STEEL: A Randomized Phase II Trial of Salvage Radiotherapy With Standard vs Enhanced Androgen Deprivation Therapy (With Enzalutamide) in Patients With Post-Prostatectomy PSA Recurrences With Aggressive Disease Features
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: RTOG Foundation, Inc.

RTOG FOUNDATION 
 
 
RTOG 3506 
 
(ClinicalTrials.gov NCT #: 03809000) 
 
 
STEEL: A Randomized Phase II Trial of Salvage Radiotherapy with Standard 
vs Enhanced Androgen Deprivation Therapy (with Enzalutamide) in Patients 
with Post Prostatectomy PSA Recurrences with Aggressive Disease Features 
 
 
Amendment 7:  July 12, 2022 

 
 
 
 
RTOG Foundation Collaboration with Pfizer/Astellas 
RTOG Foundation Trial 3506 
(Hereafter RTOG 3506) 
 
A Limited Participation Study 
STEEL: A Randomized Phase II Trial of Salvage Radiotherapy with Standard vs 
Enhanced Androgen Deprivation Therapy (with Enzalutamide) in Patients with Post-
Prostatectomy PSA Recurrences with Aggressive Disease Features  
Protocol Version Date: July 12, 2022
 
Sponsor: RTOG Foundation 
 
 
Principal Investigator / Medical Oncology 
Edwin Posadas, MD, FACP 
Co-Principal Investigator/ Radiation Oncology 
Hiram Gay, MD 
 
 
Study Co-Chairs  
 
Radiation Oncology 
Felix Feng, MD 
Urology 
Todd Morgan, MD 
Medical Physics 
Ying Xiao, PhD 
Quality of Life 
James B. Yu,MD MHS 
Senior Statistician 
Stephanie Pugh, PhD 
 
 
 
 
 
 
Protocol Acceptance 
On behalf of the RTOG Foundation, Inc. 
                                                                      July 12, 2022 
Quynh Le, RTOG Foundation Chair 
 
Date 

 
RTOG Foundation 3506 
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Version Date:  July 12, 2022 
 
 
RTOG Foundation Trial 3506 
(Hereafter RTOG 3506) 
 (ClinicalTrials.gov NCT # 03809000)(22-AUG-2019) 
 
A Limited Participation Study 
 
STEEL: A Randomized Phase II Trial of Salvage Radiotherapy with Standard vs 
Enhanced Androgen Deprivation Therapy (with Enzalutamide) in Patients with Post-
Prostatectomy PSA Recurrences with Aggressive Disease Features 
(03-FEB-2022) 
Principal Investigator/Medical Oncology 
Edwin Posadas, MD
Cedars-Sinai Medical Center  
8700 Beverly Boulevard 
Los Angeles, CA 90048 
310-423-7600/FAX 310-967-3841 
Edwin.Posadas@csmc.edu 
Co-Principal Investigator/Radiation Oncology 
Hiram Gay, MD 
Department of Radiation Oncology 
Washington University in Saint Louis 
4921 Parkview Place, Campus Box 8224 
St. Louis, MO 63110-6311 
314-362-8516/FAX 314-362-8521 
hiramgay@wustl.edu  
Radiation Oncology Co-Chair 
Felix Feng, MD  
University of California, San Francisco  
1825 4th Street, First Floor, Rm M2267 
San Francisco, CA 94143 
415-353-7183/FAX 415-353-7182 
felix.feng@ucsf.edu 
Medical Physics Co-Chair 
Ying Xiao, PhD, FAAPM 
Hospital of the University of Pennsylvania 
Perelman Center for Advanced Medicine 
3400 Civic Center Blvd, TRC 2-West 
Philadelphia, PA 19104 
215-615-2247 
Ying.Xiao@uphs.upenn.edu 
Urology Co-Chair 
Todd Morgan, MD 
University of Michigan Comprehensive Cancer 
Center 
1500 E Medical Center Drive, CCC 7308
Ann Arbor, MI, 48109 
Phone: 734-615-6662/FAX (734) 647-9480 
tomorgan@med.umich.edu 
Quality of Life Co-Chair 
James B. Yu, MD, MHS 
Columbia University 
622 West 168th St 
CHONY North B Level 
New York, NY. 10032 
212-305-7077 
jby2110@cumc.columbia.edu  
 
Senior Statistician 
Stephanie Pugh, PhD 
RTOG Foundation 
50 South 16th Street 
Suite 2800 
Philadelphia, PA 19102 
 

 
RTOG Foundation 3506 
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Version Date:  July 12, 2022 
215-717-0850 
SPugh@acr.org 
 
RTOG Foundation Headquarters Contact Information  (12-JUL-2022) 
Data Managers:   
For questions concerning eligibility or data submission 
Margaret Kennish 
215-574-3240 
mkennish@acr.org 
 
Jennifer Petrask, BS, LPN 
215-574-3909 
jpetrask@acr.org 
RTQA:  
For questions concerning RT data submission 
Denise Manfredi, BS, RT(T) 
215-717-2755 
dmanfredi@acr.org 
 
George Ballinger, RT(R)(T) 
215-574-3163 
gballinger@acr.org 
RTQA:   
For questions concerning data submission to TRIAD 
Triad-Support@acr.org 
Serious Adverse Event Coordinator 
For questions concerning serious adverse event 
reporting procedures, timelines, and queries 
Sara McCartney, MS, RN 
215-717-0835smccartney@acr.org 
Project Manager: For questions concerning regulatory 
documentation, investigational drug supply and/or 
shipment issues 
Erin Moye, 215-717-0831 
emoye@acr.org 
Clinical Trials Administration:  
For questions concerning contracts and reimbursement 
RTOG-Membership@acr.org 
 
Protocol Agent 
Agent 
Supply 
IND # 
IND Sponsor 
Enzalutamide 
Pfizer/Astellas 
 
Exempt 
N/A 
Bicalutamide 
Commercial 
Exempt 
N/A 
GnRH analog 
Commercial 
Exempt 
N/A 
 
Document History  
 
 
Version Date 
Amendment 7 
July 12, 2022 
Amendment 6 
February 03, 2022 
Amendment 5 
June 17, 2021 
Amendment 4 
May 20, 2021 
Amendment 3 
March 16, 2021 
Amendment 2 
December 02, 2019 
Amendment 1 
August 22, 2019 
Initial 
November 7, 2018 
 
This protocol was designed and developed by RTOG Foundation, Inc. It is intended to 
be used only in conjunction with institution-specific IRB approval for study entry.  No 
other use or reproduction is authorized by RTOG nor does RTOG assume any 
responsibility for unauthorized use of this protocol. 

 
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TABLE OF CONTENTS  
 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Primary Objective ....................................................................................................7 
1.2 
Secondary Objectives ...............................................................................................7 
1.3 
Exploratory Objectives ............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1       The Importance of Salvage Radiation Therapy (SRT) for Post-
Prostatectomy PSA Recurrences..............................................................................7 
2.2       The Need to Improve Outcomes for Patients With PSA Recurrences With 
Aggressive Features .................................................................................................8 
2.3       The Rationale for Adding Androgen Deprivation Therapy (ADT) to SRT .............8 
2.4       The Rationale for the Design of the Study Control Arm .........................................9 
2.5       The Rationale for Selecting Enzalutamide-Based Therapy in the Study 
Experimental Arm ....................................................................................................9 
2.6       The Rationale for the Primary Endpoint of This Study .........................................10 
2.7       The Potential Impact and Significance of This Study ...........................................11 
3. 
PATIENT SELECTION, INCLUSION, AND EXCLUSION CRITERIA .......................11 
3.1 
Inclusion Criteria ...................................................................................................11 
3.2 
Exclusion Criteria ..................................................................................................12 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..................13 
5. TREATMENT PLAN/REGIMEN DESCRIPTION..................................................................16 
5.1       Hormonal Therapy/Other Agent-Based Therapy ...................................................16 
5.2       Radiation Therapy ..................................................................................................17 
5.3       General Concomitant Medication and Supportive Care Guidelines ......................33 
5.4       Duration of Therapy ...............................................................................................34 
6. TREATMENT MODIFICATIONS/MANAGEMENT .............................................................34 
6.1  
Dose Levels ............................................................................................................34 
6.2       Management of Toxicity Related to Enzalutamide ...............................................34 
6.3  
Overdose Management ..........................................................................................35 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................35 
7.1  
Protocol Agents   ....................................................................................................35 
7.2       Adverse Events (AEs) ............................................................................................35 
7.3       Serious Adverse Events (SAEs).............................................................................38 
7.4       Serious Adverse Event (SAE) Reporting Requirements .......................................38 

 
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8. 
REGISTRATION AND STUDY ENTRY PROCEDURES .............................................41 
8.1 
Regulatory and RT Credentialing Requirements for Patient Enrollment ..............41 
9.0 
DRUG INFORMATION ...................................................................................................41 
9.1 
Investigational Study Agent: Enzalutamide, IND Exempt ....................................41 
9.2       Commercial Agent: Bicalutamide..........................................................................42 
9.3       Commercial Agent: GnRH analog .........................................................................42 
10.       PATHOLOGY/BIOSPECIMENS .....................................................................................42 
10.1    Biospecimen Submission Tables ............................................................................42 
11. 
SPECIAL STUDIES (Non-Tissue) ....................................................................................44 
11.1     The PROMIS Fatigue Scale (7 items) ....................................................................44 
11.2  EQ-5D-5L ..............................................................................................................45 
11.3    Optional Online Completion of Patient-Reported QOL Assessments ....................45 
12. 
MODALITY REVIEWS ...................................................................................................46 
12.1     Radiation Therapy Quality Assurance Reviews ....................................................46 
12.2  Medical Oncology Modality Quality Assurance Reviews .....................................47 
13. 
DATA AND RECORDS ...................................................................................................47 
13.1  Summary of Data Submission and Dosimetry Digital Data Submission ..............47 
14. STATISTICAL CONSIDERATIONS ....................................................................................47 
14.1 
Study Design ..........................................................................................................47 
14.2 
Study Endpoints .....................................................................................................48 
14.3 
Primary Objectives Study Design ..........................................................................48 
14.4 
Study Monitoring of Primary Objectives ...............................................................49 
14.5 
Accrual/Study Duration Considerations ................................................................50 
14.6 
Secondary Endpoints .............................................................................................50 
14.7     Exploratory Endpoints ...........................................................................................52 
REFERENCES ..............................................................................................................................54 
Appendix A ....................................................................................................................................59 
 
 
 
 

 
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RTOG 3506 
 
STEEL: A Randomized Phase II Trial of Salvage Radiotherapy with Standard vs 
Enhanced Androgen Deprivation Therapy (with Enzalutamide) in Patients with 
Post-Prostatectomy PSA Recurrences with Aggressive Disease Features 
 
SCHEMA (16-MAR-2021) 
 
Patients with biochemical recurrence post-RP with PSA ≥ 0.2 (or ultra-sensitive PSA ≥ 0.10) 
 
STRATIFICATION 
Number of aggressive features*  (1 vs. > 1) 
 
RANDOMIZATION 
↓ 
↓ 
Arm 1 
SRT 66.0 - 70.2 Gy/1.8-2.0Gy/33-39  
+  Standard ADT  
(24 months of GnRH analog ± 1-4 months of 
bicalutamide) 
+/- lymph node boost **  
 
 
Arm 2 
SRT 66.0 - 70.2 Gy/1.8-2.0Gy/33-39  
+ Enhanced ADT  
(24 months of GnRH analog + 24 months of 
enzalutamide) 
+/- lymph node boost ** 
 
Sample size: 242 
 
* In addition to PSA ≥ 0.2 ng/mL (or ultra-sensitive PSA ≥ 0.10), the following 
aggressive features are included in the stratification (Please see 3.1.5 for details): 
• Gleason score of 8-10 (note any Gleason score is eligible) 
• Seminal vesicle invasion (SVI) (note any pT stage is eligible [AJCC v8.0] 
but pT stage ≥ pT3b is considered aggressive) 
• Locoregional node involvement at radical prostatectomy (pN1) 
• Persistently elevated PSA post-RP (PEPP) defined as PSA > 0.1 ng/mL 
after radical prostatectomy 
• PSA ≥0.7 ng/mL 
 
** At the discretion of the radiation oncologist, suspicious lymph nodes for locoregional 
(obturator, prescral, perirectal, pelvic,inguinal or low paraaortic lymph nodes below 
T12/L1) disease in the radiology report (CT, MRI, molecular imaging [i.e. choline PET, 
FACBC, PSMA]) and/or biopsy proven lymph nodes may be sequentially or concurrently 
boosted.  
 
 
 

 
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1. OBJECTIVES 
 
1.1 Primary Objective 
The primary goal of this study is 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.   
 
1.2 Secondary Objectives 
1.2.1 To compare the rates of biochemical failure, an alternative biochemical failure 
endpoint, hormone-refractory disease (HRD), distant metastasis, cause-
specific mortality, and overall mortality between patients who receive SRT 
with standard GnRH analog-based ADT and those who receive SRT with 
enhanced ADT. 
1.2.2 To compare acute and late physician- and patient-reported toxicity between 
patients who receive SRT with standard GnRH analog-based ADT and those 
who receive SRT with enhanced ADT. 
1.2.3 To compare fatigue using the PROMIS-F SF 7a between patients who receive 
SRT with standard GnRH analog-based ADT and those who receive SRT with 
enhanced ADT. 
1.2.4 To assess global quality of life using the EQ-5D-5L between patients who 
receive SRT with standard GnRH analog-based ADT and those who receive 
SRT with enhanced ADT. 
 
1.3 
Exploratory Objectives (16-MAR-2021) 
1.3.1 To assess the prognostic and predictive value of the genomic classifier 
Decipher. 
1.3.2 To assess whether molecular classification by the PAM50 gene expression 
clustering will identify subsets of prostate cancer (Luminal A or Basal, 
Luminal B) which derive the greatest benefit from enhanced ADT. 
 
2. BACKGROUND 
 
2.1 The Importance of Salvage Radiation Therapy (SRT) for Post-Prostatectomy 
PSA Recurrences 
Radical prostatectomy (RP) is a standard treatment option for patients with localized 
prostate cancer. However, greater than 30% of patients treated with RP will 
experience biochemical recurrence (BR), as represented by a rising prostate specific 
antigen (PSA) [Han 2001, Roehl 2004].  A common option for initial management of 
patients with BR post-RP is salvage radiation therapy (SRT).  While no randomized 
data exist comparing SRT to observation alone, many retrospective analyses have 
shown that SRT can provide long-term durable responses [Goenka 2012, Katz 2003, 
Stephenson 2007], and two large retrospective studies have suggested an 
improvement in prostate cancer-specific mortality as compared to observation for 

 
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patients treated with SRT following BR [Cotter 2011, Trock 2008].  Trock et al found 
that SRT was associated with a 3-fold decrease in risk of prostate cancer-specific 
mortality compared to observation, and that this was primarily true in patients with 
aggressive disease features [Trock 2008].  Cotter et al similarly found that SRT 
improved all-cause mortality in both low- and high-risk patients, but that when 
controlling for patient comorbidities, this improvement was greatest in patients with 
high-risk features, with a 15% reduction in actuarial all-cause mortality [Cotter 2011].  
Thus, SRT is a well-accepted standard practice for patients with post-prostatectomy 
PSA recurrences, including those with aggressive disease features.   
 
