GnRH analog	Enhanced ADT: 24 months of GnRH analog (any formulation) with 24 months of enzalutamide (160 mg/day). SRT: Starting within 0-70 days of initiation of GnRH analog, 66.6-70.2 Gy as 1.8 Gy/fraction in 37-39 fractions or 66.0-70.0 Gy as 2.0 Gy/fraction in 33-35 fractions lasting approximately 7-8 weeks, and optional lymph node boost.
Salvage Radiation Therapy (SRT) + Standard androgen deprivation therapy (ADT)	Radiation Therapy	Standard ADT: 24 months of GnRH analog (any formulation) with optional 1-4 months of bicalutamide (50 mg/day). SRT: Starting within 0-70 days of initiation of GnRH analog, 66.6-70.2 Gy as 1.8 Gy/fraction in 37-39 fractions or 66.0-70.0 Gy as 2.0 Gy/fraction in 33-35 fractions lasting approximately 7-8 weeks, and optional lymph node boost.
Salvage Radiation Therapy (SRT) + Standard androgen deprivation therapy (ADT)	Bicalutamide	Standard ADT: 24 months of GnRH analog (any formulation) with optional 1-4 months of bicalutamide (50 mg/day). SRT: Starting within 0-70 days of initiation of GnRH analog, 66.6-70.2 Gy as 1.8 Gy/fraction in 37-39 fractions or 66.0-70.0 Gy as 2.0 Gy/fraction in 33-35 fractions lasting approximately 7-8 weeks, and optional lymph node boost.
Salvage Radiation Therapy (SRT) + Standard androgen deprivation therapy (ADT)	GnRH analog	Standard ADT: 24 months of GnRH analog (any formulation) with optional 1-4 months of bicalutamide (50 mg/day). SRT: Starting within 0-70 days of initiation of GnRH analog, 66.6-70.2 Gy as 1.8 Gy/fraction in 37-39 fractions or 66.0-70.0 Gy as 2.0 Gy/fraction in 33-35 fractions lasting approximately 7-8 weeks, and optional lymph node boost.
Salvage Radiation Therapy + Enhanced ADT	Radiation Therapy	Enhanced ADT: 24 months of GnRH analog (any formulation) with 24 months of enzalutamide (160 mg/day). SRT: Starting within 0-70 days of initiation of GnRH analog, 66.6-70.2 Gy as 1.8 Gy/fraction in 37-39 fractions or 66.0-70.0 Gy as 2.0 Gy/fraction in 33-35 fractions lasting approximately 7-8 weeks, and optional lymph node boost.
Salvage Radiation Therapy + Enhanced ADT	Enzalutamide	Enhanced ADT: 24 months of GnRH analog (any formulation) with 24 months of enzalutamide (160 mg/day). SRT: Starting within 0-70 days of initiation of GnRH analog, 66.6-70.2 Gy as 1.8 Gy/fraction in 37-39 fractions or 66.0-70.0 Gy as 2.0 Gy/fraction in 33-35 fractions lasting approximately 7-8 weeks, and optional lymph node boost.

Primary Outcome Measures

Name	Time	Method
Progression-Free Survival (Percentage of Participants Alive Without Progression)	From date of randomization to the date of progression, death from any cause, or last known follow-up, whichever occurs first. Maximum follow-up time was 40.2 months. The 6 and 12 months PFS estimates are reported.	Progression-free survival (PFS) is estimated by the Kaplan-Meier method. The distribution of PFS estimates between the two arms is compared using the log-rank test. PFS time is measured from randomization to the date of first PFS failure (biochemical or clinical failure, initiation of new unplanned anticancer treatment, or death from any cause) or last known follow-up (censored). Analysis was to occur after progression or death was reported for 101 participants. Biochemical failure is defined as first post-RT detectable PSA (PSA ≥ 0.05). Clinical failure is defined as either a local, regional, or distant failure.

Secondary Outcome Measures

Name	Time	Method
Biochemical Failure (Percentage of Participants With Biochemical Failure)	From date of randomization to date of failure, death, or last known follow-up, whichever occurs first, at a minimum of two years from start of treatment, and up to six years.	Biochemical failure is estimated by the cumulative incidence method. The distribution of biochemical failure estimates between the two arms is compared using the Gray's test. Biochemical failure time is measured from randomization to the date of first biochemical failure, last known follow-up (censored), or death without failure (competing risk), whichever occurs first. Biochemical failure is defined as first post-RT detectable PSA (PSA ≥ 0.05).
