Randomized Salvage Radiation Therapy Plus Enzalutamide Post Prostatectomy

Phase II Randomized Placebo-Controlled Double-Blind Study of Salvage Radiation Therapy (SRT) Plus Placebo Versus SRT Plus Enzalutamide in Men With High-Risk PSA-Recurrent Prostate Cancer After Radical Prostatectomy

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.

Study Overview

• Status: Completed
• Conditions: Adenocarcinoma of the Prostate
• Intervention / Treatment: Drug: Enzalutamide; Radiation: SRT

Detailed Description

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
• Enrollment (Actual): 86
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20016
      • Sibley Memorial Hospital
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
  • Indiana
    • Lafayette, Indiana, United States, 47904
      • Indiana University
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    • Bethesda, Maryland, United States, 20814
      • Suburban Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah - Huntsman Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Willing and able to provide written informed consent and Health Insurance Portability and Accountability Act (HIPPA) authorization for the release of personal health information.
• Males aged 18 years of age and above
• Patients must have adenocarcinoma of the prostate gland
• Patients must have received primary treatment with radical prostatectomy.
• Patients must have evidence of biochemical (PSA) relapse after prostatectomy
• Patients must have PSA within study range
• Patients must have non-metastatic (M0) disease, as defined by a lack of metastases seen on CT scan of the chest/abdomen/pelvis and whole-body radionuclide 99Technetium (Tc) bone scan, (or sodium fluoride PET scan) taken within 3 months of study entry.
• Patients must have had node negative (pN0) disease found at the time of surgery.
• Patients must have non-castrate levels of serum testosterone levels within study range.
• Patients must not have previously received hormonal therapy (LHRH agonist, antiandrogen, or both), with the exception of neoadjuvant or adjuvant hormones given in conjunction with prostatectomy.
• Patients must have Eastern Cooperative Oncology Group (ECOG)performance status of 0-1, and life expectancy greater 3 years.
• Patients must have laboratory test results within the certain ranges
• Patients must be disease-free from prior malignancies for greater than 3 years, with the exception of non-melanoma skin cancers and superficial urothelial cancers.
• Patients must have the ability to swallow the study drug whole as a tablet or capsule.
• Throughout study, male patient and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (1 of which must include a condom as a barrier method of contraception) starting at screening and continuing throughout the study period and for 3 months after final study drug administration or per local guidelines where these require additional description of contraceptive methods.
• Throughout the study, patients must use a condom if having sex with a pregnant woman.

Exclusion Criteria:

• Currently active second malignancy
• Primary treatment with radiation therapy.
• Radiographic or clinical evidence of local-regional tumor recurrence,
• Concurrent use of other antiandrogens, estrogen-like agents, or 5a-reductase inhibitors.
• Use of systemic corticosteroids equivalent to prednisone (inhaled corticosteroids are permitted).
• Concurrent use of other anti-cancer agents or treatments.
• Serious concurrent medical illnesses (including uncontrolled major cardiac, pulmonary, Child-Pugh C liver or psychiatric diseases) or active major infections (including HIV, Hepatitis A-C).

• Clinically significant cardiovascular disease including:

  • Myocardial infarction within 6 months of Screening visit.
  • Uncontrolled angina within 3 months of Screening visit.
  • Congestive heart failure (within certain ranges)
  • History of clinically significant ventricular arrhythmias
  • Prolonged corrected QT interval
  • History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place.
  • Hypotension within certain ranges
  • Uncontrolled hypertension within certain ranges
• Medications which lowers seizure threshold.
• History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumors, brain metastases, or alcoholism. Also, history of loss of consciousness or transient ischemic attack within 12months of enrollment (Day 1 visit).
• Patients taking medications that may have adverse interactions with enzalutamide

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SRT plus Enzalutamide; Arm 2 (experimental): (SRT) Salvage radiation therapy (Three dimensional conformal radiation therapy (3D-CRT)/IMRT [Intensity-modulated radiation therapy]) 66.6-70.2 Gy as 1.8 Gy M-F for 37-39 fx PLUS Enzalutamide (MDV3100) 160 mg PO once daily for 6 months (2 months prior to SRT, 2 months during SRT and 2 months following SRT)	Drug: Enzalutamide; Enzalutamide (MDV3100) 160 mg PO once daily for 6 months (2 months prior to SRT, 2 months during SRT and 2 months following SRT); Other Names: XTANDI
Placebo Comparator: SRT plus placebo; Arm 1 (control): Salvage radiation therapy (3D-CRT (Three dimensional conformal radiation therapy)/IMRT (Intensity-modulated radiation therapy)) 66.6-70.2 Gy given 1.8 Gy M-F for 37 -39 fx PLUS Placebo PO daily for 6 months (2 months prior to SRT, 2 months during SRT and 2 months following SRT)	Radiation: 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; Other Names: Salvage Radiation Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From time of randomization to date of PSA progression, approximately 2 years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Local Recurrence	Local recurrence within the radiation field (confirmed pathologically) at 2-years	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.	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).	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.	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.	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.	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.	2 years

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Astellas Pharma Inc; Medivation, Inc.
• Investigators: Principal Investigator: Daniel Song, M.D., The SKCCC at Johns Hopkins

Publications and helpful links

General Publications

• Kapoor R, Deek MP, McIntyre R, Raman N, Kummerlowe M, Chen I, Gaver M, Wang H, Denmeade S, Lotan T, Paller C, Markowski M, Carducci M, Eisenberger M, Beer TM, Song DY, DeWeese TL, Hearn JW, Greco S, DeVille C, Desai NB, Heath EI, Liauw S, Spratt DE, Hung AY, Antonarakis ES, Tran PT. A phase II randomized placebo-controlled double-blind study of salvage radiation therapy plus placebo versus SRT plus enzalutamide with high-risk PSA-recurrent prostate cancer after radical prostatectomy (SALV-ENZA). BMC Cancer. 2019 Jun 13;19(1):572. doi: 10.1186/s12885-019-5805-z.
• Tran PT, Lowe K, Tsai HL, Song DY, Hung AY, Hearn JWD, Miller S, Proudfoot JA, Deek MP, Phillips R, Lotan T, Paller CJ, Marshall CH, Markowski M, Dipasquale S, Denmeade S, Carducci M, Eisenberger M, DeWeese TL, Orton M, Deville C, Davicioni E, Liauw SL, Heath EI, Greco S, Desai NB, Spratt DE, Feng F, Wang H, Beer TM, Antonarakis ES. Phase II Randomized Study of Salvage Radiation Therapy Plus Enzalutamide or Placebo for High-Risk Prostate-Specific Antigen Recurrent Prostate Cancer After Radical Prostatectomy: The SALV-ENZA Trial. J Clin Oncol. 2023 Feb 20;41(6):1307-1317. doi: 10.1200/JCO.22.01662. Epub 2022 Nov 11.

Study record dates

Study Major Dates

• Study Start (Actual): March 28, 2015
• Primary Completion (Actual): December 31, 2022
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: June 16, 2014
• First Submitted That Met QC Criteria: July 28, 2014
• First Posted (Estimated): July 30, 2014

Study Record Updates

• Last Update Posted (Estimated): October 28, 2025
• Last Update Submitted That Met QC Criteria: October 24, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Enzalutamide; Salvage Radiation Therapy (SRT)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; enzalutamide
• Other Study ID Numbers: J1454; IRB00030471 (Other Identifier: JHMIRB)