2.2 The Need to Improve Outcomes for Patients With PSA Recurrences With 
Aggressive Features 
While SRT has been shown to provide durable responses and a survival benefit for 
many patients experiencing BR post-RP, up to 50% of patients treated with SRT, on 
average, will experience disease progression [Goenka 2012, Stephenson 2007].  
Previous studies have demonstrated that an even larger proportion of patients with 
aggressive pathologic and clinical features, such as a persistently elevated PSA post-
RP (PEPP), a pre-RT PSA >1 ng/mL, Gleason score 8-10, and seminal vesicle 
invasion, will have BR following SRT [Katz 2003, Stephenson 2007, Stephenson 
2004, Song 2002].  Analysis of a large patient database maintained at the University 
of Michigan shows that, when defining BR as the post-SRT PSA nadir + 2 ng/mL, the 
5-year post-SRT event-free survival is 30% for those with aggressive pathologic and 
clinical features treated solely with SRT, thus highlighting the critical need for better 
treatments for these patients. 
 
2.3 The Rationale for Adding Androgen Deprivation Therapy (ADT) to SRT 
Augmenting SRT with ADT represents one approach to improving long-term 
outcomes for post-prostatectomy patients treated with SRT for BR with aggressive 
disease features.  The addition of ADT has resulted in significant improvements in 
rates of BR, metastasis-free survival, and overall survival in the context of definitive 
radiation therapy for localized prostate cancer [Bolla 2010, Horwitz 2008, Jones 
2011, Lawton 2001].  More recently, it was demonstrated that the addition of ADT to 
SRT also confers a benefit [Shipley 2011].  Initial results from RTOG 9601, which 
randomized post-RP patients with BR to SRT + bicalutamide x 24 months or SRT 
alone, have shown that the addition of bicalutamide provided a benefit in reducing 
PSA progression and decreased the incidence of metastatic disease [Shipley 2011].  
Overall, patients treated with SRT + bicalutamide were 17% less likely to experience 
PSA progression and 6% less likely to develop metastases.  The decrease in risk for 
PSA progression was largest in patients with GS 8-10, who were 30% less likely to 
have PSA progression if receiving bicalutamide [Shipley 2011].  The final results of 
RTOG 9601 are notable for significant improvements in all clinical endpoints, 
including overall survival, distant metastases-free survival, and freedom from 
biochemical progression with the addition of bicalutamide [Shipley 2017]. 
 
RTOG 9601 assessed the addition of high-dose bicalutamide in a relatively 
unselected patient population with PSA recurrences following prostatectomy; in fact, 

 
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the primary selection in RTOG 9601 was to restrict eligibility to patients with a pre-
radiation PSA of 0.2 to 4 ng/mL, thus preventing enrollment of patients with higher 
pre-radiation PSA levels.  In contrast, this trial will actively select for patients with 
aggressive disease features (Gleason 8-10 disease, pre-radiation PSA >1, seminal 
vesicle invasion, or a persistently elevated PSA following prostatectomy), as these 
patients have very poor outcomes.  Thus, we expect to potentially achieve even 
greater gains given the selection for these patients with aggressive disease features.  
2.4 The Rationale for the Design of the Study Control Arm  
To enhance the risk/benefit ratio in this trial, we will preselect for patients with the 
highest risk of disease recurrence following salvage radiation (due to aggressive 
pathologic or clinical features) based on currently available data and develop 
treatment strategies aimed at intensifying therapy while preserving the tolerability of 
therapy.  The control arm will receive SRT + 24 months ADT with a GnRH analog. 
Per physician preference, patients on the control arm will be allowed to receive up to 
1-4 months of bicalutamide as lead-in therapy with the GnRH analog, for prevention 
of a testosterone flare.    
 
The use of GnRH analog therapy was chosen for this study in place of the high-dose 
bicalutamide regimen (150 mg) utilized in the RTOG 9601 trial for several reasons.  
Despite the studies conducted with high-dose bicalutamide, this regimen has not been 
widely adopted as a replacement for GnRH analogs with or without a non-steroidal 
anti-androgen. In the metastatic population, bicalutamide monotherapy was found to 
be less effective than castration, with a hazard ratio of 1.30 for time to death from 
onset of therapy favoring castration [Tyrrell 1998].  The complementary portion of 
this study that focused on high-risk, non-metastatic patients was not able to complete 
enrollment due to the demonstration of the inferior outcomes associated with 
bicalutamide monotherapy [Boccardo 2002].  A recent poll of 40 members of the 
RTOG GU Steering Committee confirmed that the predominant ADT regimen used, 
in the context of salvage radiotherapy, by this group was a GnRH analog, either alone 
or with up to 1 month of lead-in bicalutamide.  Even with the RTOG 9601 data, high-
dose bicalutamide monotherapy has not been broadly adopted even in this setting.  
Thus, to maximize the clinical relevance and scientific merit of this study, a control 
arm of GnRH analog therapy (with up to 1-4 month of bicalutamide) will be used. 
The duration of 24 months of GnRH analog therapy was selected based on RTOG 
9601, as this is the duration of therapy used in this study. 
 
2.5 The Rationale for Selecting Enzalutamide-Based Therapy in the Study 
Experimental Arm (22-AUG-2019) 
The use of next-generation anti-androgens provides a promising strategy for further 
intensifying ADT for SRT patients with aggressive disease characteristics.  In 
particular, enzalutamide (MDV3100) is a next generation anti-androgen that has a 5-
fold higher binding affinity for the androgen receptor (AR) compared to the first-
generation anti-androgen bicalutamide [Tran 2009].  As opposed to bicalutamide, 
enzalutamide prevents binding of AR to DNA and to co-activator proteins [Tran 
2009]. In addition, while bicalutamide has been shown to have analog activity in the 
setting of AR overexpression, enzalutamide acts as a pure analog [Tran 2009].  

 
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In the AFFIRM study, enzalutamide was shown to improve overall survival for 
patients with metastatic castration-resistant prostate cancer (mCRPC) previously 
treated with docetaxel-based chemotherapy [Scher 2012, Howard 2012].  In this 
setting, PSA declines with enzalutamide have been impressive, with more than half of 
patients experiencing greater than a 50% reduction in serum PSA level and 25% 
having a greater than 90% decline from initial PSA [Scher 2012]. The PREVAIL 
study showed that even prior to docetaxel, enzalutamide was effective in delaying the 
need for chemotherapy (HR 0.35), preventing skeletal-related events (HR 0.72), and 
preventing disease progression by PSA (HR 0.17) [Beer 2014].  The final analysis of 
PREVAIL showed improvement in radiographic progression (HR 0.32) and an 
improvement in overall survival (HR 0.77) compared to placebo [Beer 2017].  In an 
earlier population of men with CRPC without metastases, the PROSPER study 
demonstrated that enzalutamide reduced the risk of metastatic progression (HR 0.29) 
[Hussain 2018]. When comparing bicalutamide and enzalutamide in CRPC, the 
randomized, double-blind, phase 2, STRIVE trial, showed an improvement in PFS for 
enzalutamide over bicalutamide (HR 0.24) [Person 2016]. 
 
 Most relevant to this study was the activity of enzalutamide demonstrated in the 
castration sensitive (CSPC) space.  The ARCHES study showed a reduction in the 
rate radiographic progression (HR 0.39) [Armstrong 2019] compared to placebo.  
ENZAMET showed that in metastatic CSPC, enzalutamide showed superior activity 
to bicalutamide with a 33% improvement in overall survival as well as improvements 
in PSA progression free survival (HR 0.39) and clinical progression free survival (HR 
0.40). [Davis 2019] 
 
At the time of trial activation, there are two FDA-approved next-generation androgen 
receptor-targeting therapies: abiraterone and enzalutamide. Abiraterone is a CYP17 
inhibitor that inhibits androgen biosynthesis.  Like enzalutamide, this agent has 
shown efficacy in both the pre- and post-chemotherapy populations [Ryan 2013, 
Fizazi 2012].  However, abiraterone alters steroidogenesis and requires administration 
with corticosteroids to avoid potential toxicities resulting from this alteration.  
Enzalutamide was chosen for this study for ease of administration that may impact 
patient compliance in this setting.  Therefore, the goal of this study is to determine if 
the addition of enzalutamide to standard androgen deprivation therapy can further 
improve SRT outcomes for patients with aggressive pathologic or clinical features.   
 
2.6 The Rationale for the Primary Endpoint of This Study (12-JUL-2022) 
The primary endpoint of this study is progression-free survival, defined as a 
detectable serum PSA concentration or initiation of salvage hormones, absence of (as 
noted by the initiation of salvage hormone therapy) clinical failure, and absence of 
death from any cause. It is expected that the vast majority of events contributing to 
the primary endpoint will result from biochemical recurrence.  The definition of a 
detectable serum PSA will be any concentration greater than 0.05 ng/mL.  Given that 
all patients have undergone radical prostatectomy, it is anticipated that successful 
salvage therapy will result in an undetectable PSA.  Given the range of RTOG 

 
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performance sties and changes in PSA detection thresholds since RTOG 9601, a 
threshold of 0.05 ng/mL was recognized as deployable across participating sites.   
 
2.7 The Potential Impact and Significance of This Study 
Radical prostatectomy (RP) is the most common treatment for prostate cancer, 
according to the National Cancer Institute’s (NCI) Patterns of Care study from 14 
regional cancer registries. Greater than 30% of patients treated with RP will 
experience BR, as represented by a rising serum PSA concentration [Han 2001, Roehl 
2004]. The failure rate is significantly higher for patients with aggressive clinical or 
pathologic features. Patients with Gleason scores 8-10 or SVI more than 70% will 
experience BR by 10 years post-RP [Han 2001].  While SRT has been shown to 
improve prostate cancer-specific mortality, many patients do not experience a long-
term durable response to treatment.  The addition of ADT to RT has recently been 
shown to improve patient outcomes, with greater benefit observed in patients with 
aggressive features.  However, the ideal ADT agents in this setting have yet to be 
established, and improved treatment options are needed.   
 
By investigating the addition of enzalutamide to ADT with SRT, this trial may 
identify a more effective approach for treating patients with high-risk post-RP BR. 
Additionally, this study has the potential to provide the foundation for a future 
paradigm change for how next-generation anti-androgens are currently given, moving 
them from the context of metastatic disease to earlier in disease progression.  This 
trial also tests the hypothesis that a transcriptomic signature can be used to identify 
patients who will respond to SRT + standard (or enhanced).  The same studies may 
also identify dominant biological pathways associated with resistance to these AR 
targeted approaches.  Finally, given that patient-reported outcomes (PRO) have not 
been well studied in the post-prostatectomy setting, this study will provide critical 
information on PROs in the context of enzalutamide versus control therapy, which 
may help future patients considering whether to pursue these therapies after 
prostatectomy. 
 
3. PATIENT SELECTION, INCLUSION, AND EXCLUSION CRITERIA 
 
 
Note: Exceptions to inclusion and exclusion criteria are not permitted.  For 
questions concerning eligibility, please contact the Biostatistics/Data Management 
Center (via the contact list on the protocol cover page). For radiation therapy-related 
eligibility questions, please contact RTQA (via the contact list on the protocol cover 
page). 
 
3.1 
Inclusion Criteria (16-MAR-2021) 
A patient cannot be considered eligible for this study unless ALL of the 
following conditions are met. 
3.1.1 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. 

 
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3.1.2 Serum PSA concentration of ≥0.20 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. 
 
3.1.3   GnRH analog may be started no more than 42 days prior study entry. 
 
3.1.4 Hemoglobin 9.0 g/dL, independent of transfusion and/or growth factors within 
90 days prior to registration; 
 
3.1.5 Platelet count ≥75,000 x 109/µL independent of transfusion and/or growth factors 
within 90 days prior to registration; 
 
3.1.6 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 [AJCC v8.0] is eligible 
but a pT stage ≥ pT3b is considered aggressive) 
• Locoregional node involvement at radical prostatectomy (pN1) 
• Persistently elevated PSA post-RP nadir (PEPP) defined as PSA > 0.1 
ng/mL after radical prostatectomy 
• PSA ≥0.7 ng/mL 
 
3.1.7 Serum albumin ≥3.0 g/dL within 90 days prior to registration 
3.1.8 GFR >35 mL/min estimated by Cockcroft-Gault or measured directly by 24 hour 
urine creatinine within 90 days prior to registration 
• Cockcroft-Gault formula is as follows: 
https://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation 
CrCl (eGFR) = Sex * ((140 - Age) / (SerumCreat)) * (Weight / 72)  
3.1.9 Serum total bilirubin 1.5 × 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;  
3.1.10 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
<2.5 × ULN within 90 days prior to registration; 
3.1.11 Age ≥ 18;  
3.1.12 History and physical with ECOG Performance Status 0-1 or within 90 days prior to 
registration; 
3.1.13 The patient or legally authorized representative must provide study-specific 
informed consent prior to study entry; 
 
3.2 
Exclusion Criteria (02-DEC-2019) 
Patients with one or more of the following conditions are NOT eligible for this 
study. 
3.2.1 Definitive clinical or radiologic evidence of metastatic disease with the exception 
of locoregional lymph nodes; 

 
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3.2.2 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); 
3.2.3 Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for 
a different cancer is allowable; 
3.2.4 Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation therapy fields; 
3.2.5 History of any of the following: 
• History of 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 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. 
3.2.6 Current evidence of any of the following: 
• 
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 
3.2.7 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 also that 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.  
 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
(20-MAY-2021) 
 
ASSESSMENTS: PRE-TREATMENT 
 
Timepoint 
Procedure/test  
Notes 

 
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≤ 10 years of registration 
 Prostatectomy 
 Gleason score 
 Decipher Prostate RP (to be sent 
directly to Decipher Biosciences)  
 
Gleason score from prostatectomy 
Decipher Prostate RP will be 
collected for those who consented 
to the collection. 
≤ 120 days of registration 
 PSA 
 
≤ 90 days of registration 
 Medical history 
 Physical Exam incl. height and 
weight  
 Vital signs  
 Smoking history  
 ECOG Performance Status 
 CBC  
 Albumin 
 AST or ALT  
 Total bilirubin 
 eGFR 
 PROMIS-F SF 7a, EQ-5D-5L, 
PRO-CTCAE 
History and Physical with review 
of prostate cancer diagnosis 
 
 
CBC for hemoglobin and platelets.  
 
QOL forms can be completed any 
time after consent is signed and 
must be completed prior to any 
treatment start unless hormone 
therapy started prior to registration 
and then they must be completed 
prior to the start of RT 
 
 
 
 
 
 
ARM 1 and ARM 2 ASSESSMENTS: ON TREATMENT 
• For Arm 1, labs (CBC, albumin, hepatic and renal function) are as clinically indicated and per 
institutional standard 
• For both Arms, ADT must begin no more than 42 days prior to registration and no later than 21 days 
after registration. ADT GnRh analog will be given for 24 months. For Arm 1, bicalutamide may be 
given for 1-4 months. For Arm 2, enzalutamide will be given for 24 months. 
 
