Salvage Oligometastasectomy and Radiation Therapy in Recurrent Prostate Cancer (SOAR)
Phase: PHASE2
Conditions: Recurrent Prostate Carcinoma, Metastatic Malignant Neoplasm in the Bone, Metastatic Malignant Neoplasm in the Lymph Nodes, Oligometastasis, Prostate Adenocarcinoma, PSA Failure
Sponsor: University of Utah

Short Title: Image Guided Salvage Oligometastasectomy and Radiation Therapy in Recurrent Prostate 
Cancer (SOAR) 
Version Date: 10NOV2021  
Principal Investigator: Alejandro Sanchez, MD 
 
Image-Guided Salvage Oligometastasectomy and Radiation Therapy 
in Recurrent Prostate Cancer (SOAR) 
HCI identifier – HCI-17-GU-26/ Lead Trial ID: HCI115811/IRB #115811 
Principal Investigator 
Alejandro Sanchez, MD 
Huntsman Cancer Institute - University of Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
Phone: 801-581-2401 
Email: Alejandro.Sanchez@hci.utah.edu   
Statistician 
Ken Boucher, PhD  
Huntsman Cancer Institute - University of Utah 
2000 Circle of Hope Room 1710 
Email: Kenneth.Boucher@hci.utah.edu 
Medical Monitor 
Matthew Poppe, MD 
Huntsman Cancer Institute – University of Utah 
2000 Circle of Hope  
Salt Lake City, UT 84112 
Email: matthew.poppe@hci.utah.edu 
 
NCT Number (CT.gov) 
NCT03796767 
Historical Protocol Version Dates 
Version 1: 05SEP2018 
Version 2: 30SEP2019 
Version 3: 14AUG2020 
Version 4: 10NOV2021 
 
 

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TABLE OF CONTENTS 
Page 
TABLE OF CONTENTS ................................................................................................................ 2 
LIST OF ABBREVIATIONS ......................................................................................................... 4 
PROTOCOL SIGNATURE ............................................................................................................ 7 
STUDY SUMMARY...................................................................................................................... 8 
SCHEMA ...................................................................................................................................... 11 
1 
OBJECTIVES ....................................................................................................................... 12 
1.1 
Primary Objective ....................................................................................................... 12 
1.2 
Secondary Objectives ................................................................................................. 12 
1.3 
Exploratory Objective(s) ............................................................................................ 13 
2 
BACKGROUND .................................................................................................................. 13 
3 
TREATMENT INFORMATION ......................................................................................... 14 
3.1 
Surgery........................................................................................................................ 14 
3.2 
External Beam Radiation Therapy ............................................................................. 15 
4 
STUDY DESIGN.................................................................................................................. 15 
4.1 
Description.................................................................................................................. 15 
4.2 
Number of Subjects .................................................................................................... 15 
4.3 
Number of Study Centers ........................................................................................... 15 
4.4 
Study Duration ............................................................................................................ 15 
5 
ELIGIBILITY CRITERIA.................................................................................................... 16 
5.1 
Inclusion Criteria ........................................................................................................ 16 
5.2 
Exclusion Criteria ....................................................................................................... 17 
5.3 
Recruitment Strategies ................................................................................................ 19 
6 
TREATMENT GUIDELINES.............................................................................................. 19 
6.1 
Subjects with Bone Metastases Only .......................................................................... 19 
6.2 
Subjects with Nodal Metastases (With or Without Bone Metastases) ....................... 22 
6.3 
Concomitant Medications and Therapies ................................................................... 24 
6.4 
Duration of Therapy ................................................................................................... 24 
7 
TOXICITIES AND DOSEAGE MODIFICATION ............................................................. 25 
7.1 
Dose Modifications and Guidelines for Adverse Event Management for Radiotherapy
 
26 
7.2 
Supportive Care .......................................................................................................... 26 
7.3 
Contraception.............................................................................................................. 26 
8 
STUDY CALENDAR .......................................................................................................... 27 
8.1 
Arm A ......................................................................................................................... 27 
8.2 
Arm B ......................................................................................................................... 29 
8.3 
Arm C ......................................................................................................................... 31 
9 
STUDY PROCEDURES ...................................................................................................... 33 
9.1 
Screening Evaluations ................................................................................................ 33 
9.2 
On Treatment Evaluations .......................................................................................... 34 
9.3 
Follow-up Evaluations ................................................................................................ 35 
10 CRITERIA FOR EVALUATION OF ENDPOINTS ........................................................... 35 
10.1 
Primary Endpoint: PSA Response Rate...................................................................... 35 
10.2 
Secondary Endpoints .................................................................................................. 35 

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10.3 
Time to Recurrence .................................................................................................... 35 
11 STATISTICAL CONSIDERATIONS.................................................................................. 36 
11.1 
Sample size determination .......................................................................................... 36 
11.2 
Population for analyses ............................................................................................... 37 
11.3 
Statistical Hypotheses and Analyses .......................................................................... 37 
12 REGISTRATION GUIDELINES ......................................................................................... 38 
13 DATA SUBMISSION SCHEDULE .................................................................................... 38 
14 CORRELATIVE STUDIES ................................................................................................. 39 
14.1 
Screening .................................................................................................................... 39 
14.2 
Oligometastasectomy and/or Prostatectomy .............................................................. 39 
14.3 
Blood Correlative Studies ........................................................................................... 40 
15 ETHICAL AND REGULATORY CONSIDERATIONS .................................................... 40 
15.1 
Informed consent ........................................................................................................ 40 
15.2 
Human Subjects Protections ....................................................................................... 40 
15.3 
Institutional Review .................................................................................................... 40 
15.4 
Data and Safety Monitoring Plan ............................................................................... 40 
15.5 
Adverse Events and Serious Adverse Events ............................................................. 41 
15.6 
SAE Reporting Requirements .................................................................................... 43 
15.7 
Reporting of Pregnancy .............................................................................................. 44 
15.8 
Protocol Amendments ................................................................................................ 44 
15.9 
Protocol Deviations .................................................................................................... 44 
15.10 
FDA Annual Reporting .............................................................................................. 44 
15.11 
Clinical Trials Data Bank ........................................................................................... 44 
15.12 
Record Keeping .......................................................................................................... 45 
16 BIBLIOGRAPHY ................................................................................................................. 46 
Appendix A – Radiation Therapy Oncology Group (RTOG) toxicity grading system ................ 47 
Appendix B – Clavien-Dindo Classification of Surgical Complication ....................................... 48 
Appendix C – FACT-P Questionnaire .......................................................................................... 49 
Appendix D – Expanded Prostate Cancer Index Composite (EPIC-26)....................................... 52 
Appendix E – Charlson Comorbidity Index ................................................................................. 55 
Appendix F- Prostate Cancer Clinical Trials Working Group 3 (PCWG3) ................................. 57 
 
 

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LIST OF ABBREVIATIONS 
Abbreviation or Term1 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
β-HCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BLQ 
Below limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca++ 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
Cl- 
Chloride 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
D/C 
Discontinue 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 

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Abbreviation or Term1 
Definition/Explanation 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
e.g. 
Exempli gratia (for example) 
EQD2 
Equivalent Dose in 2 Gy Fractions 
FACS 
Fluorescence Activated Cell Sorting  
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transferase 
GLP 
Good laboratory practice  
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCO3- 
Bicarbonate 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
hr 
Hour or hours 
IC50 
Half maximal inhibitory concentration 
i.e. 
Id est (that is) 
IEC 
Independent ethics committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional review board 
IU 
International unit 
IV 
Intravenous, intravenously 
LDH 
Lactate dehydrogenase 
LLQ 
Lower limit of quantitation 
MedRA 
Medical Dictionary for Drug Regulatory Activities 
MRI 
Magnetic resonance imaging 
MRSD 
Maximum recommended starting dose 
MTD 
Maximum tolerated dose  
NOAC 
Novel Oral Anticoagulants 
NOAEL 
No-observed-adverse-effect level 

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Abbreviation or Term1 
Definition/Explanation 
NOEL 
No-observed-effect-level 
PD 
Pharmacodynamic(s) 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QC 
Quality control 
RALP 
Robotic-assisted laparoscopic prostatectomy 
RBC 
Red blood cell 
QD 
Once daily 
QTc 
QT interval corrected  
QTcF 
QT interval corrected using Fredericia equation 
SAE 
Serious adverse event 
SD 
Standard deviation or stable disease 
T1/2 
Terminal elimination half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
Tmax 
Time of maximum observed concentration 
TID 
Three times daily 
TRUS 
Transrectal ultrasonography 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
ULQ 
Upper limit of quantitation 
UV 
Ultraviolet 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WONCBP 
Women of nonchildbearing potential 
1 All of these abbreviations may or may not be used in protocol.  
 

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PROTOCOL SIGNATURE 
I confirm that I have read this protocol, and I will conduct the study as outlined herein and 
according to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practice, and the applicable laws and regulations of the 
federal government. I will promptly submit the protocol to the IRB for review and approval. Once 
the protocol has been approved by the IRB, I understand that any modifications made during the 
course of the study must first be approved by the IRB prior to implementation except when such 
modification is made to remove an immediate hazard to the subject. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that they 
are fully informed regarding the study treatment, the conduct of the study, and the obligations of 
confidentiality. 
Note: This document is signed electronically through submission and approval by the Principal 
Investigator in the University of Utah IRB Electronic Research Integrity and Compliance 
Administration (ERICA) system. 
 
 

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STUDY SUMMARY 
Title 
Image-Guided Salvage Oligometastasectomy and Radiation Therapy in 
Recurrent Prostate Cancer  
Short Title 
SOAR 
Protocol Identifiers 
(IRB – internal) 
IRB #115811 
HCI-17-GU-26 
IND number 
Exempt 
Phase 
Phase II pilot 
Design 
This study is establishing baseline data for these patients who have no 
defined standard of care currently  
Study Duration 
5 Years total study duration: 2 years for accrual and 3 years for follow 
up 
Study Center(s) 
Single-center 
Objectives 
Primary objective 
• To assess response to treatment of oligometastatic disease. 
Secondary objectives: 
• To assess additional measurements of response to treatment of 
oligometastatic disease 
• To assess PSA progression free-survival following treatment of 
oligometastatic disease. 
• To assess time to disease recurrence.  
• To assess time to initiation of ADT for metastatic prostate cancer 
following treatment of oligometastatic disease. 
• To assess the rate of undetectable PSA following treatment of 
oligometastatic disease in subjects who have been previously 
undergone prostatectomy. 
• To assess safety. 
• To assess the impact of study treatment on change in quality of life 
over three years. 
Number of Subjects 20 
Diagnosis and Main 
Eligibility Criteria 
Diagnosis 
Histologically proven adenocarcinoma of the prostate 
Inclusion Criteria 
• Recurrent adenocarcinoma of the prostate: 
• Post-prostatectomy (with/without adjuvant radiotherapy): 
Patients must have a detectable or rising PSA level that is 
>0.05 ng/mL, with a second confirmatory level that is 
>0.05ng/mL after a minimum of 1 week. 
o Post radiotherapy/ablation: PSA rise ≥ 2ng/mL over 
nadir. 
• Subjects treated with prior definitive radiotherapy for prostate 
cancer who have positive molecular imaging (e.g., fluciclovine 
PET/CT or PSMA PET/CT scan or other per PI discretion) 

