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

Phase 2Active Not RecruitingNCT03809000

RTOG Foundation, Inc.188 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

188

Conditions

Prostate Cancer

Interventions

Radiation TherapyRADIATION

daily fractions

EnzalutamideDRUG

tablet

BicalutamideDRUG

tablet

GnRH analog

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (108)

Outcomes

Primary Outcomes

Percentage of Participants Alive Without Progression (Progression-Free Survival)

Progression-free survival (PFS) is estimated by the Kaplan-Meier method. 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.

Time frame: From randomization to first failure or last known follow-up. Median follow-up time at the time of analysis was 33.1 months. The 1- and 2-year estimates are reported.

Secondary Outcomes

Percentage of Participants With Biochemical Failure

Biochemical failure is defined as the first detectable post-RT prostate-specific antigen (PSA) value (≥ 0.05) or the initiation of salvage hormone therapy. Failure rates are estimated using the cumulative incidence method, treating death as a competing risk, and otherwise censoring participants alive at time of analysis.

Time frame: From randomization to first failure, competing event, or last known follow-up, whichever occurs first. Median follow-up time at the time of analysis was 33.1 months. The 1- and 2-year estimates are reported.

Percentage of Participants With Alternative Biochemical Failure

Alternative biochemical failure is defined as first post-RT PSA ≥ 0.1 ng/mL or initiation of salvage hormone therapy. Failure rates are estimated using the cumulative incidence method, treating death as a competing risk, and otherwise censoring participants alive at time of analysis.

Percentage of Participants With Hormone-refractory Disease

Data from ClinicalTrials.gov

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Arizona Center for Cancer Care - Gilbert

Gilbert, Arizona, United States

Arizona Center for Cancer Care - Peoria

Peoria, Arizona, United States

Arizona Center for Cancer Care - Phoenix

Phoenix, Arizona, United States

Arizona Center for Cancer Care - Scottsdale East

Scottsdale, Arizona, United States

Arizona Center for Cancer Care - Scottsdale North

Scottsdale, Arizona, United States

Arizona Center for Cancer Care - Surprise

Surprise, Arizona, United States

Marin Cancer Care, Inc.

Greenbrae, California, United States

Marin Health Medical Center

Greenbrae, California, United States

University of Southern California

Los Angeles, California, United States

USC Medical Center - Los Angeles County

Los Angeles, California, United States

...and 98 more locations

Hormone-refractory disease is defined as three rises in PSA during salvage androgen deprivation, with the date determined as the midway date between the last non-rising PSA and the first of the three rises. Failure rates were to be estimated using the cumulative incidence method, treating death as a competing risk, and otherwise censoring participants alive at time of analysis, but for endpoints with \< 10 events overall, such as this one, only the counts of participants with the event are provided.

Time frame: From randomization to first failure, competing event, or last known follow-up, whichever occurs first. Median follow-up time at the time of analysis was 33.1 months.

Percentage of Participants With Distant Metastasis

Distant failure is defined as first radiographic evidence of distant metastasis (e.g., bone scan, computed tomography (CT), magnetic resonance imaging (MRI)). Failure rates were to be estimated using the cumulative incidence method, treating death as a competing risk, and otherwise censoring participants alive at time of analysis, but for endpoints with \< 10 events overall, such as this one, only the counts of participants with the event are provided.

Time frame: From randomization to first failure, competing event, or last known follow-up, whichever occurs first. Median follow-up time at the time of analysis was 33.1 months.

Percentage of Participants With Prostate Cancer Death

Cause-specific mortality is defined as death due to prostate cancer. Failure rates were to be estimated using the cumulative incidence method, treating death as a competing risk, and otherwise censoring participants alive at time of analysis, but for endpoints with \< 10 events overall, such as this one, only the counts of participants with the event are provided.

Time frame: From randomization to first failure, competing event, or last known follow-up, whichever occurs first. Median follow-up time at the time of analysis was 33.1 months.

Percentage of Participants Alive (Overall Survival)

Survival rates were to be estimated using the Kaplan-Meier method, censoring participants alive at time of analysis, but for endpoints with \< 10 events overall, such as this one, only counts are provided. In this case, the number of participants without event (death), which is the number of participants alive.

Time frame: From randomization to death or last known follow-up, whichever occurs first. Median follow-up time at the time of analysis was 33.1 months.

Change From Baseline to End of RT in the 5-level European Quality of Life Questionnaire (EQ-5D-5L) Index Score

The EQ-5D-5L is a self-assessment questionnaire. The index score is computed from 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). Change score was calculated by subtracting baseline from later score, with a positive change score indicating improvement.

Time frame: Baseline and end of radiation treatment (RT). 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.

Change From Baseline to One Year After End of RT in the EQ-5D-5L Index Score

Time frame: Baseline and one year after end RT. 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.

Change From Baseline to Two Years After End of RT in the EQ-5D-5L Index Score

Time frame: Baseline and two years after end of RT. 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.

Change From Baseline to End of RT in the 7-item Patient Reported Outcomes Measurement Information System - Fatigue Short Form (PROMIS-F SF 7a) [PROMIS Fatigue Score]

The PROMIS fatigue score measures self-reported fatigue symptoms over the past 7 days. Possible raw scores range from 29.4 to 83.2 (higher raw score indicating greater fatigue) and are converted into standardized T-scores (mean=50, standard deviation=10) with higher scores also indicating greater fatigue. Change score is calculated by subtracting baseline T-score from later T-score, with a positive change score indicating increased fatigue.

Time frame: Baseline and end of RT. 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.

Change From Baseline to One Year After the End of RT in the 7-item Patient Reported Outcomes Measurement Information System - Fatigue Short Form (PROMIS-F SF 7a) [PROMIS Fatigue Score]

Time frame: Baseline and one year after end of RT. 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.

Change From Baseline to Two Years After the End of RT in the 7-item Patient Reported Outcomes Measurement Information System - Fatigue Short Form (PROMIS-F SF 7a) [PROMIS Fatigue Score]

Time frame: Baseline, two years after end of RT. 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.

Number of Participants by Highest Grade Adverse Event Reported CTCAE v5

Common Terminology Criteria for Adverse Events (version 5) grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.

Time frame: From randomization to death or last known follow-up. Median follow-up time at the time of analysis was 33.1 months.

Number of Participants Any Adverse Event Occuring Within 30 Days Following the End of Treatment

Time frame: From randomization to 30 days after the end of RT. 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.

Number of Participants With Any Grade 3+ Adverse Event Occuring After 30 Days Following the End of RT

Time frame: From 31 days after the end of RT to death or last known follow-up. Median follow-up was 33.1 months. 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.

Number of Participants With Post-baseline Patient-reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Scores ≥ 3

PRO-CTCAE is a patient-reported outcome (PRO) measurement system developed to evaluate symptomatic toxicity in patients on cancer clinical trials, asking the patient about experience over the last seven days. Scores may reflect worst severity of the symptom (0=None, 1=Mild, 2=Moderate, 3=Severe, and 4=Very severe), frequency of the symptom (0=Never, 1=Rarely, 2=Occasionally, 3=Frequently, 4=Almost constantly), or the symptom's interference with one's "usual or daily activities" (0=Not at all, 1=A little bit, 2=Somewhat, 3=Quite a bit, 4=Very much). The symptom row title will indicate "Severity", "Frequency", or "Interference". All scores are compared between arms; statistical analysis results are entered for p-values \< 0.05.

Time frame: End of RT, one and two years after the end of RT. 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.