 
Timepoint 
 
Procedure/test/treatment 
 
Notes 
At end of RT 
 Medical history 
 Physical Exam  incl. weight  
 Vital signs 
 CBC 
 Albumin 
 AST or ALT 
 Serum total bilirubin 
 eGFR 
 PSA 
 Testosterone 
 PRO-CTCAE 
 PROMIS-F SF 7a, EQ-5D-5L 
 
 
 
CBC for hemoglobin and 
platelets; ARM 2 only:  CBC, 
albumin, hepatic and renal 
function 
 

 
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 AE Evaluation 
 
 
ASSESSMENTS: FOLLOW--UP 
Follow up assessments from end of RT  
• For Arm 1, labs (CBC, albumin, hepatic and renal function) are as clinically indicated and per 
institutional standard 
 
 
Timepoint 
 
Procedure/test/treatment 
 
Notes 
q3 months (+/- 1 month) 
for 2 years  
 Medical history 
 Physical Exam incl. weight  
 Vital signs 
 AE Evaluation 
 CBC 
 Albumin 
 AST or ALT 
 Serum total bilirubin 
 eGFR 
 PSA 
 Testosterone 
 PRO-CTCAE 
 PROMIS-F SF 7a, EQ-5D* 
 
 
 
 
CBC for hemoglobin and 
platelets; ARM 2 only:  CBC, 
albumin, hepatic and renal 
function 
 
 
 
 
*1 and 2 years from end of RT 
q6 months (+/- 1 month) 
for years 3-5 
 Medical history 
 Physical Exam incl. weight 
 Vital signs 
 AE Evaluation 
 PSA 
 Testosterone 
 PRO-CTCAE 
 
 
 
 
 
Testosterone q6mos x 1 yr 
(only) 
**Participating sites in Canada: please see Appendix A for further monitoring assessments 
recommended by Health Canada. 
 
Definition of Disease Assessments 
• Biochemical failure: Two definitions of biochemical failure will be assessed: 
o Primary (noted as PBF): PSA ≥ nadir+2 ng/mL, or initiation of salvage 
hormones in the absence of PBF, after completion of RT and hormone therapy 
o Alternate (noted as ABF):   PSA ≥ 0.4 ng/mL and rising at 5 years after 
randomization (i.e. PSA ≥ 0.4 ng/mL followed by a value higher than the first 
by any amount), or initiation of salvage hormones 
• Local failure: development of a new biopsy-proven mass in the prostate bed, after 
enrollment in the protocol 
• Regional failure: radiographic evidence (CT or MRI) of lymphadenopathy (lymph 
node size ≥ 1.0 cm in the short axis) in a patient without the diagnosis of a 
hematologic/lymphomatous disorder associated with adenopathy 
• Distant metastases: radiographic evidence of hematogenous spread (e.g., bone scan, 
CT, MRI) 

 
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• Progression: first occurrence of biochemical failure, local failure, regional failure, 
distant metastasis, initiation of new unplanned anticancer treatment, or death from 
any cause 
• Hormone-refractory disease: 3 rises in PSA during salvage androgen deprivation 
 
 
 
5. TREATMENT PLAN/REGIMEN DESCRIPTION 
 
5.1 Hormonal Therapy/Other Agent-Based Therapy (12-JUL-2022) 
 
ADT must begin no more than 42 days prior to registration and no later than 
21 days after registration. 
 
If a patient has been randomized to the enzalutamide arm and was started on 
bicalutamide prior, the bicalutamide should be stopped prior to starting 
enzalutamide. 
 
If a patient was started on abiraterone prior, abiraterone must be stopped 
prior to randomization. 
 
5.1.1 GnRH analog 
Administration: GNRH analogs should be administered per the package insert in 
any formulation, eg, monthly, multi-monthly, yearly, that is available to the site to 
provide a total of 24 month of therapy.   
 
5.1.2    Bicalutamide 
Administration: Patients randomized to the standard ADT arm may receive, at the 
physician’s discretion, bicalutamide 50 mg orally taken at approximately the same 
time each day (not mandatory). 
                     
Duration of Treatment: 1-4 months total 
 
5.1.3    Enzalutamide 
Administration: Patients randomized to enzalutamide will receive 160 mg (four 
40 mg capsules) orally once daily. Patients should take enzalutamide at 
approximately the same time each day. Enzalutamide should be started no later 
than 21 days after registration. 
 
Duration of Treatment: 24 months total (1 cycle = 90 days)  
 
Enzalutamide may be taken with or without food. Each capsule should be 
swallowed whole. Do not chew, dissolve or open the capsules. 
 
If a dose is missed, administer an additional dose and take the next dose of 
enzalutamide at the scheduled time. 
 

 
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See Section 6.0 for Enzalutamide dose management. 
 
5.2       Radiation Therapy ( 17-JUN-2021) 
 
Radiation treatment must begin within 0-70 days of initiation of GnRH 
analog therapy. Radiotherapy should be delivered over approximately 7-8 
weeks. 
 
Radiation Therapy Schema  
Prostatic Fossa  
66.6 – 70.2  Gy 1.8 Gy/fraction in 37-39 fractions  
66 – 70 Gy  2.0 Gy/fraction in 33-35 fractions 
 
Required Regional Pelvic Lymph Nodes  
45-50.4 Gy 1.8 Gy/fraction in 25-28 fractions 
44-50 Gy 2.0 Gy/fraction in 22-25 fractions 
 
There is great variability among physicians on how suspected or biopsy-proven 
lymph node(s) and/or prostatic fossa lesion are boosted. The following attempts to 
radiation oncologists significant flexibility. Consider the bulkiness of the 
suspected or biopsy proven lymph node and/or prostatic fossa lesion, small bowel, 
colon, bladder, sigmoid and rectum proximity when choosing the dose. Note that 
some boost strategies are more biologically aggressive than others. Section 5.2.7 
has EQD2 calculations that may be helpful when choosing the dose. Prioritize 
normal tissue dose constraints above dose escalation.  
 
There are 5 main decisions that the radiation oncologist has to make: 
1. Select 1.8 or 2 Gy fractions and the total dose to the prostatic fossa and 
dose to the regional pelvic lymph nodes. The next 4 items are at the 
discretion of the radiation oncologist and not mandatory. 
2. Are suspicious on imaging or biopsy proven lymph nodes being 
boosted? 
3. Are para-aortic lymph nodes from L5/S1 up to T12/L1 being treated 
electively (only if there is radiographic suspicion or biopsy proven 
lymph nodes in this area)? 
4. Is a prostatic fossa lesion (suspicious on imaging or biopsy proven) 
being boosted? 
5. If lymph nodes and/or a prostatic fossa lesion being boosted, is the 
approach concurrent or sequential? Choose ONE dose for all the lymph 
nodes. 
 
First choose either 1.8 Gy or 2 Gy fractions for treating the pelvis :  
• If 1.8 Gy per fraction, 
▪ Prostatic fossa 66.6 - 70.2 Gy in 1.8 Gy fractions 
▪ Pelvic lymph nodes to L5/S1 45 Gy – 50.4 Gy in 1.8 Gy fractions 
▪ Optional: If lymph node boost only. Choose either sequential or 

 
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concurrent: 
o If sequential 54 - 73.8 Gy in 1.8 Gy fractions 
o If concurrent with 45 Gy - 50.4 Gy pelvic lymph node radiation: 
50 – 61.6 Gy in 2 - 2.2 Gy fractions (25 – 28 fractions), 
respectively 
o Special case: If concurrent with 66.6 Gy pelvic lymph node and 
prostatic fossa radiation: 
74 Gy in 2 Gy per fraction (37 fractions). May be useful if just 
one very large/bulky lymph node is being boosted. 
▪ Optional: Para-aortics from L5/S1 anywhere up to T12/L1 at discretion 
of radiation oncologist, only if there is radiographic suspicion or biopsy 
proven lymph nodes in this area. Elective dose 45– 50.4 Gy in 1.8 Gy 
fractions. 
▪ Optional Prostate fossa lesion boost with or without lymph node 
boost(s): 
o Prostatic fossa lesion: sequential up to 73.8 Gy in 1.8 Gy fractions or 
the special case of concurrent to 74 Gy in 37 fractions of 2 Gy 
fractions when treating the prostate fossa to 66.6 Gy in 1.8 Gy 
fractions and NOT treating any lymph nodes in the prostate fossa 
o If lymph node boost. sequential only from 54 - 73.8 Gy in 1.8 Gy 
fractions 
• If 2 Gy per fraction, 
▪ Prostatic fossa 66 - 70 Gy in 2 Gy fractions 
▪ Pelvic lymph nodes 44 – 50 Gy in 2 Gy fractions 
▪ Optional: Lymph node boost only (not boosting prostatic fossa lesion). 
Choose either sequential or concurrent: 
o If sequential 54 - 70 Gy in 2 Gy fractions 
o If concurrent with 44 – 50 Gy pelvic lymph node radiation: 48.4 – 60 
Gy in 2.2 - 2.4 Gy fractions (22-25 fractions), respectively 
▪ Optional: Para-aortics from L5/S1 anywhere up to T12/L1 at discretion 
of radiation oncologist, only if there is radiographic suspicion or biopsy 
proven lymph nodes in this area. Elective dose 44 – 50 Gy in 2 Gy 
fractions. 
▪ Optional: Prostate fossa lesion boost with or without lymph node 
boost(s): 
o Prostatic fossa lesion boost: sequential only up to 74 Gy in 2 Gy 
fractions 
o If lymph node boost: sequential only 54 - 70 Gy in 2 Gy fractions 
 
5.2.1    Radiation Treatment Technology 
Photon energies ranging from 60Co to <18 MV are allowed. Treatment techniques 
such as 3D-conformal radiation therapy (CRT), intensity modulated radiation 
therapy (IMRT), volume modulated arc therapy (VMAT), MRLinac, Cyberknife 
or Tomotherapy are allowed. Use of IMRT is strongly encouraged to limit the 
radiation dose to bone marrow and normal structures in the pelvis.  All patients 
must undergo daily image guided radiation therapy (IGRT). 

 
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5.2.2    Immobilization 
Proper immobilization of patients is critical for this protocol.  An effective patient 
immobilization system reduces the inherent setup variability and minimizes 
margins.  Patient setup reproducibility must be achieved using appropriate 
immobilization devices.   
 
5.2.3    Simulation Imaging  
A treatment planning CT scan will be required to define the clinical and planning 
target volumes, and the critical normal structures. This CT will be acquired with 
the patient set up in the same position as for daily treatments. Each patient will be 
positioned in the supine position.   The CT scan of the pelvis should start at or 
above the iliac crest down to below the perineum (below the ischial tuberosities). 
All tissues to be irradiated must be included in the CT scan. CT slice thickness 
should be ≤ 0.3 cm through the region that contains the target volumes.  
 
Rectal Filling - An overly distended rectum can introduce a systematic 
positioning error that may increase the probability of missing the clinical target 
volume (CTV).  Patients should be simulated with the rectum as empty as 
possible and <3 cm in the anterior-posterior dimension is ideal. This can be 
achieved with an enema 1-2 hours prior to simulation.  If the size of the rectum is 
large due to flatus, a hollow catheter introduced into the rectum may be helpful.  
Rectal balloons for planning and treatment are not permitted on this protocol. 
 
Bladder Filling - Patients should also have a comfortably full bladder (the patient 
should not be uncomfortable at simulation because it is likely that he will have 
more difficulty maintaining a full bladder during treatment).  
 
5.2.4 Imaging for Structure Definition, Image Registration/Fusion and Follow-up 
MRI may be used to assist in volume delineation and precision in all eligible 
patients. However, care should be taken to ensure that the geometric and special 
orientation of the structure set are accurate on the treatment planning CT because 
CT is used for the dose calculation and basis for image guidance.   
 
A urethrogram or MRI may be performed, but is not required, to establish the most 
inferior portion of the prostate bed. Use of contrast, other than for the urethrogram, 
is discouraged. The placement of contrast in the rectum may cause the rectum to 
appear more anterior than it will be during treatment. 
 
5.2.5    Definition of Target Volumes and Margins 
Note: All structures must be named for digital RT data submission as listed in the 
table below.  The structures marked as “Required” in the table must be contoured 
and submitted with the treatment plan. Resubmission of data may be required if 
labeling of structures does not conform to the standard DICOM name listed.  
Capital letters, spacing and use of underscores must be applied exactly as 
indicated.  Please refer to Section 5.2.6 for a list and description of normal 

 
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structures to be contoured. 
 
Standard Name 
Description 
Validation 
 
CTV_N_xxxx 
if 1.8 Gy fractions: 
xxxx = 4500- 5040 
if 2.0 Gy fractions: 
xxxx = 4400-5000 
 
Regional pelvic lymph nodes: presacral nodes, the 
bilateral distal common iliac, external iliac, obturator 
nodes, or internal iliac to L5/S1 
 
Optional: Para-aortics from L5/S1 anywhere up to 
T12/L1 at discretion of radiation oncologist, only if there 
is radiographic suspicion or biopsy proven lymph nodes 
in this area. 
Required 
PTV_N_xxxx 
(xxxx = 4500 - 5040 or 
4400- 5000 as above) 
PTV expansion for the CTV_N_xxxx 
Required 
CTV_P_xxxx 
if 1.8 Gy fractions: 
xxxx = 6660 - 7020 
if 2.0 Gy fractions: 
xxxx = 6600 - 7000 
CTV including prostatic fossa and seminal vesicle 
remnants when present 
Required 
PTV_P_xxxx 
(xxxx =  6600 - 7020 as 
above) 
PTV expansion for the CTV_P_xxxx 
Required 
CTV_PELVIC_xxxx 
(xxxx = 4500 - 5040 or 
4400 - 5000 per the 
CTV_N_xxxx) 
CTV_P_xxxx (including prostatic fossa, seminal vesicle 
remnants when present) and the CTV_N_xxxx (regional 
lymph nodes: presacral nodes, and the bilateral distal 
common iliac, external iliac, internal iliac, and obturator 
nodes) 
 
Optional:Para-aortics from L5/S1 anywhere up to 
T12/L1 at discretion of radiation oncologist, only if there 
is radiographic suspicion or biopsy proven lymph nodes 
in this area. 
Required 
PTV_PELVIC_xxxx 
(xxxx = 4500- 5040 or 
4400 - 5000 as above) 
PTV expansion for the CTV_PELVIC_xxxx 
Required 
Optional  Lymph Node Treatment 
 
GTV_LNX_xxxx 
(X= 1-10 
xxxx = 4840 – 7400) 
Select ONE dose for all 
lymph nodes. See section 
5.2.7 for dosing details 
At the discretion of the radiation oncologist, suspicious 
lymph nodes for metastatic disease in the radiology 
report (CT, MRI, molecular imaging [i.e. choline PET, 
FACBC, PSMA]) and/or biopsy proven lymph nodes 
may be boosted no higher than T12/L1. These may be 
presacral, bilateral distal common iliac, external iliac, 
obturator, internal iliac, perirectal, inguinal or low 
paraaortic lymph nodes. 
 