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suggesting recurrent intraprostatic disease must undergo TRUS 
biopsy less than or equal to one year before study enrollment: 
o If the TRUS biopsy is negative, no additional treatment 
is required to the prostate in addition to that of scan-
positive sites. 
o If the TRUS biopsy is positive, subject must undergo 
salvage prostatectomy or salvage radiotherapy to the 
primary site concurrently with the study treatment per the 
treatment protocol algorithm. 
o Note: Biopsy is not required for prostate fossa 
recurrences after radical prostatectomy.  
• Oligometastatic disease defined as 10 or fewer metastatic lesions 
to lymph nodes and/or bones only. 
• For patients with oligometastatic disease involving lymph node, 
metastasis is confined to the pelvic or para-aortic (below IMA) 
regions on1- molecular imaging (e.g., fluciclovine PET/CT or 
PSMA PET/CT scan or other per PI discretion), CT, or MRI). 
• Subjects must be candidates for surgery if indicated per the 
treatment algorithm.  
• ECOG Performance Status ≤ 2 
Exclusion Criteria 
• Known brain or visceral metastases other than lymph nodes  
• Patients actively receiving hormone therapy for prostate cancer. 
Patients may have received hormone therapy previously but 
must have documented non-castrate levels of testosterone (>50 
ng/dL) 
• Prior or concurrent malignancy whose natural history or 
treatment, in the opinion of the enrolling investigator, may have 
the potential to interfere with the safety or efficacy assessment 
of the investigational treatment protocol of this study.  
• Use of finasteride within 30 days prior to initiation of therapy. 
• Use of dutasteride within 90 days prior to initiation of therapy.  
• Active, uncontrolled, significant intercurrent or recent illness 
Study Product, 
Dose, Route, 
Regimen 
Oligometastasectomy and/or bone radiotherapy and/or nodal 
radiotherapy and/or prostatectomy 
Duration of 
administration 
Surgery: 1 day 
Radiotherapy: up to 8 weeks 
Reference therapy 
There is no reference therapy. This is a pilot study to determine a 
baseline response to the study population. 
Statistical 
Methodology 
The planned sample size is N = 20 evaluable subjects. The primary 
outcome variable of reduction in PSA ≥ 50% at 6 months will be 
analyzed descriptively via 90% and 95% exact binomial confidence 
intervals. No hypothesis test will be performed on the primary outcome 
variables. The sample size is justified by the width of the 95% 

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confidence intervals. We anticipate that the PSA 50% response rate at 6 
months will be 30% based on the results published by Siriwardana, as 
their PSA response at 6 weeks and 12 months was 43% and 23% 
respectively. However, the definition used here is somewhat different 
than the definition in that clinical study.  If the observed PSA 50% 
response rate is 30% (6/20), the 95% exact binomial confidence interval 
(Clopper-Pearson) will be 12% to 54 %. With 20 evaluable subjects the 
maximum width of a 95% exact binomial confidence interval is 46% 
(27% to 73%) and occurs when the observed response rate is 50% 
(10/20).  
 

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SCHEMA 
Figure 1: Overall Treatment Schema (All Arms) 
 
Figure 2: Adjuvant radiotherapy (Arms B and C only) 
 
1. With completion of prostate radiotherapy (for patients who received an incomplete definitive radiation course) OR salvage prostatectomy if positive baseline TRUS biopsy 
(including subjects enrolled in Arm A) 
2. Bone radiotherapy can be completed prior to surgical resection if indicated in the opinion of the investigator. 
3. Ipsilateral involved-field radiotherapy to 45 Gy in 25 fractions using image-guided IMRT 
4. Simultaneous integrated boost to gross target volumes to be >= 76 Gy EQD2 
5. Target volume defined with inferior dosimetric border set immediately above the previously treated area. Nodal volumes will be treated to 50.4 Gy. The prostate fossa will 
be treated for post-prostatectomy patients who have not had any radiation to the prostate fossa.

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1 OBJECTIVES 
1.1 
Primary Objective 
To assess response to treatment of oligometastatic disease. 
Primary Endpoints: proportion of subjects with a reduction in PSA ≥ 50% 6 months after 
completion of all treatment (salvage and adjuvant therapy). 
1.2 
Secondary Objectives 
1.2.1 
To assess additional measurements of response to treatment of oligometastatic disease. 
Secondary Endpoints: Proportion of subjects with reductions in PSA ≥ 50% 12 
months after and ≥ 90% 6 and 12 months after completion of all treatment (salvage 
and adjuvant therapy).  
1.2.2 
To assess PSA progression free-survival following treatment of oligometastatic 
disease. 
Secondary Endpoint: Proportion of subjects without PSA progression (defined using 
Prostate Cancer Working Group 3 Criteria PCWG3), evaluated every 3 months for 3 
years after completion of all treatment (salvage and adjuvant therapy).  
1.2.3 
To assess time to disease recurrence following treatment of oligometastatic disease. 
Secondary Endpoint: The time from study enrollment until the date of confirmed 
radiographic disease progression as defined by RECIST 1.1 and PCWG3. 
1.2.4 
To assess time to initiation of ADT for metastatic prostate cancer following treatment 
of oligometastatic disease. 
Secondary Endpoint: The time from study enrollment to the initiation of ADT.  
1.2.5 
To assess the rate of undetectable PSA following treatment of oligometastatic disease 
in subjects who have previously undergone prostatectomy. 
Secondary Endpoint: In subjects who have previously undergone prostatectomy 
evaluate the proportion of patients with a PSA ≤ 0.2 ng/mL, evaluated 6 and 12 
months after completion of all treatment (salvage and adjuvant therapy).  
1.2.6 
To assess safety. 
Secondary Endpoint: Rate of AEs and SAEs as defined by CTCAE version 5.0. 
1.2.7 
To assess the impact of study treatment on change in quality of life over three years.  
Secondary Endpoint: Quality of life (QOL) questionnaires (FACT-P and Expanded 
Prostate Cancer Index Composite EPIC-26) will be administered at screening, the 
Response Assessment Visit, and each follow-up visit.  

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1.3 
Exploratory Objective(s) 
To assess the correlation of molecular biomarkers with clinical response and resistance to 
surgery and radiation therapy. 
Exploratory Endpoint(s): Evaluation for genomic alterations or abnormal protein expression 
that correlates with radiation resistance or predilection for early metastasis and worse overall 
prognosis. 
2 BACKGROUND 
Most subjects diagnosed with localized prostate cancer are cured with definitive surgery or 
radiation therapy. However, a significant proportion experience disease progression despite these 
interventions. Typically subjects will initially have a PSA only relapse, without radiographic 
evidence of metastatic disease. There is no definitive standard of care for these subjects proven 
to improve clinical outcomes. Some subjects are treated with immediate androgen deprivation 
therapy (ADT) either through intermittent or continuous administration. Other subjects are 
carefully observed until radiographic metastatic disease progression. It is not clear which 
treatment strategy, if any, is clinically superior. Some studies suggest that immediate therapy 
may lead to superior clinical outcomes. Duchesne and colleagues1 reported results from a phase 
III randomized clinical trial enrolling 293 men total, including de-novo incurable disease and 
those with a PSA relapse. Subjects were treated with either immediate or delayed ADT. In the 
PSA relapse population, 137 subjects were treated with delayed ADT while 124 were treated 
with immediate ADT. The estimated five year survival was 78.2% (95% CI, 67.2% – 85.8%) 
compared to 84.3% (95% CI, 73.9% – 90.8%) (P = 0.10) for the delayed versus immediate 
treatment groups respectively, suggesting a possible benefit based on this small study. In 
contrast, other studies do not support a clinical benefit from immediate therapy. Garcia-Albeniz 
et al2 reported on 2096 subject outcomes with immediate compared to deferred ADT. There was 
no improvement to the 5-year prostate cancer specific survival, 92.8% (95% CI, 86.7% – 98.9%) 
and 95.8% (95% CI, 92.7% – 98.9%) respectively for immediate and delayed ADT. There is a 
distinct lack of clear, clinical evidence to guide treatment decisions in this population. 
Further complicating the clinical decision making, recently advanced, molecular imaging 
techniques have been FDA approved or are in the approval process for subjects with PSA only 
relapse. The 18F-fluciclovine PET scan (also called axumin or [18F] anti-FACBC PET scan) is 
one example. It is approved specifically in subjects with PSA only relapsed prostate cancer. 
Unfortunately, there is very limited clinical data to guide any treatment recommendations for 
these subjects with 18F-fluciclovine PET positive disease. Different approaches appear to be 
used, such as continued observation, focal radiation therapy, surgical resection or immediate 
hormonal therapy. There are two reports of institutional experience using radiation or surgery 
approaches for subjects with a PSA only relapse and oligometastatic disease identified on 
molecular imaging.  
Bouman-Wammes et al3 reported on stereotactic body radiation therapy (SBRT) in forty-three 
subjects with oligometastatic (defined as < 5 metastasis) hormone sensitive prostate cancer. This 
was a single arm, prospective study. Subjects were identified through 18F-fluoromethylcholine 
positron emission tomography (PET) scans. A PSA response was seen in 67.4% of subjects, and 
the median ADT-free duration was 15.6 months (95% CI, 11.7 – 19.5 months), but 25.7 months 
(95% CI, 9.0 – 42.4 months) for subjects with a PSA response. Clinical outcomes were 

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compared against historic controls. The time until castration resistant prostate cancer was longer 
for the SBRT-treated subjects with a mean of 66.6 months (95% CI, 53.5 – 79.8 months), 
compared to 36.41 months (95% CI, 26.0 – 46.8 months) for the historic controls (P = 0.020). 
There were no significant toxicities associated with this treatment in this study. 
Siriwardana4 and colleagues enrolled 35 subjects with oligometastatic disease identified by 68Ga-
PSMA PET scans. Subjects underwent a targeted pelvic dissection (PET positive lesions only), 
unilateral extended dissection or a bilateral extended dissection. 32 subjects (91%) had 
pathologically confirmed lymph node metastasis. Subjects with a bilateral extended dissection 
appeared to benefit from this intervention on univariate analysis, suggesting that many subjects 
with biochemical recurrence have limited regional disease metastasis and may benefit from 
aggressive local therapy.  
Recently two clinical trials have demonstrated substantial clinical benefit for early, intense 
treatment for subjects with metastatic hormone sensitive prostate cancer using a combination of 
ADT plus abiraterone (NCT00268476, NCT01715285). Intensive treatment with combination 
ADT and chemotherapy (NCT00309985) has similarly been demonstrated to improve clinical 
outcomes in subjects with metastatic hormone sensitive prostate cancer. Additionally, early 
treatment in patients with non-metastatic castration-resistant prostate cancer with either 
enzalutamide5 or apalutamide6 compared with placebo both demonstrated a significant 
improvement to metastasis-free survival and a similar trend for improved overall survival. This 
body of evidence strongly suggests that early, intense therapy may provide significant clinical 
benefit in subjects with hormone sensitive oligometastatic prostate cancer. 
We hypothesize that local salvage treatment of oligometastatic disease identified on advanced 
imaging will result in long-term disease control, including optimal PSA responses and 
prolongation of radiographic progression-free survival. These results might translate into some 
men obtaining a cure of their prostate cancer, though this will have to be validated in future 
studies and with longer clinical follow up. Given that there is no standard of care for this setting, 
this clinical trial is designed to establish a standard reference for this population that can be used 
as the basis for additional clinical investigations in the future.  
3 TREATMENT INFORMATION 
3.1 
Surgery 
3.1.1 
Salvage Oligometastasectomy 
All subjects with pelvic and/or para-aortic lymph node metastases will undergo surgical 
dissection covering the bilateral nodal group identified by molecular imaging (e.g., 
fluciclovine PET/CT or PSMA PET/CT scan or other per PI discretion), and one level above 
and one level below any identified nodal region.  
Nodal groups from distal to proximal include: 1) Obturator fossa, 2) External iliac, 3) 
Common iliac, 4) Aortic-below IMA, 5) Aortic-above IMA.  
Metastases to superficial inguinal nodes will also be considered for surgical dissection in 
which cases both a superficial inguinal lymph node dissection and pelvic lymph node 
(obturator fossa and external iliac nodes) dissection will be performed. 

