The primary hypothesis of this study is that outcomes for patients with biochemically recurrent prostate cancer following radical prostatectomy will be improved by the addition of enzalutamide for 6-months compared to standard-of-care salvage radiation therapy to allow for further study in the definitive phase III setting. This study builds on the prior success of high-dose bicalutamide (for 24 months) when combined with salvage external radiation therapy (XRT), while using a newer more potent anti-androgen for a shorter duration of time (6 months) in an effort to minimize adverse effects.
Enzalutamide is a second-generation androgen receptor signaling inhibitor that significantly prolongs survival in patients with metastatic castration-resistant prostate cancer who have received prior docetaxel chemotherapy 35,36. Enzalutamide has demonstrated activity in cells that overexpress the androgen receptor. Unlike previous androgen receptor blocker (ARB) agents, Enzalutamide does not display any agonist properties and blocks translocation of the ligand-receptor complex into the nucleus preventing DNA binding 33. Enzalutamide is an oral agent that is generally well tolerated and does not require concurrent steroid administration, which makes it an ideal candidate for combination with salvage radiation therapy (SRT). Finally, provocative preliminary Phase II data presented at the American Society of Clinical Oncology (ASCO) 2013 by M. Smith and colleagues assessed the efficacy and safety of 25-weeks (\~6-mos) of enzalutamide alone in prostate cancer of all stages who had never received hormone therapy; presenting with non-castrate testosterone levels ( 230 ng/dL). Enzalutamide alone for 6-mos achieved a high PSA response rate with efficacy similar to castration, but .in contrast to castration, bone mineral density (BMD) remained stable and metabolic variables were not substantially impacted. The trial described here differs from Radiation Therapy Oncology Group (RTOG) 96-01, RTOG 05-34 and RADICALS in several ways. First, the eligibility criteria are stricter; less favorable patients have been selected. Second, short-term ARB is being tested, while in RTOG 96-01 and RADICALS long-term ARB of 2-years was examined. Finally, and most importantly, we are testing the second generation ARB agent, enzalutamide, alone in combination with SRT as opposed to RTOG 05-34 and RADICALS which use androgen deprivation (AD). This trial is not intended to address the efficacy of SRT alone over observation. The complete response rate (a drop in PSA to undetectable levels) after SRT is 70%-80% and durable responses are observed in 30%-40% of patients. For these reasons, it is not feasible or appropriate to randomize men between observation and SRT. The more important issue is whether the proportion of durable responses is increased by altering the therapeutic approach, such as the use of enhanced ARB using enzalutamide.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
86
Enzalutamide (MDV3100) 160 mg PO once daily for 6 months (2 months prior to SRT, 2 months during SRT and 2 months following SRT)
Salvage radiation therapy (3D-CRT (Three dimensional conformal radiation therapy)/IMRT) 66.6-70.2 Gy given 1.8 Gy M-F for 37 -39 fx
Sibley Memorial Hospital
Washington D.C., District of Columbia, United States
University of Chicago Medical Center
Chicago, Illinois, United States
Indiana University
Lafayette, Indiana, United States
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States
Suburban Hospital
Bethesda, Maryland, United States
University of Michigan Health System
Ann Arbor, Michigan, United States
Karmanos Cancer Center
Detroit, Michigan, United States
Oregon Health Sciences University
Portland, Oregon, United States
University of Utah - Huntsman Cancer Center
Salt Lake City, Utah, United States
Percent of Participants With Freedom of PSA (Prostate Specific Antigen) Progression
The primary efficacy endpoint is the rate of Freedom-from-PSA-progression (FFPP) at 2-years. FFPP is defined as the time from randomization to the date of PSA progression. A subject who does not have PSA progression at the time of the analysis will be censored at the last date of PSA measurement.
Time frame: From time of randomization to date of PSA progression, approximately 2 years.
Number of Participants With Local Recurrence
Local recurrence within the radiation field (confirmed pathologically) at 2-years
Time frame: 2 years from end of radiation therapy
Metastatic Free Survival Rate
Metastasis-free survival (MFS) rates at 2 years. Metastasis-free survival will be defined as the time from the date of registration to date of evidence of systemic disease on bone scan or cross sectional imaging or death, which occurs first. Number of participants with a metastasis event at 2 years is reported.
Time frame: 2 years from the time of registration
How Well Participants Tolerate Treatment Assessed by European Organization for Research & Treatment of Cancer Quality of Life (Questionnaire (EORTC-QLQ-P25)
The European Organization for the Research and Treatment of Cancer (EORTC-QLQ-P25) quality of life questionnaire, Prostate Cancer Module. Uses a 4-point Likert scale, with responses ranging from "not at all" to "very much" for sexual symptoms and treatment related symptoms. Domain scores range 0 to 100, with higher scores reflecting either more symptoms (urinary, bowel, hormonal treatment-related symptoms) or higher levels of activity or functioning (sexual).
Time frame: Baseline, End of Treatment (180 Days) and 6 Months Post-treatment
How Well Participants Tolerate Treatment Assessed by the Functional Assessment of Cancer Therapy-Prostate (FACT-P).
The Functional Assessment of Cancer Therapy (FACT-P), assesses the health-related quality of life in men with prostate cancer. The score is the sum of all 5 domain scores and ranges from 0 to156 where higher scores represent better quality of life.
Time frame: Baseline, End of Treatment (180 Days) and 6 Months Post-treatment
How Well Participants Tolerate Treatment Assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire score range is from 0 to 100. A higher score indicates a better level of functioning or quality of life.
Time frame: Baseline, End of Treatment (180 Days) and 6 Months Post-treatment
How Well Participants Tolerate Treatment Assessed by Sexual Health Inventory in Men (SHIM) Questionnaire.
Quality of life (QoL) tool used to determine participant tolerability of treatment assessed by Sexual Health inventory in Men (SHIM). The questionnaire includes 5-items, and provides a total score from 1 to 25, with higher scores indicating better erectile function and lower scores indicating more severe erectile dysfunction.
Time frame: Baseline, End of Treatment (180 Days) and 6 Months Post-treatment
Feasibility of Achieving Stated Accrual
Anticipated accrual of participants versus actual reported enrollment. The goal is 48 in each arm.
Time frame: 2 years
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