Alternative Biochemical Failure (Percentage of Participants With Alternative Biochemical Failure)	From date of randomization to the date failure, death, or last known follow-up, whichever occurs first, at a minimum of two years from start of treatment, and up to six years.	Alternative biochemical failure is estimated by the cumulative incidence method. The distribution of alternative biochemical failure estimates between the two arms is compared using the Gray's test. Alternative biochemical failure time is measured from randomization to the date of first alternative biochemical failure, last known follow-up (censored), or death without failure (competing risk), whichever occurs first. Alternative biochemical failure ("failure") is defined as first post-RT PSA ≥ 0.1 ng/mL or initiation of salvage hormone therapy.
Hormone-refractory Disease (Percentage of Participants With Hormone-refractory Disease)	From randomization to the date of failure, death, or last known follow-up, whichever occurs first, at a minimum of two years from start of treatment, and up to six years.	Hormone-refractory disease (HRD) is estimated by the cumulative incidence method. The distribution of HRD estimates between the two arms is compared using the Gray's test. HRD time is measured from randomization to the date of first instance of HRD, last known follow-up (censored), or death without HRD (competing risk), whichever occurs first. Hormone-refractory disease is defined as three rises in PSA during salvage androgen deprivation, date determined as the midway date between the last non-rising PSA and the first of the three rises.
Distant Metastasis (Percentage of Participants With Distant Metastasis)	From date of randomization to the date of failure, death, or last known follow-up, whichever occurs first, at a minimum of two years from start of treatment, and up to six years.	Distant failure is estimated by the cumulative incidence method. The distribution of distant failure estimates between the two arms is compared using the Gray's test. Distant failure time is measured from randomization to the date of first distant failure, last known follow-up (censored), or death without distant failure (competing risk), whichever occurs first. Distant failure is defined as first radiographic evidence of hematogenous spread (e.g., bone scan, computed tomography (CT), magnetic resonance imaging (MRI)).
Cause-specific Mortality (Percentage of Participants Who Have Not Died Due to Prostate Cancer)	From randomization to the date death or last known follow-up, at a minimum of two years from start of treatment, and up to six years.	Cause-specific mortality is estimated by the cumulative incidence method. The distribution of cause-specific mortality estimates between the two arms is compared using Gray's test. Cause-specific mortality time is measured from randomization to death due to prostate cancer, last known follow-up (censored), or death due to other causes (competing risk), whichever occurs first.
Overall Survival (Percentage of Participants Alive)	From date of randomization to the date of death or last known follow-up, at a minimum of two years from start of treatment, and up to six years.	Overall survival is estimated by the Kaplan-Meier method. The distribution of overall survival estimates between the two arms is compared using the log-rank test. Overall survival time is measured from randomization to the date of death from any cause) or last known follow-up (censored).
Change From Baseline in 5-level European Quality of Life Questionnaire (EQ-5D-5L)	Baseline, end* of radiation treatment (RT), one year, two years. (*End of RT can vary greatly depending on when it starts, which can be from 0 to 70 days from the start of ADT, and lasting 7-8 weeks. )	The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. Change score was calculated by subtracting baseline from later score, with a positive change score indicating improvement. The index score is reported here.
Change From Baseline in the 7 Item Patient Reported Outcomes Measurement Information System Fatigue Short Form (PROMIS-F SF 7a) Score	Baseline, end* of radiation treatment (RT), one year, two years. (*End of RT can vary greatly depending on when it starts, which can be from 0 to 70 days from the start of ADT, and lasting 7-8 weeks. )	The PROMIS fatigue score measures self-reported fatigue symptoms over the past 7 days. Possible scores range from 29.4 to 83.2, with higher scores indicating more fatigue. Change score is calculated by subtracting baseline from later score, with a positive change score indicating increased fatigue.
Toxicity as Measured by CTCAE v5	From date of randomization to date of last known follow-up, at a minimum of two years from start of treatment, and up to six years.	Common Terminology Criteria for Adverse Events (version 5) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Toxicity as Measured by Patient-reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)	From randomization to 2 years	PRO-CTCAE is a patient-reported outcome (PRO) measurement system developed to evaluate symptomatic toxicity in patients on cancer clinical trials, designed to be used as a companion to the Common Terminology Criteria for Adverse Events (CTCAE).