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3.1.2 
Salvage Prostatectomy  
Subjects previously treated with definitive radiotherapy whose TRUS biopsy is positive for 
malignancy when screening for the study (see inclusion criterion 5.1.4) must undergo salvage 
prostatectomy (or salvage radiotherapy if applicable, see Section 3.2.1). This can be done 
prior to enrollment on the study or at the same time as the nodal dissection described in 
Section 3.1.1 above.   
3.2 
External Beam Radiation Therapy 
Radiation therapy will be performed on linear accelerators capable of delivering X-ray or 
electron therapy in the 4 to 18 MeV range with image guidance systems. One of the 
fractionation schemes listed in Section 6 will be used.  
3.2.1 
Salvage Radiotherapy for Subjects with Positive TRUS Biopsy at Baseline 
Subjects previously treated with an incomplete course of definitive radiotherapy (as defined 
according to institutional standards) who have positive molecular imaging (e.g., fluciclovine 
PET/CT or PSMA PET/CT scan or other per PI discretion) suggesting recurrent intraprostatic 
disease and whose TRUS biopsy is positive for malignancy when screening for the study (see 
inclusion criterion 5.1.4) must undergo completion of their radiation course or salvage 
prostatectomy as defined in section 3.1.2.  
4 STUDY DESIGN 
4.1 
Description 
This is a Phase II non-randomized pilot study meant to establish preliminary reference 
response rate and duration of response for subjects with recurrent prostate cancer treated with 
salvage oligometastasectomy and/or radiotherapy. Treatment decisions will be based on 
molecular imaging (e.g., fluciclovine PET/CT or PSMA PET/CT scan or other per PI 
discretion): subjects with nodal disease only will be treated with oligometastasectomy, 
subjects with bone disease only will be treated with SBRT, and subjects with a combination 
of nodal and bone disease will receive both treatment. Response rates and durations will be 
based on PSA and imaging.  
4.2 
Number of Subjects 
A total of twenty (20) subjects will be enrolled on this study. 
4.3 
Number of Study Centers 
This study will open at a single center at the Huntsman Cancer Institute. 
4.4 
Study Duration 
The estimated duration of accrual is 2 years, subjects will be followed for up to 3 years for a 
total study duration of up to 5 years. 
 
 

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5 ELIGIBILITY CRITERIA 
This eligibility checklist is used to determine subject eligibility and filed with the enrolling 
investigator’s signature in the subject research chart.  
Subject No. ______________________ 
Subject’s Initials: (L,F,M) _________________ 
5.1 
Inclusion Criteria 
Yes/No (Response of “no” = subject ineligible) 
5.1.1 
_____ Male subjects age ≥ 18 years. 
5.1.2 
_____ Histologically proven adenocarcinoma of the prostate. 
5.1.3 
_____ Recurrent prostate carcinoma after definitive therapy for primary disease 
defined as: 
• Post-prostatectomy (with/without adjuvant radiotherapy): Patients must have a 
detectable or rising PSA level that is >0.05 ng/mL, with a second confirmatory 
level that is >0.05ng/mL after a minimum of 1 week. 
• Post radiotherapy/ablation (without radical prostatectomy): PSA rise ≥ 2ng/mL 
over nadir. 
5.1.4 
_____ Subjects treated with prior definitive radiotherapy for prostate cancer who have  
positive molecular imaging (e.g., fluciclovine PET/CT or PSMA PET/CT scan or 
other per PI discretion) suggesting recurrent intraprostatic disease must undergo 
TRUS biopsy less than or equal to one year before study enrollment: 
• If the TRUS biopsy is negative, no additional treatment is required to the prostate 
in addition to that of scan-positive sites. 
• If the TRUS biopsy is positive, subject must undergo salvage prostatectomy or 
salvage radiotherapy to the primary site concurrently with the study treatment per 
the treatment protocol algorithm. 
• Note: Biopsy is not required for prostate fossa recurrences after radical 
prostatectomy.  

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5.1.5 
_____ Oligometastatic disease defined as 10 or fewer metastatic lesions to lymph 
nodes and/or bones only. 
5.1.6 
_____ For patients with oligometastatic disease involving lymph nodes, metastasis is 
confined to the pelvic or para-aortic (below IMA) regions on molecular imaging (e.g., 
fluciclovine PET/CT or PSMA PET/CT scan or other per PI discretion). 
5.1.7 
_____ All subjects must be surgical candidates if surgery is indicated per the treatment 
algorithm. 
5.1.8 
_____ECOG Performance Status ≤ 2. 
5.1.9 
_____ Use of condoms for male subjects who have not had surgical removal of their 
prostate and have a partner of child bearing potential beginning at the time of ICF 
signature and lasting until at least 6 months after the last radiation treatment. Because 
of the potential side effect on spermatogenesis associated with radiation, female 
partners of childbearing potential must agree to use a highly effective contraceptive 
method during and for 6 months after completing treatment. 
5.1.10 
_____ Recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any 
prior treatments, unless AE(s) are clinically non-significant and/or stable on 
supportive therapy as determined by the treating physician. 
5.1.11 
_____ Able to provide informed consent and willing to sign an approved consent form 
that conforms to federal and institutional guidelines. 
5.2 
Exclusion Criteria 
Yes/No (Response of “yes” = subject ineligible) 
5.2.1 
_____ Known brain or visceral metastases other than lymph nodes (defined in section 
5.1.6) as defined by CT, MRI, or other molecular imaging (e.g., fluciclovine PET/CT 
or PSMA PET/CT scan or other per PI discretion). 
5.2.2 
_____ Patients actively receiving hormone therapy for prostate cancer. Patients may 
have received hormone therapy previously but must have documented non-castrate 
levels of testosterone (>50 ng/dL). 
5.2.3 
_____ Prior or concurrent malignancy whose natural history or treatment, in the 
opinion of the enrolling investigator, may have the potential to interfere with the 
safety or efficacy assessment of the investigational treatment protocol of this study.  

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5.2.4 
_____ Use of finasteride within 30 days prior to initiation of therapy. Baseline PSA 
should not be obtained prior to 30 days after stopping finasteride. 
5.2.5 
_____ Use of dutasteride within 90 days prior to initiation of therapy. Baseline PSA 
should not be obtained prior to 90 days after stopping dutasteride. 
5.2.6 
_____ Use of any prohibited therapy noted in 6.3.2. 
5.2.7 
_____ Active, uncontrolled, significant intercurrent or recent illness including, but not 
limited to, the following conditions: 
• Cardiovascular disorders: 
o Congestive heart failure New York Heart Association Class 3 or 4, unstable 
angina pectoris, serious cardiac arrhythmias.  
o Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 
mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive 
treatment. 
o Stroke (including transient ischemic attack [TIA]), myocardial infarction 
(MI), or other ischemic event, or thromboembolic event (e.g., deep venous 
thrombosis, pulmonary embolism) within 6 months before first dose.  
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration 
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy at the time of registration or 
within 30 days of registration.  
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;  
I certify that this subject meets all inclusion and exclusion criteria for enrollment onto this 
study.  
____________________________________________       _________       _____________
 
Investigator Signature  
 
 
 
Date  
Time 
 
 
 

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5.3 
Recruitment Strategies 
Potential subjects will be identified by Investigators in the setting of their outpatient clinics. 
6 TREATMENT GUIDELINES 
6.1 
Subjects with Bone Metastases Only 
Bone metastases will be treated with stereotactic body or hypofractionated radiation per 
institutional standard of care guidelines. The investigator will select the type of radiation 
based on the nature of the disease. 
Following completion of radiation treatment subjects will move on to the follow-up phase of 
the study as described in Section 9.3.  
6.1.1 
Dose Specification 
All subjects will receive stereotactic body or hypofractionated radiation to sites of bone 
disease seen on imaging studies. Radiation will be administered per institutional standard of 
care which is commonly 16-44 Gy in 1-6 fractions, using any one of the isoequivalent 
radiation regimens (based on the linear quadratic model with EQD2≥60 and an alpha/beta 
ratio for prostate cancer=2) to allow the radiation oncologist flexibility to deliver an ablative 
dose while sparing normal tissues depending on tumor location. In cases where radiation is 
administered outside of these parameters, prior approval will be obtained from the PI and 
medical monitor. 
6.1.2 
Target Localization 
This study requires the use of IGRT, a computer assisted process that uses imaging devices 
that generate a series of coordinates for shifting the patient support system in three 
orthogonal directions (sometimes including rotational changes) to position the treatment 
beams relative to target regions. The allowed technologies are as follows: cone-beam CT 
(CBCT) using either a specially mounted kV imaging head or the MV treatment beam with 
an opposed electronic imaging panel, dual fixed-position in-room kV imaging systems that 
are orthogonal or near orthogonal, an in-room standard diagnostic CT scanner that is 
geometrically linked to the treatment unit, and the tomotherapy approach. 
Simple portal imaging approaches that do not use computer assistance are not considered to 
be suitable for this study. 
When the treatment equipment is not equipped with any device that allows direct 
visualization of anatomical structures using the treatment beam, the recommendations of 
AAPM Task Group Report 142 for testing the coincidence of the imaging and treatment 
reference points must be implemented. For example, verification of treatment and imaging 
isocenter coincidence must be performed routinely for the CyberKnife, Tomotherapy units as 
well as any BrainLab equipment that does not include an electronic portal imaging device 
(EPID) that intercepts the treatment beam. 
6.1.3 
Target Volume Definition 
Non-Spinal Osseous Sites 

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GTV = gross tumor apparent on CT or MRI, or other molecular imaging (e.g., fluciclovine 
PET/CT or PSMA PET/CT scan or other per PI discretion).  
CTV = GTV.  
PTV will be uniform expansion of 3-5 mm. 
Spinal Osseous Sites 
GTV = gross tumor apparent on CT or MRI, or other molecular imaging (e.g., fluciclovine 
PET/CT or PSMA PET/CT scan or other per PI discretion). The GTV will include 1 of the 
following (as illustrated in Figure 6.1): 
a. The vertebral body only OR 
b. The vertebral body and pedicle OR 
c. Posterior elements only 
CTV = GTV.  
PTV will be as per RTOG 0631.  
Figure 6.1. Diagram of Spine Metastases and Target Volumes 
 
6.1.4 
Planning Techniques  
6.1.4.1 
General Considerations 
A variety of planning techniques can be used to deliver SBRT for each metastasis. General 
guidelines include the following: 
• Multiple coplanar or non-coplanar beam arrangements are acceptable. 
• Typically 7-13 static radiation beams with equal weighting are used. It is recommended 
that at least 10 beams be used when possible. 
• A minimum field dimension of 3 cm should be observed treating small metastases. 
• Dynamic conformal arcs are acceptable. It is recommended that arcs span at least 340 
degrees. 
• For non-IMRT or dose painting techniques, the conformal field aperture size and shape 
should correspond nearly identically to the projection of the PTV along a beam’s eye 
view (i.e., no additional “margin” for dose buildup at the edges of the blocks or MLC 
jaws beyond the PTV). The only exception will be when observing the minimum field 
dimension of 3 cm when treating small lesions. 
• The prescription isodose line covering 95% the PTV will generally be 80-90% but may 
range from 60-90% where the maximum dose is 100%. As a result, a “hotspot” will exist 