Required when 
applicable 

 
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GTV_LN_xxxx 
(xxxx = 4840 – 7400 
as above) 
All GTV_LNX_xxxx summed 
Required when 
applicable 
CTV_LN_xxxx  
(xxxx= 4840 – 7400 
as above) 
CTV expansion of the GTV_LN_xxxx 
Required when 
applicable 
PTV_LN_xxxx  
(xxxx= 4840 – 7400 
as above)  
PTV expansion of the CTV_LN_xxxx 
Required when 
applicable 
Optional Prostatic Fossa Lesion Boost 
Please note that these contours ONLY apply when boosting a prostate fossa lesion/nodule. 
GTV_PB_xxxx 
 
if 1.8 Gy fractions,  
xxxx = up to 7380 
sequential 
xxxx = 7400 in 37 
fractions of 2 Gy 
concurrent when treating 
the prostate fossa to 6660 
cGy in 1.8 Gy fractions 
 
if 2.0 Gy fractions: 
xxxx = up to 7400 
ONLY SEQUENTIAL if boosting both Prostatic Fossa 
Lesion(s) Lymph Node volume(s). 
 
SEQUENTIAL prostatic fossa lesion boosts are allowed 
when treating the prostatic fossa at 1.8 Gy or 2 Gy per fraction 
 
CONCURRENT prostatic fossa lesion boosts allowed 
ONLY in the following Special Case: 
74 Gy in 37 fractions of 2 Gy fractions when treating the 
prostate fossa to 66.6 Gy in 1.8 Gy fractions.  
**No Lymph Node boost(s) treatment allowed with the 
special case** 
 
At the discretion of the radiation oncologist, a suspicious 
prostatic fossa lesion in the radiology report (CT, MRI, 
molecular imaging [i.e. choline PET, FACBC, PSMA]) and/or 
biopsy proven prostatic fossa lesion may be boosted. 
Required 
when 
applicable 
CTV_PB_xxxx 
CTV expansion of the GTV_PB_xxxx 
 
Required 
when 
applicable 
PTV_PB_xxxx 
PTV expansion of the PTV_PB_xxxx  
Required 
when 
applicable 
 
 
Abbreviations: P = Prostatic fossa; LN = lymph node; N = nodal; PB = Prostatic fossa boost 
 
Detailed Specifications 
CTV_N_xxxx: Regional pelvic lymph nodes: presacral nodes, the bilateral distal 
common iliac, external iliac, obturator nodes, or internal iliac to L5/S1 
 
Pelvic Lymph Node Volumes for Prostate Cancer Atlas 
http://www.rtog.org/CoreLab/ContouringAtlases/ProstatePelvicLymphNodes.aspx 
 

 
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The iliac nodes will be derived by contouring the distal common iliac, and external and 
internal iliac vessels starting superiorly at L5-S1. First, the external iliac vessels will 
be contoured inferiorly to the top of the femoral heads and the internal iliac vessels will 
be contoured inferiorly until they are no longer visible on the CT scan or exit through 
the true pelvis via the greater sciatic notch.  
 
Second, the iliac vessels are expanded by 7 mm in the anterior, posterior and lateral 
dimensions, but not the superior and inferior dimensions. Muscles and bone should be 
excluded from the 7 mm expansion. Bowel and bladder may be excluded after the 7 
mm expansion. 
 
Third, with an approximately 1 cm diameter brush (use your clinical judgement) the 
obturator and presacral nodes are added avoiding bone and muscle. The obturator nodes 
will encompass tissue medial to the obturator internus muscles extending from the 
anterior border of the ilium to the posterior border of the ilium. The obturator nodes 
will be contoured starting superiorly where the internal and external iliac vessel 
contours stop and extend inferiorly to the top of the symphysis pubis. The presacral 
nodes will extend from L5-S1 to the top of S3.  
 
Optional: Para-aortics from L5/S1 anywhere up to T12/L1 at discretion of radiation 
oncologist, only if there is radiographic suspicion or biopsy proven lymph nodes in 
this area. 
 
PTV_N_xxxx: The PTV_N_xxxx will be a direct expansion of 0.5-1.0 cm beyond the 
CTV_N_xxxx.   
**More generous PTV expansion of the nodal CTV_N_xxxx within this range as 
compared to the prostatic fossa CTV_P_xxxx is allowed to account for potentially more 
set-up variability in the CTV_N_xxxx when daily set-up is defined by prostatic fossa 
CTV parameters.  Additional expansion within this range is required to account for the 
penumbra when 3D CRT is used. 
 
CTV_P_xxxx:  The contouring of the prostate bed should be in accordance with the 
RTOG consensus guidelines (Michalski 2010).  
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847420/ 
 
Briefly, the CTV should extend superiorly from the level of the caudal vas deferens 
remnant to >8-12 mm inferior to vesicourethral anastomosis (VUA). Below the 
superior border of the pubic symphysis, the anterior border extends to the posterior 
aspect of the pubis and posteriorly to the rectum, where it may be concave at the level 
of the VUA. At this level, the lateral border extends to the levator ani. Above the 
pubic symphysis, the anterior border should encompass the posterior 1-2 cm of the 
bladder wall; posteriorly, it is bounded by the mesorectal fascia. At this level, the 
lateral border is the sacrorectogenitopubic fascia. Seminal vesicle remnants, if 
present, should be included in the CTV if there is pathologic evidence of their 
involvement. 
 

 
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Prostate Bed Positive Apex Margins Sample Contour 
https://www.rtog.org/LinkClick.aspx?fileticket=mF9BE8qM8xA%3d&tabid=232 
 
Prostate Bed Positive Seminal Vesicle Sample Contour 
https://www.rtog.org/LinkClick.aspx?fileticket=_znZLMP1yco%3d&tabid=232 
 
PTV_P_xxxx: The PTV_P_xxxx margins should be a minimum of 0.5 cm and a 
maximum of 1.0 cm in all dimensions beyond the CTV_P_xxxx.  Care should be 
taken to conform the prescribed dose as closely to the PTV as possible, so as to avoid 
including the entire width of the rectum in the posterior blocked margin at the bladder 
neck-rectum interface.   
 
CTV_PELVIC_xxxx: The CTV_PELVIC_xxxx will include the CTV_P_xxxx 
(including prostatic fossa, seminal vesicle remnants when present) and the 
CTV_N_xxxx (regional lymph nodes: presacral nodes, and the bilateral distal common 
iliac, external iliac, internal iliac, and obturator nodes). 
 
PTV_PELVIC_xxxx: The PTV_PEVLIC_xxxx will include the PTV_P_xxxx 
(including prostatic fossa, seminal vesicle remnants when present) and the 
PTV_N_xxxx (regional lymph nodes: presacral nodes, and the bilateral distal 
common iliac, external iliac, internal iliac, and obturator nodes) 
 
Optional lymph node treatment (imaging suspicious or biopsy proven) 
 
GTV_LNX_xxxx: At the discretion of the radiation oncologist, suspicious lymph 
nodes for metastatic disease in the radiology report (CT, MRI, molecular imaging [i.e. 
choline PET, FACBC, PSMA]) and/or biopsy proven lymph nodes may be boosted 
no higher than T12/L1. 
 
Fusing the simulation CT and the diagnostic imaging showing the suspicious lymph 
node(s) and discussing the findings with the radiologist is encouraged.   
 
GTV_LN_xxxx: A summation of all the GTV_LNX_xxxx. 
 
CTV_LN_xxxx: CTV expansion of the GTV_LN_xxxx is at the discretion of the 
radiation oncologist. Keep in mind the total expansion from the GTV_LN_xxxx to the 
PTV_LN_xxxx should be a minimum of 0.5 cm and a maximum of 1 cm. 
 
PTV_LN_xxxx: PTV expansion of the CTV_LN_xxxx. The total expansion from the 
GTV_LN_xxxx to the PTV_LN_xxxx should be a minimum of 0.5 cm and a maximum 
of 1 cm. The PTV_LN_xxxx should not overlap more than 0.5 cm with a bowel loop 
and ideally abut it at the most. 
 
The simplest strategy to meet the lymph node expansion criteria is to expand the 
GTV_LN_xxxx by 0.5 cm, and then expand the resulting CTV_LN_xxxx between 0 to 

 
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0.5 cm to get the PTV_LN_xxxx. You can then erase the PTV_LN_xxxx as far back 
as the CTV_LN_xxxx where the bowel is close by to any given node (see Figure 1). 
 
Optional prostate fossa boost (imaging suspicious or biopsy proven) 
 
GTV_PB_xxxx: At the discretion of the radiation oncologist, a suspicious prostatic 
fossa lesion in the radiology report (CT, MRI, molecular imaging [i.e. choline PET, 
FACBC, PSMA]) and/or biopsy proven prostatic fossa lesion may be boosted.  
** See previous table for further guidance  
CTV_PB_xxxx: expand the GTV_PB_xxxx by 0.5 cm. 
 
PTV_PB_xxxx: expand the CTV_PB_xxxx between 0.5 and 1 cm. 
 
5.2.6 Definition of Critical Structures and Margins 
Note: All structures must be named for digital RT data submission as listed in the table 
below. The structures marked as “Required” in the table must be contoured and submitted 
with the treatment plan. Resubmission of data will be required if labeling of structures 
does not conform to the standard DICOM name listed. Capital letters, spacing, and use of 
underscores must be applied exactly as indicated. 
 
Standard Name  
Description  
Validation 
Rectum 
Per Male RTOG Normal Pelvis 
Atlas 
Required 
Bladder 
Per Male RTOG Normal Pelvis 
Atlas 
Required 
Femur_L 
Per Male RTOG Normal Pelvis 
Atlas 
Required 
Femur_R 
Per Male RTOG Normal Pelvis 
Atlas 
Required 
PenileBulb 
Per Male RTOG Normal Pelvis 
Atlas 
Required 
External 
External patient contour 
Required 
E-PTV 
External minus PTVs 
Required 
Bowel 
BowelBag per Male RTOG 
Normal Pelvis Atlas, but close 
to the lymph node(s) being 
treated you may reduce the 
volume to include just the bowel 
loops (Colon, Small Bowel, 
and/or Sigmoid) to help meet 
dose constraints. 
Required  
 
Male Pelvic Atlas 
http://www.rtog.org/CoreLab/ContouringAtlases/MaleRTOGNormalPelvisAtlas.aspx 
            

 
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Rectum:   Inferiorly from the lowest level of the ischial tuberosities (right or left). 
Contouring ends superiorly before the rectum loses its round shape in the axial plane and 
connects anteriorly with the sigmoid.  
 
Bladder: Inferiorly from its base, and superiorly to the dome 
  
Femurs:  The proximal femur inferiorly from the lowest level of the ischial tuberosities 
(right or left) and superiorly to the top of the ball of the femur, including the trochanters. 
Tips: Auto-contouring threshold parameters with bone can facilitate this process, but 
requires editing any auto-contouring artifacts. 
  
PenileBulb:  That portion of the bulbous spongiosum of the penis immediately inferior to 
the GU diaphragm. Do not extend this structure anteriorly into the shaft or pendulous 
portion of the penis. Tips: The penile bulb is best identified with MRI (bright on T2) or 
CT when there is contrast in the urethra. On CT, the penile bulb will be posterior to the 
urethra and has a round shape. Refer to article by Wallner et al. PubMed ID: 12095559  
 
 
 
External:   The skin encompassing all CT slices from 1.5 cm inferior to superior of the 
radiation fields. 
 
E-PTV: External patient contour minus all PTV volumes. 
 
Bowel: BowelBag per Male RTOG Normal Pelvis Atlas, but close to the lymph node(s) 
being treated you may reduce the volume to include just the bowel loops (colon, small 
bowel, and/or sigmoid) to meet dose constraints.  
 
Most importantly, carefully delineate the bowel next to the PTV_LN_xxxx which is what 
is most relevant.  The PTV_LN_xxxx should not overlap more than 0.5 cm with a bowel 
loop and ideally abut it at the most. 
 
5.2.7    Dose Prescription 
Note: The information provided in this section can be used for adjusting the dose 
constraints for treatment planning purposes.  This table together with the planning 
priority table should be used during dose optimization.  It is important to 
remember that ideal plans might not be achievable in all cases.  Thus, the 
Compliance Criteria table could be different than the information given here.  
Cases will be scored using the Compliance Criteria table. 
 
Mandatory PTVs 
 
Target Standard Name Dose (Gy) Fraction 
Size (Gy) 
# of 
fractions  
Dose specification 
technique 
PTV_P_xxxx 
66.6 - 70.2 
1.8 
37 - 39 
Covering ≥ 95% of PTV 
 
66 - 70 
2.0 
33 - 35 
Covering ≥ 95% of PTV 
PTV_N_xxxx 
45 – 50.4 
1.8 
25 - 28 
Covering ≥ 95% of PTV 

 
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44 - 50 
2.0 
22 - 25 
Covering ≥ 95% of PTV 
PTV_PELVIC_xxxx 
45 - 50.4 
1.8 
25 - 28 
Covering ≥ 95% of PTV 
 
44 -50  
2.0 
22 - 25  
Covering ≥ 95% of PTV 
 
Optional lymph node boost 
The optional lymph node(s) boost can be done either sequentially or concurrently 
as described below. The dose and fractionation is left at the discretion of the 
radiation oncologist but should be within the concurrent and sequential ranges 
below. Prioritize normal tissue dose constraints above dose escalation.  
 
Select ONE dose for all lymph nodes. If also boosting the prostatic fossa 
(PTV_PB_xxxx), SEQUENTIAL prostatic fossa AND lymph node boosts are 
allowed. (Concurrent boosts to prostatic fossa lesions are only allowed in one 
special case as described in the section 5.2.5 table). 
 
WARNING: When boosting lymph nodes using a concurrent approach, if the 
lymph nodes are inferior enough, clinically significant hot spots may result. This is 
bound to happen when the concurrent boost delivered to the lymph nodes overlaps 
with scattered dose from the subsequent prostate bed boost. This could result in hot 
spots near the rectum, bladder or small bowel. A sequential approach may be best 
in these situations. 
 