Trial Locations

Locations (108): USC Medical Center - Los Angeles County
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Los Angeles, California, United States
University of Southern California
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Los Angeles, California, United States
Sutter Roseville Medical Center
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Roseville, California, United States
Waldo Count General Hospital - Belfast
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Belfast, Maine, United States
McLaren Cancer Institute - Clarkston
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Clarkston, Michigan, United States
McLaren Cancer Institute - Lapeer Region
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Lapeer, Michigan, United States
Maine Health CC of York County - Sanford
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Sanford, Maine, United States
Cedars-Sinai Medical Center
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Los Angeles, California, United States
Marin Cancer Care, Inc.
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Greenbrae, California, United States
Penobscot Bay Medical Center - Rockport
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Rockport, Maine, United States
William Beaumont Hospital - Dearborn
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Dearborn, Michigan, United States
Exeter Hospital
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Exeter, New Hampshire, United States
Loyola University Medical Center
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Maywood, Illinois, United States
Arizona Center for Cancer Care - Surprise
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Surprise, Arizona, United States
Maine Health/SMHC Cancer Care and Blood Disorders-Biddeford
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Biddeford, Maine, United States
Maine Medical Center - Bramhall S Portland
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Portland, Maine, United States
UT Southwestern/Simmons Cancer Center - Dallas
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Dallas, Texas, United States
Maine Medical Cancer Center - Scarborough Campus
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Scarborough, Maine, United States
Sentara Virginia Beach General Hospital
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Virginia Beach, Virginia, United States
Crossroads Cancer Center
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Effingham, Illinois, United States
East Jefferson General Hospital
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Metairie, Louisiana, United States
WellSpan Health - Adams Cancer Center
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Gettysburg, Pennsylvania, United States
Intermountain Medical Center
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Murray, Utah, United States
Aspirus Cancer Care - Wisconsin Rapids
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Wisconsin Rapids, Wisconsin, United States
McLaren Cancer Institute - Bloomfield
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Bloomfield, Michigan, United States
21st Century Oncology MHP - Clarkston
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Clarkston, Michigan, United States
Minnesota Oncology Hematology PA - Maplewood
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Maplewood, Minnesota, United States
Rex Cancer Center of Wakefield
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Raleigh, North Carolina, United States
Singh and Arora Hematology Oncology PC
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Flint, Michigan, United States
Upstate Cancer Center at Hill Radiation Oncology
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Syracuse, New York, United States
SUNY Upstate Medical University
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Syracuse, New York, United States
McLaren Cancer Institute - Northern Michigan
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Petoskey, Michigan, United States
University Physicians at Oneida
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Oneida, New York, United States
University Physicians at Oswego
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Oswego, New York, United States
Utah Valley Regional Medical Center
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Provo, Utah, United States
HealthPartners, Inc.
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Saint Louis Park, Minnesota, United States
Aspirus Langlade Hospital
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Antigo, Wisconsin, United States
McLaren Cancer Institute - Port Huron
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Port Huron, Michigan, United States
Upstate Cancer Center Radiation Oncology at Oneida
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Oneida, New York, United States
Froedtert West Bend Hospital
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West Bend, Wisconsin, United States
William Beaumont Hospital - Troy
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Sterling Heights, Michigan, United States
Froedtert Menomonee Falls Hospital
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Menomonee Falls, Wisconsin, United States
Sentara Cancer Institute at Sentara CarePlex Hospital
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Hampton, Virginia, United States
University of Pittsburgh Medical Center - Shadyside Hospital
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Pittsburgh, Pennsylvania, United States
University of California, San Francisco
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San Francisco, California, United States
Kansas University Cancer Center Westwood
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Westwood, Kansas, United States
University of Kansas Cancer Center
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Kansas City, Kansas, United States
Kansas University Cancer Center Overland Park
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Overland Park, Kansas, United States
Arizona Center for Cancer Care - Phoenix
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Phoenix, Arizona, United States
Wayne State/Karmanos Cancer Institute
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Detroit, Michigan, United States
Washington University School of Medicine
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Saint Louis, Missouri, United States
CHU de Quebec - L'Hotel-Dieu de Quebec
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Québec City, Quebec, Canada
CIUSS de l'Estrie - Centre Hospitalier Universitaire de Sherbrooke-Fleurimont
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Sherbrooke, Canada
Froedtert Hospital & the Medical College of Wisconsin