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within the PTV that is equal to the prescription dose divided by the prescription isodose 
line (i.e., 45Gy/0.6 = 75Gy when 45Gy is prescribed to the 60% isodose). 
• Doses higher than the prescription isodose (i.e., hotspots) should be manipulated to occur 
within the target. 
6.1.4.2 
Dose calculations 
All dose distributions shall include corrections for tissue heterogeneities. 
6.1.4.3 
Normalization 
The treatment plan should be initially normalized such that 100% corresponds to the 
maximum dose within the PTV (MAXPTV). While this point will typically correspond to the 
PTV center of mass, it can be located elsewhere within the PTV. 
1. Prescription Isodose Surface Coverage: The prescription isodose surface will be 
chosen such that 95% of the target volume (PTV) is conformally covered by the 
prescription isodose surface. Doses less than 95% of the prescription dose are restricted 
to the outside edges of the PTV. The prescription isodose surface selected MUST be ≥ 
60% and ≤90% of the dose maximum within the PTV (MAXPTV). The MAXPTV 
corresponds to the normalization point (100%) of the plan as noted above. 
2. Target Dose Heterogeneity: Rather than prioritizing target dose homogeneity, SBRT 
treatment planning prioritizes adequate minimum target coverage and rapid dose fall-off 
gradients outside of the target. Hot spots within targets are generally accepted without 
consequence since targets are mostly tumor. The only exception is when the hotspot 
within the PTV also intersects an OAR. 
3. Critical Organ Doses: Respect all critical organ dose-volume limits as Described by 
either: The report of AAPM Task Group 101, the NRG BR-001 protocol, or the RTOG 
0631 treatment protocol.  
4. High-Dose Spillage: 
a. Location: Any dose > 105% of the prescription dose should occur within the PTV and 
not within the normal tissues outside the PTV.  
b. Volume: Acceptable isodose distributions should be as conformal as possible. To this 
end the ratio of prescription isodose volume to PTV should be as small as possible. 
i. The ratio of the prescription isodose volume to the PTV volume should be < 1.2. 
Acceptable variations include a ratio of 1.2-1.5. Ratios above 1.5 will be 
considered unacceptable variations. The prescription line for each lesion will be 
contoured for calculation of this ratio. The prescription line will be labelled as 
V_5000 with the 5000 changing to reflect the prescription dose in cGy.  
ii. Guidelines for the ratio of the 50% prescription isodose volume to the PTV 
volume (R50%) and for the maximum dose at 2 cm (D2cm) from the PTV are 
given in Table 6.1. Because it may become more difficult to restrict the 50% 
isodose volume when dose is summed from treatment of multiple metastases, this 
ratio should be evaluated for dose calculated for a single metastasis (i.e., not for 
composite dose). This is acceptable as long as normal tissue constraints are met. 

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iii. Elliptically shaped metastases as well as extremity metastases may not meet these 
guidelines. This is acceptable as long as normal tissue constraints are respected. 
iv. These criteria will not be required in treating very small tumors (< 2.5 cm axial 
GTV dimension or < 1.5 cm craniocaudal GTV dimension) in which the required 
minimum field size of 3 cm results in the inability to meet a conformity ratio of 
1.5. 
Table 6.1: Guidelines for the Ratio of the 50% Prescription Isodose Volume to 
the PTV Volume (R50%) and for the Maximum Dose at 2 cm (D2cm) from the 
PTV 
PTV Volume 
(cc) 
Ratio of 50% Prescription 
Isodose Volume to PTV 
Volume, R50% 
Maximum Dose at 2cm (D2cm) from 
PTV in any direction as % of 
Prescribed Dose 
1.8 
< 7.5 
< 57.0 
3.8 
< 6.5 
< 57.0 
7.4 
< 6.0 
< 58.0 
13.2 
< 5.8 
< 58.0 
22.0 
< 5.5 
< 63.0 
34.0 
< 5.3 
< 68.0 
50.0 
< 5.0 
< 77.0 
70.0 
< 4.8 
< 86.0 
95.0 
< 4.4 
< 89.0 
126.0 
< 4.0 
< 91.0 
163.0 
< 3.7 
< 94.0 
NOTE: For values of PTV dimension or volume not specified, linear interpolation between 
table entries is required. 
NOTE: For tumors within 2 cm of the skin, it may be difficult to meet the values for D2cm 
and R50%. In these cases, these criteria will not be used. 
6.2 
Subjects with Nodal Metastases (With or Without Bone Metastases) 
Subjects with nodal metastases will initially be treated with salvage resection of their nodal 
disease followed, as needed, by treatment of their bone metastases. In some cases and at the 
discretion of the investigator (e.g., painful bone lesions), treatment of the bone lesions can 
take place before nodal resection. 
6.2.1 
Oligometastasectomy 
Subjects with pelvic or para-aortic lymph node metastases will undergo surgical dissection. 
Treatment will cover the bilateral nodal group identified by molecular imaging (e.g., 
fluciclovine PET/CT or PSMA PET/CT scan or other per PI discretion), and one level above 
and one level below any identified nodal region.  
Nodal groups from distal to proximal include: 1) Obturator fossa, 2) External iliac, 3) 
Common iliac, 4) Aortic-below IMA, 5) Aortic-above IMA.  

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Metastases to superficial inguinal nodes will also be considered for surgical dissection in 
which cases both a superficial inguinal lymph node dissection and pelvic lymph node 
(obturator fossa and external iliac nodes) dissection will be performed. 
For subjects who were treated with definitive radiotherapy pre-study and have a positive 
TRUS biopsy at baseline, or less than or equal to a year before study enrollment, salvage 
prostatectomy will be performed along with the procedure described above (unless salvage 
radiotherapy is indicated as described in Section 3.2.1). 
6.2.2 
Radiotherapy to Bone Metastases (As Applicable) 
Following recovery from their nodal resection, subjects with bone metastases will be treated 
with radiotherapy as described above in Section 6.1. 
6.2.3 
Adjuvant Nodal Radiation Therapy 
Within 4 months following completion of salvage therapy (defined as the combination of 
oligometastasectomy and/or bone radiation) and depending on PSA response as well as 
previous treatment, patients may receive adjuvant nodal IMRT as highlighted in Figure 2 and 
as described below. 
6.2.3.1 
Subjects whose PSA declines to 0 following resection 
This will be considered a complete PSA response (PSA CR) and no further treatment will be 
required. Subjects will move on to the follow-up phase of the study as described in Section 
9.3. 
6.2.3.2 
Subjects whose PSA declines by ≥ 1/3 but remains > 0.2 ng/mL 
Following confirmation of the lack of PSA response (2 consecutive PSA values obtained at 
least 3 weeks apart which have decreased from the pre-resection value by ≥ 1/3 yet remain > 
0.2 ng/mL, considered a partial PSA response or PSA PR), subjects will receive IMRT based 
on their previous treatment history: 
Option 1 
• Subjects who have undergone prior salvage/adjuvant radiotherapy to the pelvis (with or 
without treatment of para-aortic lymph nodes) 
OR  
• Subjects who have undergone prior prostate radiotherapy with pelvic/nodal irradiation  
 Ipsilateral involved-field image-guided IMRT with boost to any identifiable lesions. 
- 
Dose will be 45 Gy in 25 fractions 
- 
Simultaneous integrated boost to gross target volumes must be ≥ 76 Gy in total 
equieffective dose (EQD2) 
Option 2 
• Subjects who have undergone prior prostate radiotherapy without pelvic/nodal irradiation 
OR 

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• Subjects who have undergone prior prostatectomy without adjuvant/salvage radiotherapy:  
 Bilateral pelvic image-guided IMRT with boost to any identifiable lesions. 
- 
Inferior field border functioned immediately above the previously treated field to 
50.4 Gy 
- 
Simultaneous integrated boost to gross target volumes must be ≥ 76 Gy in total 
equieffective dose (EQD2) 
Following adjuvant radiation therapy, subjects will move on to the follow-up phase of the 
study as described in Section 9.3. 
6.2.3.3 
Subjects whose PSA declines by < 1/3 
This will be considered a treatment failure (PSA response failure), no adjuvant therapy will 
be given. Subjects will enter the follow-up period until diagnosis of metastatic disease and 
will not receive any further treatment. 
6.3 
Concomitant Medications and Therapies 
6.3.1 
Allowed Therapy 
Any medication which is considered necessary for a subject’s welfare is permitted and may 
be given at the discretion of the investigator. Medications for treatment of underlying disease 
and symptomatic treatment of adverse events are permitted. Exceptions are listed in the 
section below. 
6.3.2 
Prohibited Therapy 
• Concurrent anti-cancer therapy (chemotherapy, androgen deprivation therapy, 
immunotherapy, biologic therapy, or tumor embolization) and external beam radiation 
other than those specified in this protocol. 
• Concurrent use of another investigational drug or device therapy (i.e., outside of study 
treatment) during, or within 4 weeks of trial entry (signing of the informed consent form). 
• Major surgery within 30 days prior to enrollment.  
6.4 
Duration of Therapy 
6.4.1 
Criteria for the Discontinuation of Treatment (“Off Treatment”) 
Patients may withdraw from treatment or the study overall at any time at their own request, 
or they may be withdrawn at the discretion of the Investigator for safety, behavioral reasons, 
or the inability of the patient to comply with the protocol-required schedule of study visits or 
procedures.  
In addition to the drug-specific discontinuation criteria listed in Dose Modification Section, 
the following will result in treatment discontinuation: 
• Adverse events or intercurrent illness that in the opinion of the investigator warrants 
the subject’s withdrawal from study treatment 

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• The subject or legally authorized representative requests to discontinue the study 
treatment and/or study procedures 
• Salvage treatment failure defined as radiographic progression per PCWG3 criteria OR 
RECIST 1.1. Patients taken off treatment for treatment failure will continue to be 
followed for toxicity assessments only every 6 months. 
• Failure to initiate adjuvant radiotherapy within 4 months of completion of salvage 
therapy (oligometastasectomy and/or bone radiotherapy). 
• Patient refused further treatment 
• Significant noncompliance with the protocol schedule or treatment administration in 
the opinion of the investigator 
• Clinical deterioration that, in the opinion of the investigator, increases the risk to the 
subject 
Surgery may be aborted if unforeseen complications arise. 
Radiation therapy courses may be shortened in case of RTOG Grade III-IV or persistent (≥ 2 
weeks) Grade II toxicities. Continuation of treatment during Grade III toxicities may be 
allowed if the patient is benefiting as assessed by the treating investigator.  
6.4.2 
Criteria for the Discontinuation of Study (“Off Study”) 
Subjects will be taken off study for the following: 
• Study terminated by investigator sponsor 
• Completed study follow-up period 
• Participant or legally authorized representative requests to be fully withdrawn from 
the study 
• If, in the investigator's opinion, continuation of the trial would be harmful to the 
subject's well-being. 
• Development of an intercurrent illness or situation which would, in the judgment of the 
investigator, significantly affect assessments of clinical status and trial endpoints. 
• Initiation of new anti-cancer therapy 
• Subject is lost to follow-up 
• Death 
• Screen failure 
7 TOXICITIES AND DOSEAGE MODIFICATION 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for adverse event and serious adverse event reporting. Radiation toxicities will be 
graded according to the Radiation Therapy Oncology Group (RTOG) toxicity grading system 
(Appendix A) and surgical complications will graded according to the Clavien-Dindo 
classification (Appendix B). 