Target 
Standard 
Name 
Lymph Node Boost 
Type 
(Choose one) 
Dose (Gy) Fraction 
Size (Gy) 
# of 
fractions  
Dose specification 
technique 
Using 1.8 Gy 
fractions: 
 
 
 
 
 
PTV_LN_xxxx 
Sequential to  
PTV_PELVIC_xxxx 
54 - 73.8 
1.8 
30 - 41 
Covering ≥ 95% of 
PTV 
PTV_LN_xxxx 
Concurrent with 
PTV_PELVIC_xxxx 
50 – 61.6 
2 – 2.2 
25 - 28 
Covering ≥ 95% of 
PTV 
PTV_LN_xxxx 
(special case) 
Concurrent 
with 
PTV_PELVIC_4500 
and 
PTV_P_6660 
74 
2 
37 
Covering ≥ 95% of 
PTV 
Using 2.0 Gy 
fractions: 
 
 
 
 
 
PTV_LN_xxxx 
Sequential to 
PTV_PELVIC_xxxx 
54 - 70 
2 
27 - 35 
Covering ≥ 95% of 
PTV 
PTV_LN_xxxx 
Concurrent 
with 
PTV_PELVIC_xxxx 
48.4 - 60 
2.2 - 2.4 
22-25 
Covering ≥ 95% of 
PTV 

 
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EQD2 for the Lymph Node Boost Various Fractionation Schemes if choice was 1.8 Gy 
fractions for pelvis and prostatic fossa: 
 
Dose 
(Gy) 
Fraction 
Size (Gy) 
# of 
fractions 
EQD2 (Gy) 
normal 
tissues  
(α/β = 3) 
EQD2 (Gy) 
prostate 
cancer 
(α/β = 1.5) 
 
Boost technique 
54 - 73.8 
1.8 
30 - 41 
52 - 71 
51 - 70 
Sequential to 
PTV_PELVIC_xxxx 
50 – 61.6 
2 - 2.2 
25 - 28 
50 - 64 
50 - 65 
Concurrent with 
PTV_PELVIC_xxxx 
74 
2.0 
37 
74 
74 
Special case: 
concurrent with  
PTV_PELVIC_4500 
and 
PTV_P_6660 
 
 
EQD2 for the Lymph Node Boost Various Fractionation Schemes if choice was 2.0 Gy 
fractions for pelvis and prostatic fossa: 
 
Dose (Gy) 
Fraction 
Size (Gy) 
# of 
fractions 
EQD2 
(Gy) 
normal 
tissues  
(α/β = 3) 
EQD2 (Gy) 
prostate 
cancer 
(α/β = 1.5) 
 
Boost technique 
54 - 70 
2.0 
27 - 35 
54 - 70 
54 - 70 
Sequential to 
PTV_PELVIC_xxxx 
48.4 - 60 
2.2 - 2.4 
22 - 25 
50 - 65 
51 - 67 
Concurrent with 
PTV_PELVIC_xxxx 
 
Optional prostatic fossa boost 
 
Target Standard 
Name 
Dose (Gy) 
Fraction 
Size (Gy) 
# of 
fractions  
Dose specification 
technique 
PTV_PB_xxxx 
Sequential up 
to 73.8 
1.8 
up to 41 
Covering ≥ 95% of PTV 
 
Sequential up 
to 74 
2.0 
up to 37 
Covering ≥ 95% of PTV 
 
** Concurrent 
to 74 
2.0 
Up to 37 
Covering ≥ 95% of PTV 
**Concurrent prostatic fossa lesion boost allowed in Special Case Only (see Section 5.2.5)  

 
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5.2.8          Compliance Criteria 
The compliance criteria listed here will be used to score each case.  Given the 
limitations inherent in the treatment planning process, the numbers given in 
this section can be different than the prescription table.  The Per Protocol and 
Variation Acceptable categories are both considered to be acceptable.  The Per 
Protocol cases can be viewed as ideal plans, and the Variation Acceptable 
category can include more challenging plans that do not fall at or near the 
ideal results.  A final category, called Deviation Unacceptable, results when 
cases do not meet the requirements for either Per Protocol or Variation 
Acceptable. Plans falling in this category are considered to be suboptimal and 
additional treatment planning optimization is recommended. 
 
Normalization of Dose. The plan is normalized such that 95% of the 
PTV_P_xxxx volume receives prescription dose of 66.0-70.2 Gy. 
 
Note: Deviation Unacceptable occurs when dose limits for Variation 
Acceptable are not met 
 
Target Volume Constraints and Compliance Criteria 
 
Structure 
Dosimetric 
Parameter 
Per Protocol 
Variation Acceptable 
PTV_P_xxxx 
 
 
V100%[%] 
>= 95 
>=94 
D0.03cc[%] 
<= 115 
<= 120 
D99%[%] 
>= 95 
>= 93 
PTV_PELVIC_4500 
(4680, 4860, 5040) 
 (1.8 Gy/fraction) 
D95%[Gy] 
>=45 
>= (46.8, 48.6, 50.4) 
>=43 
>= (44.8, 46.6, 48.4) 
PTV_PELVIC_4400 
(4600, 4800, 5000) 
(2.0 Gy/fraction) 
D95%[Gy] 
>=44 
>= (46, 48, 50) 
>=42 
>= (44, 46, 48) 
PTV_LN_xxxx 
(optional) 
D95%[%] 
>=95 
>=85 
PTV_PB_xxxx 
(Optional) 
D95%[%] 
>=95 
>=85 
Per Protocol, range is excluded from Variation Acceptable range. 
 
Normal Structure Constraints and Compliance Criteria 
The following normal tissue dose constraints represent the minimum level of acceptability for 
protocol therapy.  Whenever possible, maximal sparing of normal tissues should be achieved to 
minimize the risk of toxicity. 
 
Normal Tissue Dose Constraints 
Structure 
Dosimetric 
Per Protocol 
Variation Acceptable 

 
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Parameter 
Rectum 
V40 Gy[%] 
V65 Gy[%] 
<= 55 
<= 35 
<= 60 
<= 39 
Bladder 
V40 Gy[%] 
V65 Gy[%] 
<= 70 
<= 50 
<= 77 
<= 55 
Femur_L 
V50 Gy[%] 
< 10 
< 11 
Femur_R 
V50 Gy[%] 
< 10 
< 11 
E-PTV 
D0.03cc[%]* 
<=110  
<=112 
*If the global maximum exceeds 107% check if a concurrently treated lymph node overlaps with 
the sequentially treated prostate bed. 
 
Carefully delineate the bowel next to the PTV_LN_xxxx. The PTV_LN_xxxx should not overlap 
more than 0.5 cm with a bowel loop and ideally abut it at the most. 
 
Figure 1 A. PTV_LN_xxxx (pink) ideally abutting small bowel. GTV_LN1_xxxx, red.
 
 
Figure 1 B. PTV_LN_xxxx (pink) overlaps less than 0.5 cm of small bowel. GTV_LN1_xxxx, 
red. 

 
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Structure 
Lymph Node 
Boost Type 
Dosimetric 
Parameter 
Per Protocol 
Variation Acceptable 
Bowel 
(Optional) 
Concurrent 
V53 Gy[cc] 
V60 Gy[cc] 
<= 3.5 * (# of 
lymph nodes) 
<= 1 * (# of lymph 
nodes) 
<= 4.5 * (# of lymph 
nodes) 
<= 2 * (# of lymph 
nodes) 
Bowel 
(Optional) 
Sequential 1.8 or 
2.0 Gy/fraction 
V55 Gy [cc] 
V65 Gy [cc] 
<= 3.5 * (# of 
lymph nodes) 
<= 1 * (# of lymph 
nodes) 
<= 4.5 * (# of lymph 
nodes) 
<= 2 * (# of lymph 
nodes) 
 
For example, a patient with 3 lymph nodes receives a sequential boost of 64.8 Gy. Meeting the 
Bowel V55 Gy<= (3.5 * 3) = 10.5 cc, and the V65 Gy<= (1 * 3) = 3 cc would be per protocol. A 
patient with 2 lymph nodes receives a concurrent boost of 55 Gy. Meeting the Bowel V53 Gy<= 
(3.5 * 2) = 7 cc, and the V60 Gy<= (1 * 2) = 2 cc would be per protocol.  
 
 
 
Recommended dose acceptance criteria for other normal tissue, but not to be used for plan score 

 
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Structure 
Recommended dose acceptance criteria 
PenileBulb 
Mean[Gy] <= 52.5 Gy 
 
Delivery Compliance criteria 
 
 
Per Protocol 
Variation Acceptable 
RT start date 
<= 70 days after start of GnRH 
therapy 
N/A 
Interruptions 
1-7 days 
8-14 days 
 
Note: A delay in RT start outside the Per Protocol window is considered a Protocol Deviation. 
 
5.2.9 Treatment Planning Priorities and Instructions 
 
In order of priority, the following critical structures are listed in order of 
decreasing importance. The following list is given as an example 
1. PTV_P_xxxx 
2. PTV_PB_xxxx 
3. PTV_PELVIC_xxxx 
4. Bowel 
5. Rectum  
6. PTV_LN_xxxx 
7. Bladder 
8. Femurs_L\R 
9. PenileBulb 
 
• Beam arrangement  
Static gantry IMRT beam arrangements must be designed with a minimum of 5 
gantry angles.  If the beams are intercepted by a non-IGRT couch, the couch 
should be included in the treatment plan.  For VMAT plans ≤ 2 arcs is 
recommended.  
  
• Acceptable algorithms   
The following is a list of acceptable algorithms for dose calculation: 
Convolution/Superposition, AAA, Monte Carlo and Collapsed Cone Convolution. 
All doses should be reported in terms of dose-to-water and not in terms of dose-
to-medium.  
  
• Dose matrix resolution  
Dose grid size should be ≤ 3 mm in all directions.  
 
5.2.10  Patient specific QA  
 
Any patient-specific QA that needs to be performed should follow institutional 
guidelines.  
 

 
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For photon IMRT/VMAT plans, patient specific QA is highly recommended. QA 
is performed by delivering the plan onto a phantom and measuring the dose using 
an ion chamber array or other 2D/3D device. Measured dose distribution will be 
compared to planned dose distribution using a Gamma criterion of 3% dose 
difference and 3 mm distance to agreement. The pass rate should be ≥ 90% 
measured for the entire plan when excluding points less than 10% of the 
maximum dose. 
 
5.2.11        Daily Treatment Localization/IGRT  
Image-guided radiation therapy (IGRT) is radiation therapy using imaging to 
facilitate accuracy and precision throughout its entire process from target and 
normal tissue delineation, to radiation delivery, to adaptation of therapy to 
anatomic and biological changes over time in individual patients. In this 
section, we use the terminology IGRT to focus on image-guidance at the time 
of radiation delivery to ensure its adherence to the planned treatment. 
 
At the start of each fraction, patients should be initially positioned by laser 
alignment of skin surface tattoos.   
 
Daily IGRT is required.  Fiducial marker placement is preferred but not 
required. Daily fiducial based volumetric IGRT is ideal because fiducials aid 
in the interpretation by radiation therapists. If fiducial markers are not present, 
volumetric IGRT based on soft-tissue alignment needs to be performed.  
Finally, volumetric 3D IGRT is preferred because bladder and rectal filling 
can be assessed for patient coaching purposes.  Orthogonal 2D kV imaging 
requires fiducials.   Electromagnetic transponders or transabdominal 
ultrasound to identify the VUA may also be used for daily IGRT. 
 
Three fiducial markers or electromagnetic transponders may be placed in the 
prostate bed. At least one near the vesicourethral anastomosis (VUA) and two 
in the retrovesical (RV) space under sterile conditions with antibiotic 
prophylaxis consistent with local practice standards.   The three markers or 
electromagnetic transponders should be identified and contoured on the 
simulation CT. The appropriate shifts should be made to ensure daily 
registration of the markers or transponders with the position defined by the 
treatment plan. 
 
All image/signal-guidance data should be recorded, archived at the site, and 
available for review, if requested. 
 
Management of Radiation Dose to the Patient from IGRT  
RTOG Foundation is concerned about the estimated doses given from IGRT, 
and is committed to limiting the imaging dose when IGRT is used in any of its 
protocols. This can be accomplished by avoiding the use of this technology to 
make small changes in patient positioning that are within the stated PTV 
margins. The imaging dose to the patient may become significant if repeated 
studies are done for patients with severe set up problems (e.g. requiring frequent 

 
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corrections that are larger than the PTV margins). It is recommended that 
patients demonstrating severe set up problems during the first week of treatment 
be moved to a treatment with larger margins. 
 
5.3      General Concomitant Medication and Supportive Care Guidelines 
5.3.1    Permitted Supportive/Ancillary Care and Concomitant Medications 
 
All supportive therapy for optimal medical care will be given during the study 
period at the discretion of the attending physician(s) within the parameters of the 
protocol and documented on each site’s source documents as concomitant 
medication. 
▪ Anticonvulsants 
▪ Antiemetics 
▪ Anticoagulants 
▪ Antidiarrheals 
▪ Analgesics 
▪ Hematopoietic Growth Factors 
▪ Herbal products 
▪ Nutritional supplementation 
 
5.3.2    Drugs That May Affect Exposure to Enzalutamide 
 
Drugs That Inhibit or Induce CYP2C8 
Coadministration of a strong CYP2C8 inhibitor (eg, gemfibrozil) increased the 
composite AUC0-∞ of enzalutamide plus its active metabolite in healthy 
volunteers by 2.2-fold; therefore, coadministration of enzalutamide with strong 
CYP2C8 inhibitors should be avoided if possible. If coadministration of 
enzalutamide with strong CYP2C8 inhibitors cannot be avoided, the enzalutamide 
dose should be reduced to 80 mg once daily. If coadministration of the strong 
inhibitor is discontinued, the enzalutamide dose should be returned to the dose 
used before initiation of the strong CYP2C8 inhibitor. 
The effects of CYP2C8 inducers on the PK of enzalutamide have not been 
evaluated in vivo. Coadministration of enzalutamide with strong or moderate 
CYP2C8 inducers (eg, rifampin) may alter the plasma exposure of enzalutamide 
and should be avoided if possible. Selection of a concomitant medication with no 
or minimal CYP2C8 induction potential is recommended. 
 
Drugs That Induce CYP3A4 
The effects of CYP3A4 inducers on the PK of enzalutamide have not been 
evaluated in vivo. Coadministration of enzalutamide with strong CYP3A4 
inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, 
rifapentine) may decrease the plasma exposure of enzalutamide and should be 
avoided if possible. Selection of a concomitant medication with no or minimal 
CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (eg, 
bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also 
reduce the plasma exposure of enzalutamide and should be avoided if possible. 
 

 
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5.3.3    Prohibited Concomitant Medications 
Medications that lower seizure threshold and other investigational compounds 
(non-FDA approved therapies for prostate cancer). 
 
5.4       Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may 
continue as specified in the above treatment modality sections or until one of the 
following criteria applies: 
▪ 
Disease progression, 
▪ 
Intercurrent illness that prevents further administration of treatment, 
▪ 
Unacceptable adverse event(s), 
▪ 
Patient decides to withdraw consent for participation in the study, or 
▪ 
General or specific changes in the patient's condition render the patient 
unacceptable  
 
6. TREATMENT MODIFICATIONS/MANAGEMENT 
NOTE:  PRO-CTCAE data should not be used for determining dose delays or dose 
modifications or any other protocol directed action.  
 
            6.1  
Dose Levels 
 
Enzalutamide 
# of Capsules 
(taken at approximately the same time each day) 
Original dose 
160 mg 
4 
Dose level -1 
120 mg 
3 
Dose level -2 
80 mg 
2 
 
Dose reductions, once initiated, are permanent for all future cycles. Re-escalation 
may be attempted after discussion with the Principal Investigator, Dr. Edwin 
Posadas. 
 
If enzalutamide is co-administered with a strong CYP2C8 inhibitor, the dose of 
enzalutamide should be reduced to 80 mg (two 40 mg capsules) once daily. If co-
administration of the strong CYP2C8 inhibitor is discontinued, the enzalutamide 
dose should return to the dose used before initiation of the strong CYP2C8 
inhibitor.  
 
6.2       Management of Toxicity Related to Enzalutamide (16-MAR-2021) 
Patients who experience a grade 3 or higher toxicity that is attributed to 
enzalutamide and cannot be ameliorated by the use of adequate medical 
intervention will interrupt treatment with enzalutamide for 1 week or until the 
toxicity grade improves to grade 2 or lower severity. Similarly, patients with 
persistent and intolerable grade 2 toxicity that does not improve with adequate 
medical intervention may also have enzalutamide held for 1 week or until the 
toxicity improves to grade 1 or better. Subsequently, study drug dosing may be 
restarted at the original dose or a reduced dose (see table above) in consultation 

 
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with the medical oncology co-chair.  
 