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Milwaukee, Wisconsin, United States
Moffitt Cancer Center
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Tampa, Florida, United States
Regions Hospital
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Saint Paul, Minnesota, United States
Maine Health/SMHCancer Care and Blood Disorders - Sanford
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Sanford, Maine, United States
Roseville Radiation Oncology Center
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Roseville, California, United States
Mid-Michigan Physicians - Lansing
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Lansing, Michigan, United States
21st Century Oncology MHP - Madison Heights
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Madison Heights, Michigan, United States
21st Century Oncology MHP - Macomb
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Macomb, Michigan, United States
McLaren Cancer Institute - Macomb
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Mount Clemens, Michigan, United States
William Beaumont Hospital - Royal Oak
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Royal Oak, Michigan, United States
21st Century Oncology MHP - Troy
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Troy, Michigan, United States
Arizona Center for Cancer Care - Gilbert
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Gilbert, Arizona, United States
Arizona Center for Cancer Care - Peoria
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Peoria, Arizona, United States
Arizona Center for Cancer Care - Scottsdale East
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Scottsdale, Arizona, United States
Arizona Center for Cancer Care - Scottsdale North
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Scottsdale, Arizona, United States
Marin Health Medical Center
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Greenbrae, California, United States
Valley View Hospital Cancer Center
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Glenwood Springs, Colorado, United States
Nancy N. & J.C. Lewis Cancer & Research Pavilion
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Savannah, Georgia, United States
Rush University Medical Center
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Chicago, Illinois, United States
Coastal Cancer Treatment Center - Bath
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Bath, Maine, United States
LSU Healthcare Network/Metairie Multi-Specialty Clinic
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Metairie, Louisiana, United States
Maine Health/Stephens Memorial - Norway
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Norway, Maine, United States
Maine Medical Partners - South Portland
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South Portland, Maine, United States
21st Century Oncology MHP - Farmington
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Farmington Hills, Michigan, United States
McLaren Cancer Institute - Flint
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Flint, Michigan, United States
McLaren Cancer Institute - Greater Lansing
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Lansing, Michigan, United States
McLaren Cancer Institute - Central Michigan
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Mount Pleasant, Michigan, United States
McLaren Cancer Institute - Owosso
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Owosso, Michigan, United States
Coborn Cancer Center
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Saint Cloud, Minnesota, United States
Kansas University Cancer Center Lee's Summit
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Lee's Summit, Missouri, United States
Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center
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Lebanon, New Hampshire, United States
Upstate Cancer Radiation Oncology at Oswego
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Oswego, New York, United States
Penn State Milton S. Hershey Medical Center
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Hershey, Pennsylvania, United States
WellSpan Health - Ephrata Cancer Center
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Ephrata, Pennsylvania, United States
WellSpan Health - Sechler Family Cancer Center
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Lebanon, Pennsylvania, United States
Cedar City Hospital
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Cedar City, Utah, United States
American Fork Hospital
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American Fork, Utah, United States
Dixie Regional Medical Center
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Saint George, Utah, United States
Dartmouth Hitchcock Medical Center/Norris Cancer Ctr. - St. Johnsbury
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Saint Johnsbury, Vermont, United States
Sentara Norfolk General Hospital
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Norfolk, Virginia, United States
University Cancer Center Johnson Creek
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Johnson Creek, Wisconsin, United States
Aspirus Regional Cancer Center
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Wausau, Wisconsin, United States
Drexel Town Square
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Oak Creek, Wisconsin, United States
Sutter Medical Center Sacramento
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Sacramento, California, United States
Logan Regional Medical Center
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Logan, Utah, United States
Gibbs Cancer Center - Pelham
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Greer, South Carolina, United States
Mercy Hospital
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Coon Rapids, Minnesota, United States
AdventHealth Orlando
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Orlando, Florida, United States
Decatur Memorial Hospital
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Decatur, Illinois, United States
UNC Rex Cancer Center
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Raleigh, North Carolina, United States
WellSpan Health - York Hospital
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York, Pennsylvania, United States
Spartanburg Medical Center
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Spartanburg, South Carolina, United States
University of Florida Health Science Center
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Gainesville, Florida, United States
Kansas University Cancer Center North
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Kansas City, Missouri, United States
University of Wisconsin Hospital and Clinics
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Madison, Wisconsin, United States