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7.1 
Dose Modifications and Guidelines for Adverse Event Management for 
Radiotherapy 
7.1.1 
Dose Modifications 
In the event of a clinically significant CTCAE v5 adverse event ≥ grade 3, which is felt to be 
at least possibly related to radiation therapy, treatment will be discontinued. Treatment 
related adverse events ≤ grade 2 may result in a reduction in the dose of radiation therapy if 
the treating physician feels that further radiation would be likely to exacerbate harm to the 
patient. 
Radiation therapy courses may be shortened in case of RTOG Grade III-IV or persistent (≥ 2 
weeks) Grade II toxicities. Continuation of treatment during Grade III toxicities may be 
allowed if the patient is benefiting as assessed by the treating investigator.  
7.1.2 
Guidelines for Management of Adverse Events 
Adverse events related to radiation therapy will be managed at the discretion of the treating 
radiation oncologist, per institutional standards. 
7.2 
Supportive Care 
All supportive measures consistent with optimal subject care may be given throughout the 
study. 
7.3 
Contraception 
Subjects who have not had surgical removal of their prostate and have a partner of child 
bearing potential must agree to use condoms beginning at the signing of the ICF until at least 
6 months after the last dose of study treatment. Because of the potential side effect on 
spermatogenesis associated with radiation, female partners of childbearing potential must 
agree to use a highly effective contraceptive method during and for 6 months after 
completing treatment.

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8 STUDY CALENDAR 
8.1 
Arm A  
Procedures 
Screening1 
(-4 weeks) 
On Treatment 
Follow-up2 
 
Salvage 
Therapy 
 
Response 
Assessment3 
(45 days ± 5 
days after 
last day of RT) 
Year 1 
(Q3M ± 
2 weeks) 
Year 2-3 
(Q3M ± 
1 month) 
 
Radiation 
 
Informed Consent 
X 
 
 
 
 
Medical History4 
X 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
Clinical Assessments 
Vital Signs, Weight5 
X 
 
X 
X 
X 
Physical Exam 
X 
 
X 
X 
X 
ECOG Performance Status 
X 
 
X 
X 
X 
Adverse Event Collection6 
 
At each visit 
 
Concomitant Medication Collection 
X 
At each visit 
 
Laboratory Studies 
Hematology7 
X 
 
 
 
 
Chemistry8 
X 
 
 
 
 
LDH 
X 
 
 
 
 
PSA9 
X 
 
X 
X 
X 
Disease Assessments 
Molecular imaging (e.g., fluciclovine 
PET/CT or PSMA PET/CT scan or 
other per PI discretion)10 
X 
 
 
 
 
CT Scans 
 
 
 
X11 
X11 
Nuclear Medicine Bone Scans (if 
clinically indicated) 
X 
 
 
X12 
X12 
TRUS Biopsy13 
X 
 
 
 
 
Intervention 
SBRT or Hypofractionated Bone 
Radiotherapy 
 
X 
 
 
 
Correlative Studies 
Optional Blood14 
X 
X 
X15 
Optional Archival Tissue16 
X 
 
 
 
 
Optional Fresh Tissue17 
X 
 
 
 
 
Questionnaires 
PRO and QOL Questionnaires18 
X 
 
X 
X 
X 
RTOG Toxicity Evaluation19 
 
 
X 
X 
X 
 

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1 All pre-study/screening procedures should be completed within 4 weeks of study enrollment - with the exception 
of laboratory tests which need to be completed within 2 weeks prior to study enrollment, and imaging assessments 
which must be completed within 90 days of enrollment. 
2 Follow-up procedures will occur every 3 months for 3 years beginning from the last day of RT unless stated 
otherwise.  
3 The response assessment visit will take place 45 ± 5 days after completion of salvage therapy (surgery and/or 
radiation). 
4 To include Charlson Comorbidity Index (See Appendix E) 
5 Vital signs include systolic/diastolic blood pressure, heart rate, respiration rate, pulse oximetry, and body 
temperature. Height will be captured at screening only. 
6 Adverse events will be assessed after treatment has begun and at each time a patient is seen in clinic or scheduled 
for correlative sample collections. Adverse events will be collected every three months for one year after treatment 
discontinuation. 
7 Hematology includes CBC with differential and platelets. 
8 Chemistry includes sodium, potassium, chloride, carbon dioxide or bicarbonate, blood urea nitrogen (BUN), 
creatinine, glucose, total protein, albumin, calcium, AST, ALT, alkaline phosphatase, total bilirubin. 
9 PSA progression must be confirmed according to PCWG3 criteria, after at least 1 week. See Section 10.2.1. 
10 To be performed at screening (within 90 days prior to enrollment). 
11 CT scans of the chest/abdomen/pelvis scans recommended to be performed 6 months and 1 year after completion 
of ALL treatments (salvage and adjuvant therapy) (± 2 weeks), and annually for 2 additional years (± 1 month) in 
patients without evidence of disease progression, otherwise as clinically indicated. 
12 Nuclear medicine bone scans recommended to be performed 6 months and 1 year after completion of ALL 
treatments (salvage and adjuvant therapy) (± 2 weeks), and annually for 2 additional years (± 1 month) in patients 
without evidence of disease progression, otherwise as clinically indicated. 
13 TRUS biopsy must be performed at screening (within 1 year prior to enrollment) only for subjects who have been 
previously treated with definitive prostate radiotherapy and have disease recurrence in the prostate evidenced by 
positive molecular imaging (e.g., fluciclovine PET/CT or PSMA PET/CT scan or other per PI discretion). 
14 Optional blood draws may be performed prior to starting salvage therapy, at the next standard of care follow up 
visit after completion of salvage therapy, and at the time of confirmed PSA progression or radiological progression. 
See Section 14.3 for details. 
15  After completion of salvage treatment, optional blood will only be collected once at time of confirmed disease 
progression. 
16 Optional archival tissue may be collected at baseline for all subjects for whom it is available. Archival tissue 
slides should not be cut until requested from the Central Lab. Lack of archival tissue will not be exclusionary. 
17 Optional fresh tissue may be collected prior to starting salvage therapy during the TRUS biopsy (if performed) 
and at the time of oligometastasectomy or prostatectomy (if indicated and if available after SOC tissue collection). 
See Section 14.1 and 14.2 for details. 
18 Quality of life (QOL) questionnaires (FACT-P and Expanded Prostate Cancer Index Composite EPIC-26) will be 
collected prior to starting salvage therapy, at the Response Assessment Visit, and at each follow-up visits. See 
Appendices C and D. 
19To be performed at the Response Assessment Visit and at each follow-up visits See Appendix A. 
                                                 
 
 
 
 
 
 
 
 
 
 

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8.2 
Arm B 
Procedures 
Screeninga 
(-4 weeks) 
On Treatment 
Follow-upb 
 
Salvage 
Therapy 
 
Response 
Assessmentc 
(45 days ± 5 
days after 
last day of 
RT) 
 
Adjuvant 
Radiotherapy4 
(within 4 
months after 
completion of 
salvage 
therapy) 
 
Year 
1 
(Q3M 
± 2 
weeks) 
Year 
2-3 
(Q3M 
± 1 
month) 
 
Surgery 
 
Informed Consent 
X 
 
 
 
 
 
Medical Historyd 
X 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
Clinical Assessments 
Vital Signs, Weighte 
X 
 
X 
 
X 
X 
Physical Exam 
X 
 
X 
 
X 
X 
ECOG Performance Status 
X 
 
X 
 
X 
X 
Adverse Event Collectionf 
 
At each visit 
 
Concomitant Medication 
Collection 
X 
At each visit 
 
Laboratory Studies 
Hematologyg 
X 
 
 
 
 
 
Chemistryh 
X 
 
 
 
 
 
LDH 
X 
 
 
 
 
 
PSAi 
X 
 
X 
 
X 
X 
Disease Assessments 
Molecular imaging (e.g., 
fluciclovine PET/CT or PSMA 
PET/CT scan or other per PI 
discretion)j 
X 
 
 
 
 
 
CT Scans 
 
 
 
 
Xk 
Xk 
Nuclear Medicine Bone Scans 
(if clinically indicated) 
X 
 
 
 
Xl 
Xl 
TRUS Biopsym 
X 
 
 
 
 
 
Intervention 
Oligometastasectomy 
 
X 
 
 
 
 
Salvage Prostatectomyn 
 
X 
 
 
 
 
Nodal IMRTo 
 
 
 
X 
 
 
Correlative Studies 
Optional Bloodp 
X 
X 
X 
Xq 
Optional Archival Tissuer 
X 
 
 
 
 
 
Optional Fresh Tissues 
X 
 
 
 
 
 
Questionnaires 
PRO and QOL Questionnairest 
X 
 
X 
 
X 
X 
RTOG Toxicity Evaluationu 
 
 
X 
 
X 
X 

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a All pre-study/screening procedures should be completed within 4 weeks of study enrollment - with the exception 
of laboratory tests which need to be completed within 2 weeks prior to study enrollment, and imaging assessments 
which must be completed within 90 days of enrollment. 
b Follow-up procedures will occur every 3 months for 3 years beginning from the last day of RT unless stated 
otherwise.  
c The response assessment visit will take place 45 ± 5 days after completion of salvage therapy (surgery and/or 
radiation). 
d To include Charlson Comorbidity Index (See Appendix E) 
e Vital signs include systolic/diastolic blood pressure, heart rate, respiration rate, pulse oximetry, and body 
temperature. Height will be captured at screening only. 
f Adverse events will be assessed after treatment has begun and at each time a patient is seen in clinic or scheduled 
for correlative sample collections. Adverse events will be collected every three months for one year after treatment 
discontinuation. 
g Hematology includes CBC with differential and platelets. 
h Chemistry includes sodium, potassium, chloride, carbon dioxide or bicarbonate, blood urea nitrogen (BUN), 
creatinine, glucose, total protein, albumin, calcium, AST, ALT, alkaline phosphatase, total bilirubin. 
i PSA progression must be confirmed according to PCWG3 criteria, after at least 1 week. See Section 10.2.1. 
j To be performed at screening (within 90 days prior to enrollment). 
k CT scans of the chest/abdomen/pelvis scans recommended to be performed 6 months and 1 year after completion 
of ALL treatments (salvage and adjuvant therapy) (± 2 weeks), and annually for 2 additional years (± 1 month) in 
patients without evidence of disease progression, otherwise as clinically indicated. 
l Nuclear medicine bone scans recommended to be performed 6 months and 1 year after completion of ALL 
treatments (salvage and adjuvant therapy) (± 2 weeks), and annually for 2 additional years (± 1 month) in patients 
without evidence of disease progression, otherwise as clinically indicated. 
m TRUS biopsy must be performed at screening (within 1 year prior to enrollment) only for subjects who have been 
previously treated with definitive prostate radiotherapy and have disease recurrence in the prostate evidenced by 
positive molecular imaging (e.g., fluciclovine PET/CT or PSMA PET/CT scan or other per PI discretion). 
n Only for subjects who have been previously treated with an incomplete course of definitive prostate radiotherapy 
and whose baseline TRUS biopsy is positive. Can be replaced with salvage prostatectomy at the discretion of the 
treating physician. 
o Only required for subjects with a confirmed lack of PSA response (see section 6.2.3.2) following salvage therapy 
(see PCWG3 criteria in appendix) 
p Optional blood draws may be performed prior to starting salvage therapy, at the next standard of care follow up 
visit after completion of salvage therapy, and at the time of confirmed PSA progression or radiological progression. 
See Section 14.3 for details. 
q After completion of salvage treatment, optional blood will only be collected once at time of confirmed disease 
progression. 
r Optional archival tissue may be collected at baseline for all subjects for whom it is available. Archival tissue slides 
should not be cut until requested from the Central Lab. Lack of archival tissue will not be exclusionary. 
s Optional fresh tissue may be collected prior to starting salvage therapy during the TRUS biopsy (if performed) and 
at the time of oligometastasectomy or prostatectomy (if indicated and if available after SOC tissue collection). See 
Section 14.1 and 14.2 for details. 
t Quality of life (QOL) questionnaires (FACT-P and Expanded Prostate Cancer Index Composite EPIC-26) will be 
collected prior to starting salvage therapy, at the Response Assessment Visit, and at each follow-up visits. See 
Appendices C and D. 
uTo be performed at the Response Assessment Visit and at each follow-up visits See Appendix A 
                                                 