For grade ≥ 3 events of ischemic heart disease, treatment with enzalutamide 
should be stopped. 
 
If enzalutamide must be held for more than 4 weeks, the patient should 
permanently discontinue therapy. 
 
6.3  
Overdose Management 
The medical oncology chair, Dr. Edwin Posadas must be contacted in the event of 
an enzalutamide overdose.  
 
An overdose is defined as any dose greater than the protocol-specified dose of 
enzalutamide 160 mg once daily. In the event of an overdose, treatment with 
study drug should be stopped and general supportive measures initiated, taking 
into consideration the half-life is 5.8 days for enzalutamide. Patients may be at 
increased risk of seizures following an overdose of enzalutamide. There is no 
known antidote to overdose.  
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1  
Protocol Agents  (22-AUG-2019) 
Investigational Agent 
The investigational agent, enzalutamide, administered in RTOG 3506 is IND 
exempt and is distributed by a third party drug distributor.   
Commercial Agents 
The commercial agents in RTOG 3506 are Bicalutamide and GnRH analog. 
 
To determine whether an adverse event meets expedited reporting criteria see the 
reporting tables in section 7.4 of the protocol. 
 
7.1.1 Adverse Events for Investigational Study Agents (Enzalutamide) 
Investigators must obtain the current version of the enzalutamide Investigator 
Brochure (IB) for comprehensive pharmacologic and safety information. The IB 
can be accessed on the RTOG Foundation 3506 protocol page of the RTOG 
website, www.rtog.org. Sites must use their username and password to access the 
protocol page and the IB.  
 
7.1.2 Adverse Events for Commercial Study Agents  
Refer to the package insert for detailed pharmacologic and safety 
information 
 
7.2      Adverse Events (AEs) (02-DEC-2019) 
This study will use the Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 for adverse event reporting.  All appropriate treatment areas should have 
access to a copy of the CTCAE version 5.0. 
 

 
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7.2.1  Definition of an Adverse Event (AE)  
Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  Therefore, an AE can be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product 
(attribution of unrelated, unlikely, possible, probable, or definite). (International 
Conference on Harmonisation [ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of 
protocol treatment including radiation therapy, surgery, device, and drug. 
 
AEs, as defined above, experienced by patients accrued to this protocol should be 
reported on the AE section of the appropriate case report form (see Section 12.1).  
 
Clinician graded CTCAE is the AE safety standard.  PRO-CTCAE items are to 
complement CTCAE reporting.  Patients will respond to PRO-CTCAE items but 
no protocol directed action will be taken. The specific PRO-CTCAE items for this 
protocol can be found on the forms section of the 3506 protocol webpage on the 
RTOG Foundation website and is titled “RTOGF 3506 NCI PRO-CTCAE Item 
Library.” PRO-CTCAE is not intended for expedited reporting, real time review or 
safety reporting. PRO-CTCAE data are not currently intended for use in data 
safety monitoring or adverse event stopping rules. 
 
NOTE: If the event is a Serious Adverse Event (SAE) (see next section), further 
reporting will be required. Reporting AEs only fulfills Data Management reporting 
requirements.  
 
7.2.2 Adverse Event of Special Interest 
The following adverse events of special interest must be reported expeditiously via 
the SAE report form in Rave within 24 hours of awareness regardless of grade: 
▪ Seizure or loss of consciousness 
▪ Posterior reversible encephalopathy syndrome (symptoms include seizure, 
headache, confusion, reduced eyesight, blurred vision) 
 
7.2.3 Overdose 
 
An overdose as defined in Section 6.3 should be reported expeditiously via the SAE 
report form in Rave within 24 hours of awareness. 
 
7.2.4 Adverse Events and PRO-CTCAE 
The PRO-CTCAE instrument will be used to assess patient reported toxicity 
outcomes.  
 
PRO-CTCAE is a validated instrument developed by the National Cancer Institute 
to assess clinical trial toxicity outcomes by patient report; it complements 
information collected by physician-reported CTCAE. It characterizes the frequency, 

 
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severity and interference of 78 symptomatic treatment toxicities [Basch 2014]. 
These include symptomatic toxicities such as pain, fatigue, nausea, and cutaneous 
side effects such as rash and hand-foot syndrome.  Items are scored on a Likert 
scale (e.g., for severity, 0=none, 1=mild, 2=moderate, 3=severe, and 4=very 
severe).  PRO-CTCAE is available in English, Spanish, and French for this study.   
 
PRO-CTCAE assessments will be collected before registration and as specified in 
the Section 4 assessment tables. 
 
The patient-reported AEs that will be assessed using PRO-CTCAE are listed in the 
table below. These adverse events are considered expected and, if reported, should 
also be clinician graded using the CTCAE v.5. 
 
CTCAE v.5  
PRO-CTCAE Items With Attributes 
Fatigue 
Fatigue (severity, interference) 
Pain 
Pain (frequency, severity, interference) 
Abdominal Pain 
Abdominal Pain (frequency, severity, interference) 
Breast pain; 
Gynecomastia 
Breast swelling and tenderness (severity) 
Hot flashes 
Hot flashes (frequency, severity) 
Concentration impairment 
Concentration (severity, interference) 
Memory impairment 
Memory (severity, interference) 
Nausea 
Nausea (frequency, severity) 
Palpitations 
Pounding or racing heartbeat (frequency, severity) 
Diarrhea 
Diarrhea (frequency) 
Fecal incontinence 
Fecal incontinence (frequency, interference) 
Constipation 
Constipation (severity) 
Headache 
Headache (frequency, severity, interference) 
Dysgeusia 
Taste changes (severity) 
Anorexia 
Decreased appetite (severity, interference) 
Rash maculo-papular; Refer 
to Skin and subcutaneous 
tissue disorders for 
clinically accurate CTCAE 
term  
Rash (presence/absence/amount) 
Pruritus 
Itching (severity) 
Urinary tract pain  
Painful urination (severity)  
Urinary urgency  
Urinary urgency (frequency, interference)  
Urinary frequency  
Urinary frequency (presence/absence/amount, 
interference)  
Urinary incontinence  
Urinary incontinence (frequency, interference)  
Erectile dysfunction  
Achieve and maintain erection (severity)  
Ejaculation disorder  
Ejaculation (frequency)  
Libido decreased  
Decreased libido (severity)  
Delayed orgasm  
Delayed orgasm (presence/absence/amount)  
Anorgasmia  
Unable to have orgasm (presence/absence/amount)  

 
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7.3        Serious Adverse Events (SAEs)  
Serious Adverse Events as defined below will be reported via the SAE report form.   
 
Definition of an SAE: Any adverse drug event (experience) occurring at any dose 
that results in any of the following outcomes: 
• Death; 
• A life-threatening adverse drug experience; 
• Inpatient hospitalization or prolongation of existing hospitalization ≥24 
hours; 
• A persistent or significant disability/incapacity; 
• A congenital anomaly/birth defect; 
• Other serious/important medical events; 
• Important medical events that may not result in death, be life threatening, 
or require hospitalization may be considered an SAE, when, based upon 
medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in the 
definition.  
 
  
7.4         Serious Adverse Event (SAE) Reporting Requirements (22-AUG-2019) 
 
An SAE that occurs during any part of protocol treatment and 30 days after end of 
treatment, whether or not related to protocol treatment, must be reported by the 
investigator via the RTOG SAE Report Form in RAVE per the reporting table 
below. In addition, any SAEs which occur as a result of protocol specific 
diagnostic procedures or interventions also must be reported.   
 
The SAE report should comprise a full written summary, detailing relevant aspects 
of the SAE in question. The SAE summary also must include the investigator’s 
assessment of relatedness to specific protocol treatment. Amend the SAE report 
with follow-up information, when it becomes available. In the rare event when 
Internet connectivity is disrupted, a 24-hour notification must be made to RTOG 
Operations Office by phone, 215-574-3191.  An electronic report must be 
submitted immediately upon re-establish of the Internet connection.  
 
SAEs that occur during the follow-up period beginning 30 days after end of 
treatment and are considered by the investigator to be possibly, probably, or 
definitely related to protocol treatment must be reported expeditiously via the SAE 
Report Form.  
 
For Arm 2, all SAEs must be reported in RAVE within 24 hours of awareness. 
RTOG will complete a preliminary review of the SAE details and will contact 
the site with queries, as applicable. RTOG will report the SAE to Astellas 
within 24 hours or 1 business day of notification of the event.  RTOG will 
report to the FDA per 21 CFR 312.  Note: The individual completing the SAE 

 
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Report Form should remain vigilant for RTOG’s review and be prepared to 
respond expeditiously in order to ensure regulatory reporting within FDA-
mandated timeframes. 
 
For Canadian Sites ONLY: 
 
During a clinical trial the sponsor is required to inform Health Canada, in an 
expedited manner, of any serious unexpected adverse drug reaction, in respect of 
the drug that has occurred inside or outside Canada [C.05.014]: 
 
a) Where it is neither fatal nor life-threatening, within 15 days after becoming 
aware of the information; 
 
b) Where it is fatal or life-threatening, within 7 days after becoming aware of 
the information. Within 8 days after having initially informed Health Canada 
of the fatal or life-threatening ADR, submit as complete a report as possible. 
Follow-up reports of fatal or life-threatening reactions must include an 
assessment of the importance and implication of the findings, including 
relevant previous experience with the same or similar drugs. 
 
Arm 2 Expedited Reporting Requirements for Serious Adverse Events  
Report all adverse events that meet seriousness criteria within 24 hours of 
awareness.  
 
In addition, the following adverse events should be reported expeditiously within 
24 hours regardless of grade or seriousness criteria met:  Seizure or loss of 
consciousness, posterior reversible encephalopathy syndrome (symptoms include 
seizure, headache, confusion, reduced eyesight, blurred vision), and overdose. 
 
The 24 hour report must include, at a minimum, CTCAE term and grade, reporter 
information, event description with available information, and attribution to all 
components of protocol treatment. All other report fields must be completed 
within 5 days. The report must be amended within 24 hours of receipt of any 
additional information.  
 
SAEs that occur during the follow-up period beginning 30 days after end of 
treatment and are considered by the investigator to be possibly, probably, or 
definitely related to protocol treatment must be reported within 24 hours of 
awareness. 
 
 
 
 
 
 
 

 
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ARM 1 Expedited Reporting Requirements: Any Phase Study Utilizing a Commercial Agent1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to RTOG 
via the SAE Report Form within the timeframes detailed in the table below. 
Attribution 
Grade 4 
Grade 5 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
Unlikely 
 
10 day 
10 day 
Possible 
Probable 
Definite 
24-h/5 day 
 
24-h/5 day 
24-h/5 day 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via the SAE Report 
Form within 24 hours of learning of the AE, followed by a complete expedited 
report within 5 calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted 
within 10 calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of protocol treatment and 
are related to protocol treatment require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
Unexpected Grade 4 and all Grade 5 AEs 
 
 
 
 
 

 
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8. REGISTRATION AND STUDY ENTRY PROCEDURES 
Each individual user must have an RTOG user name and password in order to access all 
protocol-specific documents and to register patients on the RTOG web site. To get a user name 
and password: 
• The investigator and research staff must have completed Human Subjects Training  
• The investigator and research staff must complete the Password Authorization Form on 
the RTOG website. https://www.rtog.org/AboutUs/RTOGPasswordApplication.aspx.   
RTOG Headquarters requires 3-4 days to process the requests and grant user access. 
 
8.1 Regulatory and RT Credentialing Requirements for Patient Enrollment  
Please refer to the RTOG Foundation 3506 Study Guide on the RTOG website 
www.rtog.org for: patient enrollment instructions, regulatory collection requirements, 
and RT credentialing requirements.  
 
 
Access requirements for Medidata Rave and TRIAD Installation:  
Medidata Rave and TRIAD installation is needed prior to patient enrollment. See the 
Data Management Plan of the Study Guide for installation instructions.  
 
 
9.0       DRUG INFORMATION  
 
9.1 
Investigational Study Agent: Enzalutamide, IND Exempt (20-MAY-2021) 
 
 
To supplement the toxicity information contained in this document, investigators must 
obtain the current version of the Enzalutamide (Astellas-MDV3100) Investigator 
Brochure for comprehensive pharmacologic and safety information. The IB can be found 
on the RTOG Foundation 3506 protocol page of the RTOG website, www.rtog.org 
 
How supplied: Enzalutamide is provided as 40 mg capsules for oral administration.  
Enzalutamide will be provided in 30-day supply bottles of 124-capsules.  
 
Appearance: The 40 mg enzalutamide capsules are white to off-white oblong soft gelatin 
imprinted in black ink with ENZ.  
 
Classification: Androgen receptor inhibitor 
 
Route of Administration: Take by mouth with or without food 
 
Stability: Refer to the package label for expiration.   
 
Storage and Handling: Enzalutamide will be shipped from McKesson at refrigerated 
temperatures (2 to 8°C). Upon receipt drug must be stored at room temperature 20° to 25°C 
(68° to 77°F), excursions permitted between 15 to 30°C (59 to 85°F). If a storage 
temperature excursion is identified, promptly return enzalutamide to controlled room 
temperature and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 

 
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clinicalresearchservices@mckesson.com for determination of suitability. For more 
information, please follow the storage instructions provided in the package insert. 
 
Enzalutamide should not be handled by persons other than the patient and his caregivers, 
and especially not by females who are or may become pregnant. 
 
Drug Supply and Accountability:  Pfizer will supply enzalutamide free of charge to 
subjects enrolled on study.  
 
Adverse events 
Please refer to the investigator brochure for enzalutamide for toxicity information and 
Section 7. In addition, the pharmacovigilance section of Health Canada has also noted the 
following risk information: 
• very likely development of shortness of breath (21%) on enzalutamide and is 
rarely fatal 
• risk of hyperglycemia 
• rare incidence of severe cutaneous adverse reactions [including Stevens-Johnson 
syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), drug 
reaction with eosinophilia and systemic symptoms (DRESS) and acute 
generalized exanthematous pustulosis (AGEP)].   
 
The drug will be packaged and labeled by Pfizer and sent to a third-party vendor, under 
contract to RTOG Foundation, for distribution.  Drug accountability records must be 
maintained at all sites according to good clinical practices. 
 
See the study-specific guide on the RTOG Foundation 3506 protocol page of the 
RTOG website, www.rtog.org , for details of drug shipment and destruction 
logistics. 
 
9.2    Commercial Agent: Bicalutamide 
Please refer to the current FDA-approved package insert provided with each drug and the 
site-specific pharmacy for toxicity information and instructions for drug preparation, 
handling, and storage. Please see Section 5 for administration instructions.  
 
9.3    Commercial Agent: GnRH analog 
Please refer to the current FDA-approved package insert provided with each drug and the 
site-specific pharmacy for toxicity information and instructions for drug preparation, 
handling, and storage. Please see Section 5 for administration instructions.  
 