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8.3 
Arm C 
Procedures 
Screeningi 
(-4 weeks) 
On Treatment 
Follow-upii 
 
Salvage 
Therapy 
 
Response 
Assessmentiii 
(45 days ± 5 
days after 
last day of 
RT) 
 
Adjuvant 
Radiotherapy4 
(4 months after 
completion of 
salvage 
therapy) 
 
Year 
1 
(Q3M 
± 2 
weeks) 
Year 
2-3 
(Q3M 
± 1 
month) 
 
Surgery 
 
Radiation 
Informed Consent 
X 
 
 
 
 
 
 
Medical Historyiv 
X 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
Clinical Assessments 
Vital Signs, Weightv 
X 
 
 
X 
 
X 
X 
Physical Exam 
X 
 
 
X 
 
X 
X 
ECOG Performance 
Status 
X 
 
 
X 
 
X 
X 
Adverse Event 
Collectionvi 
 
At each visit 
 
Concomitant 
Medication 
Collection 
X 
At each visit 
 
Laboratory Studies 
Hematologyvii 
X 
 
 
 
 
 
 
Chemistryviii 
X 
 
 
 
 
 
 
LDH 
X 
 
 
 
 
 
 
PSAix 
X 
 
 
X 
 
X 
X 
Disease Assessments 
Molecular imaging 
(e.g., fluciclovine 
PET/CT or PSMA 
PET/CT scan or other 
per PI discretion)x 
X 
 
 
 
 
 
 
CT Scans 
 
 
 
 
 
Xxi 
Xxi 
Nuclear Medicine 
Bone Scans (if 
clinically indicated) 
X 
 
 
 
 
Xxii 
Xxii 
TRUS Biopsyxiii 
X 
 
 
 
 
 
 
Intervention 
Oligometastasectomy 
 
X 
 
 
 
 
 
Salvage 
Prostatectomyxiv 
 
X 
 
 
 
 
 
Salvage Prostate 
Radiotherapyxv 
 
 
X 
 
 
 
 

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SBRT or 
Hypofractionated 
Bone Radiotherapy 
 
 
X 
 
 
 
 
Nodal IMRTxvi 
 
 
 
 
X 
 
 
Correlative Studies 
Optional Bloodxvii 
X 
X 
 
Xxviii 
Optional Archival 
Tissuexix 
X 
 
 
 
 
 
 
Optional Fresh 
Tissuexx 
X 
X 
 
 
 
 
 
Questionnaires 
PRO and QOL 
Questionnairesxxi 
X 
 
 
X 
 
X 
X 
RTOG Toxicity 
Evaluationxxii 
 
 
 
X 
 
X 
X 
 
 
 
 
 
i All pre-study/screening procedures should be completed within 4 weeks of study enrollment - with the exception of 
laboratory tests which need to be completed within 2 weeks prior to study enrollment, and imaging assessments 
which must be completed within 90 days of enrollment. 
ii Follow-up procedures will occur every 3 months for 3 years beginning from the last day of RT unless stated 
otherwise.  
iii The response assessment visit will take place 45 ± 5 days after completion of salvage therapy (surgery and/or 
radiation). 
iv To include Charlson Comorbidity Index (See Appendix E) 
v Vital signs include systolic/diastolic blood pressure, heart rate, respiration rate, pulse oximetry, and body 
temperature. Height will be captured at screening only. 
vi Adverse events will be assessed after treatment has begun and at each time a patient is seen in clinic or scheduled 
for correlative sample collections. Adverse events will be collected every three months for one year after treatment 
discontinuation. 
vii Hematology includes CBC with differential and platelets. 
viii Chemistry includes sodium, potassium, chloride, carbon dioxide or bicarbonate, blood urea nitrogen (BUN), 
creatinine, glucose, total protein, albumin, calcium, AST, ALT, alkaline phosphatase, total bilirubin. 
ix PSA progression must be confirmed according to PCWG3 criteria, after at least 1 week. See Section 10.2.1. 
x To be performed at screening (within 90 days prior to enrollment). 
xi CT scans of the chest/abdomen/pelvis scans recommended to be performed 6 months and 1 year after completion 
of ALL treatments (salvage and adjuvant therapy) (± 2 weeks), and annually for 2 additional years (± 1 month) in 
patients without evidence of disease progression, otherwise as clinically indicated. 
xii Nuclear medicine bone scans recommended to be performed 6 months and 1 year after completion of ALL 
treatments (salvage and adjuvant therapy) (± 2 weeks), and annually for 2 additional years (± 1 month) in patients 
without evidence of disease progression, otherwise as clinically indicated. 
xiii TRUS biopsy must be performed at screening (within 1 year prior to enrollment) only for subjects who have been 
previously treated with definitive prostate radiotherapy and have disease recurrence in the prostate evidenced by 
positive molecular imaging (e.g., fluciclovine PET/CT or PSMA PET/CT scan or other per PI discretion). 
xiv Only for subjects who have been previously treated with an incomplete course of definitive prostate radiotherapy 
and whose baseline TRUS biopsy is positive. Can be replaced with salvage prostatectomy at the discretion of the 
treating physician. 
 
                                                 

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xv Only for subjects who have been previously treated with an incomplete course of definitive prostate radiotherapy 
and whose baseline TRUS biopsy is positive. Can be replaced with salvage prostatectomy at the discretion of the 
treating physician. 
xvi Only required for subjects with a confirmed lack of PSA response (see section 6.2.3.2) following salvage therapy 
(see PCWG3 criteria in appendix) 
xvii Optional blood draws may be performed prior to starting salvage therapy, at the next standard of care follow up 
visit after completion of salvage therapy, and at the time of confirmed PSA progression or radiological progression. 
See Section 14.3 for details. 
xviii After completion of salvage treatment, optional blood will only be collected once at time of confirmed disease 
progression. 
xix Optional archival tissue may be collected at baseline for all subjects for whom it is available. Archival tissue 
slides should not be cut until requested from the Central Lab. Lack of archival tissue will not be exclusionary. 
xx Optional fresh tissue may be collected prior to starting salvage therapy during the TRUS biopsy (if performed) 
and at the time of oligometastasectomy or prostatectomy (if indicated and if available after SOC tissue collection). 
See Section 14.1 and 14.2 for details. 
xxi Quality of life (QOL) questionnaires (FACT-P and Expanded Prostate Cancer Index Composite EPIC-26) will be 
collected prior to starting salvage therapy, at the Response Assessment Visit, and at each follow-up visits. See 
Appendices C and D. 
xxiiTo be performed at the Response Assessment Visit and at each follow-up visits. See Appendix A 
 
 
9 STUDY PROCEDURES 
9.1 
Screening Evaluations 
• Informed Consent 
• Review of medical history (including Charlson Comorbidity Index), baseline symptoms 
and medications  
• Physical exam with ECOG Performance Status 
• Vital signs with weight and height 
• Laboratory assessments: 
o CBC with differential 
o CMP to include Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, 
Alanine Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, Creatinine, 
Chloride, Glucose, Potassium, Protein, Sodium, and Urea Nitrogen 
o Lactate Dehydrogenase (LDH) 
o PSA 
• Molecular imaging (e.g., fluciclovine PET/CT or PSMA PET/CT scan or other per PI 
discretion) 
• TRUS biopsy (and fresh tissue collection for correlative studies) only for patients who 
have received prior definitive prostate radiotherapy and have disease recurrence in the 
prostate evidenced by positive molecular imaging (e.g., fluciclovine PET/CT or PSMA 
PET/CT scan or other per PI discretion).  
• Optional Blood and archival tissue for correlative studies. Archival tissue slides should 
not be cut until requested from the Central Lab (see Section 14 for details) 
• Questionnaires (FACT-P and Expanded Prostate Cancer Index Composite (EPIC-26)) 
• Review of eligibility 

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• Technetium bone scan (optional) 
9.2 
On Treatment Evaluations 
• Safety (as defined in Section 15.5, using CTCAE v5.0 and the Clavien-Dindo 
Classification) as well as concomitant medication and treatments must be assessed 
every time a patient is seen in clinic once treatment has begun. Optional blood and 
tissue for correlative studies may also be collected. 
 
9.2.1 
Salvage Therapy 
• Oligometastasectomy for subjects with nodal metastases (Arms B or C, without or with 
bone metastases). 
o Subjects who have received a full course of definitive prostate radiotherapy and 
whose TRUS biopsy is positive at screening (or less than or equal to one year before 
enrollment) can undergo simultaneous salvage prostatectomy, or, if their initial dose 
of radiation was felt to be insufficient, complete a course of salvage prostate 
radiotherapy. 
o Some optional tissue resected during the procedures (oligometastasectomy and/or 
prostatectomy) may be collected for correlative research purposes if available after 
SOC tissue collection. 
• SBRT (or hypofractionated RT) for subjects with bone metastases only (Arm A). 
• For subjects with both nodal and bone metastases, surgery will take place on Day 1 and 
SBRT will follow once the subject has recovered from surgery. (Arm C) 
9.2.2 
Prior to Response Assessment 
• Optional blood collection for correlative studies (see Section 14 for details) may be 
collected at the first standard of care follow-up visit after completing all salvage therapy. 
This can be collected any time after completion of salvage therapy but prior to the 
response assessment visit. 
9.2.3 
Response Evaluation & Adjuvant Treatment 
To be completed 45 days after completion of salvage therapy: 
• Physical exam with ECOG 
• Vital signs with weight 
• Evaluation of PSA response (with confirmation in case of PSA progression) 
• Questionnaires (FACT-P and EPIC-26) 
• RTOG toxicity evaluation (only required for patients who underwent radiotherapy) 
• Optional blood for correlative studies (see Section 14 for details) 
9.2.4 
Adjuvant Therapy 
To be initiated within 4 months in case of confirmed non-complete PSA response: 
• Adjuvant radiotherapy course  

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o The exact treatment modality will be a function of previous treatments received by 
the subject. See Schema and Section 6.2.3 for details) 
9.3 
Follow-up Evaluations 
The follow-up calendar will be based on the date of completion of all study treatments 
(salvage and adjuvant therapy as needed) 
To be completed every 3 months for 3 years after completion of treatment (salvage ± 
adjuvant): 
• Physical exam with ECOG 
• Vital signs with weight  
• Evaluation of PSA response (with confirmation in case of PSA progression) 
• Safety assessments 
• Concomitant medication and treatments 
• Questionnaires (FACT-P and EPIC-26) 
• RTOG toxicity evaluation (only required for patients who underwent radiotherapy) 
• Optional blood for correlative studies 
• Adverse event collection for long term safety, mandatory 
To be completed every 6 months for 1 year after completion of treatment (salvage ± 
adjuvant) then yearly for years 2-3: 
• CT scans and technetium bone scan (optional) 
10 CRITERIA FOR EVALUATION OF ENDPOINTS 
10.1 
Primary Endpoint: PSA Response Rate 
The PSA response rate is defined according to the PCWG3 criteria as the proportion of 
patients achieving a PSA decline ≥ 50% at 6 months after completion of treatment (salvage ± 
adjuvant).  
10.2 
Secondary Endpoints 
10.2.1 
PSA Progression Free Survival 
PSA measurements will take place every 3 months after completion of treatment (salvage ± 
adjuvant) for a total of 3 years.  
The PSA PFS is defined as the time elapsed between completion of treatment (salvage ± 
adjuvant) and the first occurrence of confirmed PSA progression as assessed according to the 
PCWG3 criteria: a ≥ 25% relative increase of ≥ 2 ng/mL above the baseline or nadir, which 
is confirmed by a second consecutive value recorded a minimum of 1 week later.  
10.3 
Time to Recurrence 
CT scans and optional bone scans will take place every 6 months for the first year after 
completion of per-protocol directed therapy then annually thereafter for a total of 3 years.  