10. PATHOLOGY/BIOSPECIMENS (16-MAR-2021) 
10.1  Biospecimen Submission Tables  (17-JUN-2021) 
10.1.1 Optional Decipher Prostate RP Testing 
 
Patients must be offered the chance to participate in a data acquisition study from radical 
prostatectomy (RP) tissue that has been analyzed using the commercially available Prostate RP 
assay from Decipher Biosciences. 

 
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This assay is a standard of care genomic classifier that is indicated for men undergoing salvage 
radiotherapy following BCR that ensures after RP.  This genomic classifier has been shown to be 
predictive of metastasis and prostate cancer mortality and is endorsed by the National 
Comprehensive Cancer Network guidelines. 
 
RP tissue must be sent directly to Decipher Biosciences using a study specific requisition.  For 
patients within the United States, the service will be considered standard of care and will be 
billed by the company through typical channels.  For Canadian patients, the cost of the Decipher 
RP assay will be covered by the RTOG foundation.  Tissue should ONLY be sent to Decipher 
Biosciences.   
 
If a patient has already had the RP assay done, it does not need to be repeated, but the requisition 
form should be completed and noted that the test has already been completed so that the 
information is tagged for extraction at the conclusion of the study. 
 
Gene expression data from the Decipher RP will be used to look at molecular classifiers 
including PAM50 to evaluate their utility in distinguishing molecular subtypes of prostate cancer 
with greater benefit from intensifier AR suppression via enzalutamide at the conclusion of the 
study. 
 
Optional Study: Decipher RP Analysis for Subtyping via the PAM50 and other classifiers   
 
To subtype prostate cancers into luminal versus basal subtypes via the PAM50 classifier, gene expression in 
prostate cancer specimens (from prostatectomy blocks) will be assessed using high-density oligonucleotide 
microarrays (Affymetrix Human Exon (HuEx) 1.0 ST GeneChips) in a CLIA-certified laboratory in collaboration 
with Decipher Biosciences.   
 
Forms to include with tissue submission: 1) RTOG-3506 Study Specific Requisition Form and 2) redacted 
pathology report.   
 
Please note: If the patient has already had Decipher analysis of his tumor specimen then a copy of the 
original Decipher report and the forms listed above must be emailed to Decipher Biosciences 
(RUO@decipherbio.com) for validation and for Decipher Biosciences to provide the Decipher score needed for 
researchers. Please be sure that the original Decipher report is redacted as only the Accession ID # is necessary 
along with the study/case number as an identifier. If result is validated by Decipher then the patient does not have 
to submit tissue to Decipher for analysis.  
 
Decipher RUO Biospecimen Collection Kits can be requested from the Decipher Biosciences via an email to 
RUO@decipherbio.com.  
 
 
For questions about FFPE specimen submission, contact:  
Decipher Biosciences Laboratory 
Department of Clinical Development 
6925 Lusk Blvd, Suite 200 San Diego, California 92121 
Email: RUO@decipherbio.com 
Phone: 1-888-520-8718 
Specimen Type  
Collection Time Points 
 
Collection Information 
and  
Requirements/Instructions 
for Site 
Shipping  
 

 
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FFPE Block and a 
representative H&E slide 
OR 
Unstained sections from a 
block. Either: 
a) 6 unstained sections 
(five micron thickness) 
or  
b) 5 unstained sections 
(five micron thickness) 
and 1 H&E slide 
Pre-treatment 
Using a Decipher Specimen 
collection Kit provide: H&E 
and FFPE Block or  
unstained slides (6 
unstained slides or 5 
unstained slides and 1 H&E 
slide) 
 
Ship ambient or with 
cold pack in a specimen 
collection kit to Decipher 
Biosciences at above 
address. 
 
11. SPECIAL STUDIES (NON-TISSUE) (20-MAY-2021) 
The Patient Reported outcomes (PROs) include the PROMIS Fatigue Scale and EQ-5D.  The 
forms are available in English, French, and Spanish. Patients able to read and speak these 
languages will participate in this component of the study. 
 
11.1  The PROMIS Fatigue Scale (7 items)  
The PROMIS Fatigue Scale (7 items) was developed by the Patient-Reported 
Outcome Measurement Information System (PROMIS), part of the NIH Roadmap 
Initiative, focused on developing a publicly available resource of standardized, 
accurate, and efficient patient-reported outcome (PRO) measures of symptoms, 
distress, and functioning. Using item response theory and extensive testing and 
validation, the PROMIS investigators identified efficient, flexible, and precise 
measurement of common PRO domains [Cella 2010]. This process identified fatigue 
(defined as “an overwhelming, debilitating, and sustained sense of exhaustion that 
decreases one’s ability to carry out daily activities”) as a core domain of PROMIS.   
 
A 7 item PROMIS-derived fatigue short-form (PROMIS-F SF 7a) survey was created 
with the purpose of measuring fatigue within cancer populations undergoing clinical 
trials [Garcia 2007].  First, to generally create a fatigue-related question bank, two 
content domains of fatigue, experience and impact, were identified by a panel of 
experts. An item pool of 54 fatigue experience and 58 fatigue impact items were 
developed. The psychometric properties of these items were evaluated in a sample of 
450 individuals from the general US population using classical test theory indices, 
monotonicity, and scalability. From this item pool, to enhance the cancer relevance of 
the PROMIS-F SF 7a, domain experts selected the 10 best items in each domain 
based on statistical and conceptual considerations. These 20 items were presented to a 
panel of clinical cancer experts. Only one item was dropped because of redundancy. 
From the remaining 19 items, a preliminary fatigue short-form measure of 7 items 
was created using items selected for consistency in the response scale, broad coverage 
across the fatigue continuum (i.e., high to low), and good precision of measurement 
(discrimination function) [Garcia 2007]. The PROMIS-F SF 7a has been validated for 
diverse populations [Ameringer 2016].  
 
PROMIS- SF 7a was chosen as the PRO instrument to assess differences in quality of 
life at 1 and 2 years rather than a prostate cancer-specific instrument such as the 
Expanded Prostate Index Composite (EPIC) because it is hypothesized that 
differences in quality of life will be concentrated in domains relevant to differences in 

 
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type of enhanced ADT (4 months of bicalutamide vs. 24 months of enzalutamide), 
since the prostate-directed local therapy is identical in both control and experimental 
arms of this study.  Physician-reported early-onset fatigue occurred slightly more 
frequently in enzalutamide treated patients in a pooled analysis of four clinical trials 
[Chowdhury 2016]. Furthermore, dose-dependent fatigue was the most common 
grade 3 / 4 adverse event in initial trials of enzalutamide [Scher 2010]. Therefore, if 
there are differences in patient reported outcomes; fatigue is the most likely domain. 
 
11.2  EQ-5D-5L 
The EQ-5D-5L is a 6-item validated utility assessment instrument that takes less than 
5 minutes to complete [Janssen 2013, Herdman 2011]. The first part consists of 5 
items covering 5 dimensions including: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension is graded on 5 levels: 1-no 
problems, 2-slight problems, 3-moderate problems, 4-severe problems, and 5-unable 
to perform/extreme problems.  The sixth item is a visual analogue scale for overall 
health.  The 5-item index score is transformed into a utility score between 0, “Worst 
health state,” and 1, “Best health state.” 
 
 
11.3    Optional Online Completion of Patient-Reported QOL Assessments (02-DEC-
2019) 
Typically, QOL forms are filled out in hardcopy (paper). To provide a more 
convenient method of completing QOL assessments, RTOG Foundation is working 
with VisionTree Software, Inc., San Diego, CA. VisionTree offers patients on this 
study the option of completing their QOL forms online from any location that has a 
computer, mobile device or tablet with Internet access, including the patient’s home, 
and provides reminders to patients to complete the assessments.  
 
VisionTree Optimal Care (VTOC), a HIPAA-secure, user friendly, web-based 
software system (Gorgulho 2005; Gorgulho 2007; Pedroso 2006). The VTOC tool 
contains a web-based system for global patient and trial administration access, which 
allows improved compliance and accuracy of data collection, validation, and 
reporting. It is compliant with the Title 21, Code of Federal Regulations, Part 11 
statistical process control system and provides a mobile solution for clinical trials. 
QOL data are collected with Microsoft Excel and PDF export of reports. VTOC also 
has mobile messaging and e-mail reminders. Surveys can be “pushed” to patients for 
completion at timed intervals (see http://www.visiontree.com for details). This 
technology allows patients on this study to fill out their QOL forms online from any 
location and to receive e-mail reminders to complete assessments. E-mail reminders 
also can be sent to research associates (RAs) at the appropriate institutions to remind 
them that a QOL time point window is about to close so that a patient can be 
contacted to fill out QOL information on time, before it becomes “missing data.” 
 
RTOG Foundation is offering VisionTree as an option for other studies, including this 
one. Patients preferring to complete hardcopy QOL assessments can do so. The QOL 
forms completed via VTOC are identical to the hardcopy forms; this technology does 
not add to or change the QOL assessments in this study. 
 

 
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For this trial, the baseline QOL forms must be completed in hardcopy (on paper) prior 
to registration. The PROMIS fatigue short form 7a, and EQ-5D-5L.To complete 
subsequent QOL forms online, patients will be asked for an e-mail address that they 
consent to use so that e-mail reminders may be sent to them. The patient’s e-mail 
address also will be used for password-protected access to VTOC. Patients who are 
interested in participating but do not yet have an e-mail address can obtain one for 
free from a number of sources (e.g. Yahoo!, Hotmail, or AOL). Note: The site RA is 
responsible for setting up the patient’s account on VTOC. The RA may do so by 
logging on the VTOC portal at the following link: https://rtog.optimalcare.com - 
medical team.  RA login information will be provided by VTOC after the patient is 
randomized to the study. The patient’s VTOC account must be set up within 14 days 
after randomization.  
 
Patients will receive a login card (either printed or sent via e-mail) with which to log 
in using the secure, web-based VTOC portal. VTOC meets all HIPAA guidelines and 
is encrypted (via 128-bit SSL) for the security, privacy, and confidentiality of QOL 
information. It is similar to the secure login commonly used when performing online 
banking. The login card can then be kept and maintained by the patient. 
 
Patients will be sent e-mail reminders to complete QOL forms. The patient’s e-mail 
address only will be used by VisionTree for this purpose. The reminders will be 
created and placed into a study template that will be sent to patients at customized 
intervals (at the time points when QOL forms are due). The first reminder will be sent 
at the beginning of the “window” to complete a QOL form, with a second reminder 
halfway through the window period if the QOL forms are not yet completed at that 
time point. A maximum of 3 reminders will be sent for each of the PRO time points 
following the baseline QOL forms, which are completed in hardcopy.  
 
After a patient has completed all forms in the VTOC portal, a dialogue box will 
appear that says “Thank you for completing your Quality of Life forms,” and the 
patient will no longer receive any remaining notices for that time point. The site RA 
or study administrator will be informed through the VTOC “At-A-Glance” form 
management system when QOL forms have been completed. 
 
 
12.       MODALITY REVIEWS 
 
12.1     Radiation Therapy Quality Assurance Reviews 
The Radiation Oncology co-chair, Dr. Hiram Gay, MD, and his designee(s), will 
perform the RT Quality Assurance Review for cases enrolled and complete data has 
been received in TRIAD. The RT reviews will be ongoing and performed remotely. 
The final cases will be reviewed within 6 months after this study has reached the target 
accrual or as soon as complete data has been received in TRIAD for all cases enrolled, 
whichever occurs first. The scoring mechanism is: Per Protocol, Variation Acceptable, 
and Unacceptable Deviation. 
 

 
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12.2  Medical Oncology Modality Quality Assurance Reviews 
The Medical Oncology Co-Chair, Edwin Posadas, M.D., will perform a Hormonal 
Therapy Assurance Review of all patients who receive or are to receive hormonal 
therapy in this trial.  The goal of the review is to evaluate protocol compliance.  The 
review process is contingent on timely submission of hormonal therapy treatment data. 
The scoring mechanism is: 1) Per Protocol, 2) Unacceptable Deviation, and 3) Not 
Evaluable.   
 
Dr. Posadas will perform a Quality Assurance Review after RTOG Headquarters has 
received complete data for the first 20 cases enrolled. Dr. Posadas will perform the next 
review after Headquarters has received complete data for the next 20 cases enrolled. 
The final cases will be reviewed within 3 months after this study has reached the target 
accrual or as soon as Headquarters has received complete data for all cases enrolled, 
whichever occurs first. 
 
13.       DATA AND RECORDS  
This study will utilize Medidata Rave. 
 
13.1  Summary of Data Submission and Dosimetry Digital Data Submission 
 
Please refer to the RTOG Foundation 3506 Study Guide on the RTOG website 
www.rtog.org. 
 
14. STATISTICAL CONSIDERATIONS 
 
14.1 
Study Design (02-DEC-2019) 
This is a randomized phase II trial in which patients will be stratified by number of 
aggressive features (1 vs. >1) and then randomized 1:1 to receive standard ADT or to 
enhanced ADT using permuted block randomization [Zelen 1974].  Aggressive features, 
fully defined in Section 3.1.5, consist of a Gleason score of 8-10, SVI, pN1, PEPP and PSA 
≥0.7 ng/mL. 
The target accrual is 242 patients.  All analyses will be conducted on an intent-to-treat 
basis of all at-risk patients (regardless of eligibility).  The primary endpoint analysis will 
take place once 99 PFS events have occurred. 

 
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14.2 
Study Endpoints 
14.2.1 Primary endpoint: Progression-free survival 
14.2.2 Secondary endpoints: 
• Biochemical failure  
• Biochemical failure using an alternative definition 
• Development of hormone-refractory disease 
• Distant metastasis 
• Cause-specific mortality 
• Overall survival 
• Acute and late toxicity, as measured by CTCAE v5 and PRO-CTCAE 
• Quality of life, as measured by EQ-5D-5L 
• Fatigue, as measured by PROMIS-F SF 7a 
 
14.3 
Primary Objectives Study Design (12-JUL-2022) 
14.3.1 Primary Hypothesis and Endpoints 
The primary hypothesis is to determine whether, in men with post-prostatectomy PSA 
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 (PFS) compared to SRT with 
standard GnRH analog-based ADT.   
 
14.3.2 How Primary Endpoints Will Be Analyzed 
Progression is defined as first occurrence of biochemical failure, clinical failure, or 
initiation of new unplanned anticancer treatment.  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 as defined in Section 4.  PFS is defined as the time from 
randomization to the date of progression, death from any cause, or last known follow-up 
time.  The PFS function will be estimated using the Kaplan-Meier method [Kaplan 1958]. 
The null and alternative hypotheses are: 
 
𝐻0: 𝐻𝑅≥1.0 𝑣𝑠. 𝐻𝐴: 𝐻𝑅< 1.00  
A stratified log rank test with one-sided significance level of 0.1 will be used to test this 
hypothesis [Mantel 1966]. The Cox proportional hazards regression model will be used to 
compare treatment differences, computing both unadjusted and covariate-adjusted hazard 
ratios (HRs) with respective 95% confidence interval [Cox 1972].  Typical covariates, 
such as treatment arm and stratification variables will be adjusted for in the multiple 
regression analysis. 
 
14.3.3 Sample Size and Power Calculations:  
The standard ADT arm is expected to have 41.7% of patients progression-free at 5 years 
which corresponds to a hazard rate of 0.175.  It is hypothesized that 56.6% of patients 
will be progression-free at 5 years on the enhanced ADT arm (hazard rate of 0.114), 
providing a hazard ratio of 0.65 (treatment/control). Assuming an accrual period of 2 
years at a rate of 115 patients per year with 3 years of additional follow-up and one 
interim analysis, a one-sided log-rank test with alpha=0.10 would require 99 events for 

 
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80% statistical power.  In order to obtain 99 events, 229 patients would need to be 
enrolled.  Adjusting for 5% lost to follow-up, the target accrual would be 242 patients. 
 
Updated Sample Size Calculation 
Due to the change in eligibility of making PSA ≥ 0.7 ng/mL an aggressive feature (as 
opposed to being required in addition to at least 1 aggressive feature), the 5 year PFS rate 
on the standard ADT arm is expected to be higher, 48.0% (hazard rate of 0.147).  
Lowering the hazard ratio to 0.63 (treatment/control) results in a hypothesized 5 year PFS 
rate of 64.4% on the enhanced ADT arm (hazard rate of 0.092).  Assuming an accrual 
period of 2 years at a rate of 115 patients per year with 3 years of additional follow-up 
and one interim analysis, a one-sided log-rank test with alpha=0.10 would require 86 
events from 230 patients for 80% statistical power.  Adjusting for 5% lost to follow-up, 
the target accrual is 242 patients. 
 
Updated Sample Size Calculation 
Due to the change in the PFS definition, the 3-year PFS rate on the standard ADT arm is 
expected to be 24.0% (hazard rate of 0.476).  Assuming a hazard ratio of 0.65 
(treatment/control) results in a hypothesized 3-year PFS rate of 39.5% on the enhanced 
ADT arm (hazard rate of 0.309).  Assuming an accrual period of 2 years at a rate of 51.7 
patients/year (based on actual accrual) and a second period of 82.6 patients/year, with just 
over 1 year of additional follow-up, one interim analysis, and 5% drop-out up to 5 years, 
a one-sided log-rank test with alpha=0.10 would require 101 events from 170 patients for 
80% statistical power.  Thus the target accrual is 170 patients. 
 
14.4 
Study Monitoring of Primary Objectives (12-JUL-2022) 
(Interim Analysis) 
Interim Analysis for the DMC 
The RTOG Foundation Data Monitoring Committee (DMC) will review the study twice a 
year with respect to patient accrual and morbidity. The DMC also will review the study 
on an “as needed” basis.  
 
There is one interim analysis for both efficacy and futility that will occur once 75% of the 
events (76) have occurred.  For the futility analysis, if the observed HR is ≥1.0, the study 
statistician and DMC will consider early release of these findings, with the conclusion 
that the experimental arm may not provide acceptable disease control. If the observed 
hazard ratio is < 1.0, then the statistician will recommend that the trial continue as 
planned. 
 
The interim efficacy analysis will follow an O’Brien and Fleming boundary as outlined in 
the table below.  If the boundary is crossed, the study statistician and DMC will consider 
early release of these findings, with the conclusion that the experimental arm provides 
acceptable disease control.  If the boundary is not crossed, then the statistician will 
recommend that the trial continue as planned. 
 
Look 
Information 
Fraction 
Events 
Cumulative α 
spent 
Boundaries (Z-
scale) 

 
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1 
0.75 
76 
0.058 
-1.572 
2 
1.0 
101 
0.100 
-1.38 
 
14.5 
Accrual/Study Duration Considerations (12-JUL-2022) 
 
Based on patient accrual in previous RTOG randomized prostate studies, it is expected 
that there will be no enrollment during the initial 6 months while institutions are 
obtaining IRB approval. An average uniform accrual rate of 115 patients per year is 
projected over 2 years, with an additional 3 years of follow-up required. The total 
duration of the study is expected to be 5.5 years from the time the study opens to the time 
of the final analysis.  The interim analysis is projected to occur 39 months from 
activation. 
 
For the first 26 months, the study accrued at a rate of 51.7 patients/year.  Assuming a 
higher accrual of 82.6 patients/year, 170 patients will be met in just under 3 years from 
study activation.  The number of events is projected to be reached just over a year later. 
 
14.6 
Secondary Endpoints (12-JUL-2022) 
14.6.1 Secondary Hypotheses and Endpoints:  
• Biochemical failure 
• Biochemical failure as determined by an alternate definition 
• Development of hormone-refractory disease 
• Distant metastasis 
• Cause-specific mortality 
• Overall survival 
• Acute and late toxicity, as measured by CTCAE v5 and PRO-CTCAE 
• Fatigue, as measured by PROMIS-F SF 7a 
• Quality of life as measured by the EQ-5D-5L 
 
14.6.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
 
Efficacy endpoints 
Overall survival (OS) is defined as the time from randomization to the date of death or 
last known follow-up time.  OS will be estimated by the Kaplan-Meier method [Kaplan 
1958] and compared with the log-rank test [Mantel 1966].  Two definitions of 
biochemical will be assessed.  The definition used in the primary endpoint of PFS (noted 
as PBF), PSA ≥ 0.05 or initiation of salvage hormones, and an alternative definition 
(ABF), post-RT PSA ≥ 0.1 ng/mL or initiation of salvage hormones.   Biochemical 
failure will be measured from the date of randomization to the date of failure or last 
known PSA assessment. Hormone-refractory disease (HRD) will be measured from the 
date of randomization to the midway date between the last non-rising PSA and the first-
rise PSA out of three consecutive rises in PSA during treatment with salvage androgen 
deprivation. Cause-specific mortality (CSM) will be measured from the date of 
randomization to the date of death due to prostate cancer. Distant metastasis (DM) will be 
measured from the date of randomization to the date of documented distant 
metastasis/clinical and/or radiographic appearance of disseminated disease. Competing-
risk endpoints BF, ABF, HRD, CSM, and DM will be estimated by the cumulative 

 
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incidence method [Gray 1988]. Cox regression [Cox 1972] will be used to obtain HRs for 
OS. Fine and Gray’s regression [Fine 1999] also will be used for the endpoints with 
competing risks. Both unadjusted and adjusted HRs and the respective 95% confidence 
interval will be computed. 
 
Adverse events 
Adverse events (AEs) will be scored according to the CTCAE v5. Counts of all AEs by 
grade will be provided by treatment arm.  Counts and frequencies will be provided for the 
worst grade AE experienced by the patient by treatment arm and within the subset of AEs 
related to treatment.   
 
An acute AE will be defined as the first occurrence of worst severity of the AE occurring 
less than or equal to 30 days after the completion of treatment. Logistic regression 
[Agresti 1990], both univariate and multivariate, will be used to model the distribution of 
acute AEs. Both unadjusted and adjusted odds ratios and the respective 95% confidence 
interval will be computed and tested. Late grade 3+ AEs will be defined as grade 3+ AEs 
occurring more than 30 days after the completion of RT. The time to late grade 3+ AE 
will be measured from randomization to the time of the worst late grade 3+ AE. If no 
such late adverse event is observed at the time of the analysis, the patient will be 
censored at the time of the analysis. Death without a late AE will be considered as the 
competing risk and the distribution of time to late grade 3+ AEs will be estimated using 
the cumulative incidence approach [Gray 1988]. A Fine and Gray’s regression model 
[Fine 1999] will be used to compare the treatment differences of time to late AE with and 
without adjusting for other covariates. Both unadjusted and adjusted hazard ratios and the 
respective 95% confidence interval will be computed. At least the treatment arm, the 
stratification variables, and, as appropriate, age, and race will be adjusted for in the 
analysis. 
 
Adverse events will also be assessed using PRO-CTCAE items. The specific symptoms 
to be evaluated for this study are listed in Section 7.2.2.  Assessments will be collected 
before the start of radiotherapy treatment and as specified in the Section 4 assessment 
tables.  For each symptom and each domain (i.e., frequency, severity, and interference), 
counts and frequencies will be provided for the worst score experienced by the patient by 
treatment arm.  The proportion of patients with scores ≥1 and ≥3 will be compared 
between groups using a chi-square test, or Fisher’s exact test if cell frequencies are < 5.  
Analysis of changes in patient reported outcomes over time will analyzed by fitting GEE 
models using a logit link (dichotomizing the symptom scores as 0 vs. >1 and 0-2 vs. 3-4) 
with time of assessment, treatment arm, and treatment-by-time interaction terms in the 
model. 
 
Fatigue 
Fatigue will be measured by the 7-question PROMIS-F SF 7a (Patient-Reported Outcome 
Measurement Information System fatigue short form) questionnaire.  It is collected at 
baseline and end of RT, and 1 and 2 years post RT.  Scores are translated into a T score 
for each participant, rescaling the raw score into a standardized score with a mean of 50 
and standard deviation of 10.  A higher T score indicates worse fatigue.  Change scores 

 
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from baseline to each follow-up time point will be presented by treatment arm and 
between arm differences compared using a t-test.  Whether patients experience moderate 
fatigue (T score 55-74) or severe fatigue (>=75) [Cella 2014] is also of interest and will 
be compared between treatment arms using a chi-square test at each follow-up time point. 
 
A generalized linear mixed effects model will be used to assess the dichotomous variable, 
moderate to severe fatigue, over time, adjusting for baseline fatigue, treatment arm, 
components of the stratification factor (PSA, Gleason score, SVI, and PEPP), age, race, 
and other covariates as applicable. 
 
Prior to performing analyses, an evaluation of the amount, reasons and patterns of 
missing data will be performed, using the well-known categories of missing completely 
at random (MCAR), missing at random (MAR) and missing not at random (MNAR) 
[Fairclough 2010, Verbeke 2000].  If ≥15% of the data is missing at any time point, 
patient characteristics will be compared between patients with completed assessments 
and those with missing assessments. If any are found to differ significantly, they will be 
included in the mixed effects model, which assumes that the data is MAR.  If the 
missingness is determined to be non-ignorable, other methods may be applied.  
Specifically, a joint model that allows a shared parameter between the repeated 
measurements and time to death or drop out can be used if considered MNAR due to the 
high number of patient deaths or dropouts [Rizopoulos 2012].  Other options for MNAR 
data are pattern mixture and selection models [Fairclough 2010, Little 1995].  Sensitivity 
analyses will be performed to compare the results of different analytic strategies 
[Fairclough 1998]. 
 
Health-Related Quality of Life 
Global HQOL will be measured by EuroQol’s EQ-5D-5L.  It is collected at baseline and 
end of RT, and 1 and 2 years post RT.  Changes scores from baseline to each follow-up 
time point will be presented by treatment arm and between arm differences compared 
using a t-test.   
 
An exploratory longitudinal analysis incorporating all of the follow-up time points will be 
conducted separately for the index and VAS scores using longitudinal linear modeling 
methods, adjusting for baseline score, treatment arm, components of the stratification 
factor (PSA, Gleason score, SVI, and PEPP), age, race, and other covariates as 
applicable.  Missing data will be assessed as described above for fatigue. 
 
14.7     EXPLORATORY ENDPOINTS (16-MAR-2021) 
Both PAM50 (Luminal A or Basal vs. Luminal B) and the 22-marker genomic classifier 
(GC) Decipher, a continuous variable ranging in score from 0 to 1, are of interest.  The 
GC score will also be analyzed as a categorical variable (<0.4, 0,4-0.6, >0.6) since both 
the continuous and categorical variables have been found to be associated with incidence 
of metastasis in prostate cancer [Karnes 2013]. The Cox proportional hazards regression 
model will be used to determine associations between these variables and OS and PFS  
and cause-specific Cox models will be used for BF, ABF, HRD, CSM, and DM [Cox 
1972] while adjusting for typical covariates, such as treatment arm and stratification 

 
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variables.  The interaction of treatment arm with PAM50 and the GC score (both 
categorical and continuous) will also be considered in the model to assess predictive 
ability of these markers. 
 
 
 

 
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APPENDIX A. ADDITIONAL ASSESSMENTS FOR CANADIAN SITES (22-AUG-2019) 
 
The use of potent AR signaling inhibitors such as enzalutamide has been associated with adverse 
events including cardiac and endocrine events that are important for optimization of care.  Use of 
such agents should be conducted following standards of good medical practice as outlined in the 
NCCN guidelines (https://www.nccn.org/professionals/physician_gls/pdf/prostate_blocks.pdf).  
We would recommend consultation and collaboration with a medical oncologist experienced 
with the administration of enzalutamide to address the known risks to heart and bone health. 
Given these concerns and by working in concert with Health Canada, we had included additional 
monitoring guidance that will be required of Canadian sites as listed below.   
 
I. 
Additions to Section 4, Assessments:  Pre-Treatment  
• In order to identify patients at risk for cardiac adverse events including QTc prolongation, 
assess electrolytes and perform an ECG. 
• Screening recommendation for osteoporosis should follow the guidelines established by 
the National Osteoporosis Foundation (www.nof.org) (see section III below). 
 
II. 
Additions to Section 4, Assessments:  On Treatment 
 
• In order to identify patients at risk for cardiac adverse events including QTc prolongation, 
assess electrolytes and an ECG every cycle (1 cycle=90 days) for the first 36 weeks of 
exposure to drug 
• Evaluate for bone health support (see section III below).  
 
III. 
MANAGEMENT RECOMMENDATIONS 
 
A. Electrolytes 
Electrolyte abnormalities should be corrected and monitored during the course of 
enzalutamide therapy within limits consistent with good medical practice.   
 
In particular, we recommend maintenance of a K+ and Mg2+ within institutionally 
established normal ranges for the duration of trial therapy. 
 
B. QT prolongation 
Patients on agents associated with a risk of a QT prolongation should be advised of the 
risk of serious ventricular dysthymia and advised to identify safer agents when available. 
 
Patients with QTc intervals in excess of 440 ms should have regular monitoring by ECG 
(e.g. every 3 months or more frequently at the discretion of the treatment team) while 
receiving enzalutamide and should be considered for consultation with a cardiologist. 
 
C. Osteoporosis 
Screening recommendation for osteoporosis follow the guidelines established by the 
National Osteoporosis Foundation (www.nof.org) 
 
The following recommendations are part of a thorough evaluation of bone health; refer to 
the NOF and the NCCN guidelines (www.nccn.org) for detailed recommendations: 

 
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• Bone mineral density should be assessed by dual-energy X-ray absorptiometry 
(DXA) as clinically indicated. 
• Calcium (1000-1200 mg daily from food and supplements) and vitamin D3 (400–
1000 IU daily) should be initiated upon start of therapy. 
• Additional treatment for men should be started for men with a 10-y probability of 
hip fracture ≥3% or a 10-y probability of a major osteoporosis-related fracture 
≥20%. Fracture risk can be assessed using FRAX®, the algorithm recently released 
by WHO.  
• Treatment options to increase bone density, a surrogate for fracture risk in men 
without metastases, include denosumab (60 mg SQ every 6 mo), zoledronic acid (5 
mg IV annually), and alendronate (70 mg PO weekly).  Treatment should be initiated 
in consultation with an internist or medical oncologist. 
PHARMACOLOGIC AGENTS ASSOCIATED WITH QT PROLONGATION 
PLEASE REFER TO THE FOLLOWING WEBSITE AS A REFERENCE: 
HTTPS://WWW.CREDIBLEMEDS.ORG/