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The disease-free survival is defined as the time elapsed between study enrollment and first 
occurrence of confirmed radiographic disease progression as assessed according to the 
PCWG3 criteria (soft tissue by CT or MRI scans according to RECIST v1.1, bone metastasis 
by bone scan according to the PCWG3 criteria). 
Soft tissue recurrence is defined by RECIST 1.1 as a ≥ 20% increase and absolute ≥ 5 mm 
increase in the sum of diameters of target lesions (at most 5 lesions and 2 lesions per organ) 
OR the appearance of one or more new unequivocal lesions OR the unequivocal progression 
of existing non-target lesions. Soft tissue progression does not require confirmatory scans. 
Bone progression is defined PCWG3 criteria as the appearance at any restaging scan of ≥ 2 
new lesions which persist or increase at the confirmatory scan (to be performed ≥ 6 weeks 
later) OR, if ≥ 2 new lesions are observed at the first restaging scan, the appearance of ≥ 2 
additional new lesions at the confirmatory scan (to be performed ≥ 6 weeks later). 
10.3.1 
Time to ADT Therapy  
Time to initiation of ADT is defined as the time elapsed between study enrollment and 
initiation of ADT for metastatic prostate cancer. 
10.3.2 
Rate of Undetectable PSA  
The rate of undetectable PSA is defined as the proportion of patients ever treated with 
prostatectomy whose PSA remains ≤ 0.2 ng/mL after 6 and 12 months following completion 
of treatment (salvage ± adjuvant). 
10.3.3 
Safety 
Routine safety and tolerability will be evaluated from the results of reported signs and 
symptoms, scheduled physical examinations, vital sign measurements, and clinical laboratory 
test results. More frequent safety evaluations may be performed if clinically indicated or at 
the discretion of the investigator.  
Physical Examination 
Complete and symptom-directed physical examinations will be performed by a licensed 
physician (or physician’s assistant or nurse practitioner). 
Vital Signs 
Vital signs include blood pressure, respiratory rate, pulse rate and temperature.  
Safety Laboratory Determinations 
Laboratory evaluations will be performed as noted in the flow chart. 
11 STATISTICAL CONSIDERATIONS 
11.1 
Sample size determination 
The planned sample size is N = 20 evaluable subjects. The primary outcome variable of 
reduction in PSA ≥ 50% at 6 months will be analyzed descriptively via 90% and 95% exact 
binomial confidence intervals. No hypothesis test will be performed on the primary outcome 

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variables. The sample size is justified by the width of the 95% confidence intervals. We 
anticipate that the PSA 50% response rate at 6 months will be 30% based on the results 
published by Siriwardana, as their PSA response at 6 weeks and 12 months was 43% and 23% 
respectively. However, the definition used here is somewhat different than the definition in that 
clinical study.  If the observed PSA 50% response rate is 30% (6/20), the 95% exact binomial 
confidence interval (Clopper-Pearson) will be 12% to 54 %. With 20 evaluable subjects the 
maximum width of a 95% exact binomial confidence interval is 46% (27% to 73%) and occurs 
when the observed response rate is 50% (10/20).  
11.2 
Population for analyses 
11.2.1 
Evaluable for safety  
Patients receiving any amount of treatment or any invasive procedure/surgery will be 
evaluable for safety.   
11.2.2 
Evaluable for response 
Patients are only evaluable if they complete their designated intervention:  
• Patients on Arm A must complete at least 70% of planned radiation treatments;  
• Patients on Arm B must complete surgery;  
• Patients on Arm C must complete surgery and at least 70% of planned radiation 
treatments.  
Patients that are unevaluable for response will be replaced.  
11.3 
Statistical Hypotheses and Analyses 
This study is establishing baseline data for patients who have no defined standard of care 
therapy. All study data will use descriptive statistics and will be exploratory only.  
Since this study is not using any hormonal therapy, we expect that using PSA analysis will be 
accurate and provide an early readout regarding the potential efficacy and clinical utility of 
this approach. 
Primary Objective 
The primary endpoint is the proportion of subjects with a reduction in PSA ≥ 50% 6 months 
after completion of all treatment (salvage and adjuvant therapy). The observed proportion 
and a 95% exact binomial confidence interval with be reported for the entire group of 
evaluable patients (Arms A, B and C together) as well as for each cohort separately.  
Secondary Objectives 
1. 95% exact confidence intervals will be reported for the observed proportions with 
reductions in PSA ≥ 50% 12 months after and ≥ 90% 6 and 12 months after completion 
of all treatment (salvage and adjuvant therapy). This will be done for the entire group of 
evaluable patients (Arms A, B and C together) as well as for each Arm separately.  
2. The proportion of subjects without PSA progression (defined using Prostate Cancer 
Working Group 3 Criteria PCWG3), will be evaluated every 3 months for 3 years after 
completion of all treatment (salvage and adjuvant therapy and analyzed using Kaplan-

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Meier methodology. This will be done for the entire group of evaluable patients (Arms A, 
B and C together) as well as for each Arm separately. 
3. The time from study enrollment until the date of confirmed radiographic disease 
progression as defined by RECIST 1.1 and PCWG3 will be analyzed using Kaplan-Meier 
methods. This will be done for the entire group of evaluable patients (Arms A, B and C 
together) as well as for each Arm separately. 
4. The time from study enrollment to the initiation of ADT will be analyzed using Kaplan-
Meier methods. This will be done for the entire group of evaluable patients (Arms A, B 
and C together) as well as for each Arm separately. 
5. The proportion of patients with a PSA ≤ 0.2 ng/mL will be evaluated 6 and 12 months 
after completion of all treatment (salvage and adjuvant therapy) in the subset of patients 
who have previously undergone prostatectomy. This will be done for the entire group of 
evaluable patients (Arms A, B and C together) as well as for each Arm separately. 
6. The number and proportions of subjects with AEs and SAEs as defined by CTCAE 
version 5.0 will be tabulated both for the entire safety population and also stratified by 
Arm.  
7. 95% confidence intervals will be reported for summary scales of the quality of life (QOL) 
questionnaires (FACT-P and Expanded Prostate Cancer Index Composite EPIC-26) 
measured at screening, response assessment visit, and each follow up visit. This will be 
done for the entire group of evaluable patients (Arms A, B and C combined) and also 
stratified by Arm. Normal approximations will be used for computation of confidence 
intervals.  
Exploratory Objective  
Genomic alterations or abnormal protein expression that correlate with radiation 
resistance or predilection for early metastasis and worse overall prognosis will be 
tabulated.  
12 REGISTRATION GUIDELINES 
Study related screening procedures can only begin once the subject has signed a consent form.  
Subjects must meet all of the eligibility requirements listed in Section 5 prior to registration.  
Subjects must be registered before receiving any study treatment and must begin treatment as 
soon as possible after registration.  
To register eligible subjects on study, complete a Clinical Trials Office Subject Registration Form 
and submit to CTORegistrations@hci.utah.edu. 
13 DATA SUBMISSION SCHEDULE 
The Case Report Forms (CRFs) are a set of (electronic or paper) forms for each subject that provides 
a record of the data generated according to the protocol. CRF’s should be created prior to the study 
being initiated and updated (if applicable) when amendments to the protocol are IRB approved. 
These forms will be completed on an on-going basis during the study. The medical records will be 

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source of verification of the data. During the study, the CRFs will be monitored for completeness, 
accuracy, legibility and attention to detail by a member of the Research Compliance Office. The 
CRFs will be completed by the Investigator or a member of the study team as listed on the 
Delegation of Duties Log. The data will be reviewed no less than annually by the Data and Safety 
Monitoring Committee. The Investigator will allow the Data and Safety Monitoring Committee or 
Research Compliance Office personnel access to the subject source documents, clinical supplies 
dispensing and storage area, and study documentation for the above-mentioned purpose. The 
Investigator further agrees to assist the site visitors in their activities. 
Data capture should be restricted to endpoints and relevant subject information required for 
planned manuscripts. 
14 CORRELATIVE STUDIES 
Optional Tissue and blood may be collected at the time points notated in the Study Calendar. 
Samples will be used to identify biomarkers of response or resistance to the prescribed 
treatments. For those patients with both archival and fresh tissue, comparison between the pre- 
and post-treatment tissue will be performed as applicable. All correlative tissue collection is 
optional and not mandatory.  
Testing may include, but is not limited to:  
• Genomic alterations such as deletions, mutations or amplifications;  
• Transcriptome RNA assessments;  
• Immunohistochemistry testing for protein expression.  
• Cytokine/chemokines 
• Circulating free DNA (cfDNA) 
• Circulating tumor cells (CTC) detection, enumeration, and characterization 
Specimen collection and processing instructions can be found in the lab manual. 
14.1 
Screening 
Archival tissue may be requested for all subjects. Archival tissue slides should not be cut 
until requested from the Central Lab. Lack of archival tissue will not be exclusionary. 
For subjects previously treated with definitive radiotherapy for prostate cancer with 
molecular imaging (e.g., fluciclovine PET/CT or PSMA PET/CT scan or other per PI 
discretion)-positive findings at baseline (or less than or equal to one year before study 
enrollment), a TRUS biopsy may be performed as per institutional standard. Up to 6 cores 
from the TRUS biopsy may be obtained for correlative studies. 
14.2 
Oligometastasectomy and/or Prostatectomy 
For subjects undergoing oligometastasectomy and/or salvage prostatectomy, 2 sections of 
tissue may be collected from the prostate and each of the lymph node dissection if available 
after SOC tissue collection.  

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14.3 
Blood Correlative Studies 
Up to 20 mL of blood may be collected at each time point. Instructions for processing and 
shipping will be detailed in the lab manual.  
15 ETHICAL AND REGULATORY CONSIDERATIONS 
15.1 
Informed consent  
Informed consent will be obtained from all research participants prior to performing any 
study procedures using the most recent IRB-approved version.  
15.2 
Human Subjects Protections 
15.2.1 
Participation of Children 
Subjects must be at least 18 years of age to participate. 
15.2.2 
Participation of Subjects Unable To Give Consent 
Subjects must be able to provide informed consent and willing to sign an approved consent 
form that conforms to federal and institutional guidelines. 
15.3 
Institutional Review 
This study will be approved by the Institutional Review Board of the University of Utah. 
15.4 
 Data and Safety Monitoring Plan 
A Data and Safety Monitoring Committee (DSMC) is established at Huntsman Cancer 
Institute (HCI) to ensure the well-being of subjects enrolled on Investigator Initiated Trials 
that do not have an outside monitoring review. The roles and responsibilities of the DSMC 
are set forth in the NCI-approved Data and Safety Monitoring (DSM) plan. The activities of 
the committee include reviewing adverse events (including SAEs), deviations, important 
medical events, significant revisions or amendments to the protocol, and approving 
cohort/dose escalations. If the DSMC and/or the PI have concerns about unexpected safety 
issues, the study will be stopped and will not be resumed until the issues are resolved. The 
DSMC also reviews and approves audit reports generated by the Research Compliance 
Office. 
This study is classified as moderate risk per the NCI-approved DSM plan.  
Each moderate risk study may be assigned a physician member of the DSMC as medical 
monitor, or in rare cases, an external medical monitor. The medical monitor will be notified 
of all serious adverse events (SAEs). SAEs occurring in subjects treated at HCI or its 
affiliates will also be reviewed by the full DSMC monthly. The full committee will also 
review all toxicities for subjects on treatment and within 45 days of their last treatment on a 
quarterly basis.  
Each moderate-risk study will be assigned a dedicated research compliance officer who will 
monitor the trial. Moderate-risk trials will be monitored by RCO personnel after the first 
subject is enrolled and every six months thereafter during active enrollment. The RCO 

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monitor will review the study status and summarize enrollment, toxicities, SAEs, dose 
escalation, statistical endpoints (e.g., stopping rules), deviations, etc. for the full DSMC 
membership at the regularly scheduled meetings. Amendments that increase risk, change 
dosing, or impact study objectives will be reviewed by the DSMC and approved by the 
PRMC and IRB. Moderate-risk trials will be formally reviewed by the DSMC after the first 
subject is enrolled and then semi-annually thereafter.  
An initial audit of moderate-risk studies will be conducted by the RCO approximately one 
year after enrollment begins and annually thereafter. Audits of moderate-risk studies may be 
conducted more frequently as requested by the DSMC, IRB, PRMC, RCO management, or 
the PI. 
15.5 
Adverse Events and Serious Adverse Events  
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for AE and SAE reporting.  
In addition, the Clavien-Dindo classification will be used to evaluate surgical complications. 
15.5.1 
Adverse Events (AEs) 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study treatment even if the event is not 
considered to be related to study treatment. For the purposes of this study, the terms toxicity 
and adverse event are used interchangeably. Medical conditions/diseases present before 
starting study salvage treatment are only considered adverse events if they worsen after 
starting study salvage treatment. Abnormal laboratory values or test results constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, or 
require therapy. 
Collection of adverse events will begin with the first study salvage treatment (surgery OR 
radiotherapy for bone metastases) and end 1 year after the last study treatment (including 
palliative radiotherapy if applicable) or until a new cancer treatment is initiated.  
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. 
The occurrence of adverse events should be sought by non-directive questioning of the 
subject at each visit or phone contact during the study. Adverse events also may be detected 
when they are volunteered by the subject during or between visits or through physical 
examination, laboratory test, or other assessments. As far as possible, each adverse event 
should be evaluated to determine: 
1. The severity grade based on CTCAE v5 (grade 1-5) 
2. Its relationship to the study treatments(s) (definite, probable, possible, unlikely, not 
related) 
3. Its duration (start and end dates or if continuing at final exam) 
4. Action taken (no action taken; study salvage treatment dosage adjusted/temporarily 
interrupted; study salvage treatment permanently discontinued due to this adverse 

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event; concomitant medication taken; non-drug therapy given; 
hospitalization/prolonged hospitalization) 
5. Whether it constitutes an SAE 
All adverse events will be treated appropriately. Such treatment may include changes in 
study salvage treatment as listed in the dose modification section of this protocol (see section 
8 for guidance). Once an adverse event is detected, it should be followed until its resolution, 
and assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the study salvage treatment, the 
interventions required to treat it, and the outcome. 
All adverse events will be immediately recorded in the subject research chart.  
15.5.2 
Serious Adverse Event (SAE) 
Information about all serious adverse events will be collected and recorded. A serious 
adverse event is an undesirable sign, symptom or medical condition which: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Is medically significant, i.e., defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Causes congenital anomaly or birth defect 
• Requires subject hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
o Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (procedures such as central line placements, 
paracentesis, pain control) 
o Elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since the start of study  salvage 
treatment 
o Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
o Social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
Collection of serious adverse events will begin at the time of salvage treatment and end 1 
year after the last dose of study treatment or until a new cancer treatment is initiated, 
whichever happens the soonest. 
Any death from any cause while a subject is receiving treatment on this protocol or up to 365 
days after the last dose of protocol treatment will be reported. Any death which occurs up to 
3 years after protocol treatment has ended but which is felt to be treatment related, must be 
reported. 

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Toxicities which fall within the definitions listed above must be reported as an SAE 
regardless if they are felt to be treatment related or not. Toxicities unrelated to treatment that 
do NOT fall within the definitions above, must simply be documented as AEs in the subject 
research chart.  
15.6 
SAE Reporting Requirements 
SAEs must be reported to the DSMC, the FDA, and the IRB according to the requirements 
described below: 
A MedWatch 3500A form must be completed and submitted to HCI-RCO@utah.edu as soon 
as possible, but no later than 1 working day of first knowledge or notification of event. 
DSMC Notifications: 
An HCI Research Compliance Officer (RCO) will process and submit the MedWatch form to 
the proper DSMC member as necessary for each individual study.  
The RCO will summarize and present all reported SAEs according to the Data and Safety 
Monitoring Plan at the monthly DSMC meeting. 
FDA Notifications: 
Adverse events occurring during the course of a clinical study that meet the following criteria 
will be promptly reported to the FDA: 
• Serious 
• Unexpected 
• Definitely, Probably or Possibly Related to the investigational treatment 
• Fatal or life-threatening events that meet the criteria above will be reported within 7 
calendar days after first knowledge of the event by the investigator; followed by as 
complete a report as possible within 8 additional calendar days. 
All other events that meet the criteria above will be reported within 15 calendar days after 
first knowledge of the event by the investigator. 
The RCO will review the MedWatch report for completeness, accuracy and applicability to 
the regulatory reporting requirements. 
The RCO will ensure the complete, accurate and timely reporting of the event to the FDA. 
The Regulatory Coordinator will submit the report as an amendment to the IND application. 
All other adverse events and safety information not requiring expedited reporting that occur 
or are collected during the course of the study will be summarized and reported to the FDA 
through the IND Annual Report. 
IRB Notification: 
Events meeting the University of Utah IRB reporting requirements 
(http://www.research.utah.edu/irb/) will be submitted through the IRB’s electronic reporting 
system within 10 working days. 

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15.7 
Reporting of Pregnancy  
Although pregnancy is not considered an adverse event, it is the responsibility of 
investigators or their designees to report the pregnancy of a male subjects’ female partner as 
an SAE. Pregnancies or lactation that occurs during the course of the trial or with 45 days of 
completing treatment or starting another new anticancer therapy, whichever is earlier, must 
be reported to the DSMC, IRB, FDA, and the sponsor as applicable. All female partners who 
become pregnant must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events.  
15.8 
Protocol Amendments 
Any amendments or administrative changes in the research protocol during the period, for 
which the IRB approval has already been given, will not be initiated without submission of 
an amendment for IRB review and approval.   
These requirements for approval will in no way prevent any immediate action from 
being taken by the investigator in the interests of preserving the safety of all subjects 
included in the trial.  
Any amendments to the protocol that significantly affect the safety of subjects, scope of 
the investigation, or the scientific quality of the study are required to submit the 
amendment for FDA review. 
15.9 
Protocol Deviations 
A protocol deviation (or violation) is any departure from the defined procedures and 
treatment plans as outlined in the protocol version submitted and previously approved by the 
IRB. Protocol deviations have the potential to place participants at risk and can also 
undermine the scientific integrity of the study thus jeopardizing the justification for the 
research. Protocol deviations are unplanned and unintentional events.  
Because some protocol deviations pose no conceivable threat to participant safety or 
scientific integrity, reporting is left to the discretion of the PI within the context of the 
guidelines below. The IRB requires the prompt reporting of protocol deviations which are: 
• 
Exceptions to eligibility criteria. 
• 
Intended to eliminate apparent immediate hazard to a research participant or  
• 
Harmful (caused harm to participants or others, or place them at increased risk of 
harm - including physical, psychological, economic, or social harm), or  
• 
Possible serious or continued noncompliance  
15.10 FDA Annual Reporting  
This study is IND exempt therefore there are no annual reporting requirements to the FDA.   
15.11 Clinical Trials Data Bank  
The study will be registered on http://clinicaltrials.gov and the NCI CTRP (Clinical Trials 
Reporting Program) by the Clinical Trials Office. 

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15.12 Record Keeping 
Per 21 CFR 312.57, the Investigator records shall be maintained for a period of 2 years 
following the date a marketing application is approved; or, if no application is filed or the 
application is not approved, until 2 years after the investigation is discontinued and the FDA 
is notified. 
 
 

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16 BIBLIOGRAPHY 
1. Duchesne GM, Woo HH, Bassett JK, et al: Timing of androgen-deprivation therapy in 
patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 
[TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Lancet Oncol 17:727-37, 
2016 
2. Garcia-Albeniz X, Chan JM, Paciorek A, et al: Immediate versus deferred initiation of 
androgen deprivation therapy in prostate cancer patients with PSA-only relapse. An 
observational follow-up study. Eur J Cancer 51:817-24, 2015 
3. Bouman-Wammes EW, van Dodewaard-De Jong JM, Dahele M, et al: Benefits of Using 
Stereotactic Body Radiotherapy in Patients With Metachronous Oligometastases of 
Hormone-Sensitive Prostate Cancer Detected by [18F]fluoromethylcholine PET/CT. Clin 
Genitourin Cancer, 2017 
4. Siriwardana A, Thompson J, van Leeuwen PJ, et al: Initial multicentre experience of 68 
Gallium-PSMA PET/CT guided robot-assisted salvage lymphadenectomy: acceptable safety 
profile but oncological benefit appears limited. BJU Int, 2017 
5.  Hussain M, Fizazi K, Saad F, Shore ND, Heidenreich A, Hirmand M, Perabo F, Khondher Z, 
Modelska K, Sternberg CN: PROSPER: A phase 3 study of enzalutamide in nonmetastatic 
(M0) castration-resistant prostate cancer (CRPC) patients. J Clin Oncol 36, 2018 (suppl 6S; 
abstr 3). 
6. Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, 
Mainwaring PN, Lee JY, Uemura H, Lopez-Gitlitz A, Trudel GC, Espina BM, Shu Y, Park 
YC, Rackoff WR, Yu MK, Small EJ; SPARTAN Investigators: Apalutamide Treatment and 
Metastasis-free Survival in Prostate Cancer. N Engl J Med. 2018 Apr 12; 378(15):1408-
1418.  
 
 
 
 

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Appendix A – Radiation Therapy Oncology Group (RTOG) toxicity grading system 
Patient ID: __________ 
Date: __________ 
Time point: ________________
 
Physician signature: ________________ 
Date: ________________
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
No 
symptoms 
Minor 
symptoms 
requiring no 
treatment 
Symptoms responding 
to simple out patient 
management, lifestyle 
(performance status) not 
affected 
Distressing symptoms 
altering the patient’s 
lifestyle (performance 
status) 
Hospitalization for 
diagnosis or minor 
surgical intervention 
(such as urethral dilation) 
may be required 
Major surgical intervention 
(such as laparotomy 
colostomy, cystectomy) or 
prolonged hospitalization 
required 
Fatal 
complications 

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Appendix B – Clavien-Dindo Classification of Surgical Complication 
 
 
 

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Appendix C – FACT-P Questionnaire 
Patient ID: ___________ 
Date: ___________ 
Time point: ___________
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 

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FACT-P Questionnaire (page 2/3) 
 
 
 

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FACT-P Questionnaire (page 3/3) 
 
Subject signature: ________________ 
Date: ________________
 
 
 

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Appendix D – Expanded Prostate Cancer Index Composite (EPIC-26) 
Patient ID: ___________ 
Date: ___________ 
Time point: ___________
This questionnaire is designed to measure Quality of Life issues in patients with Prostate cancer. 
To help us get the most accurate measurement, it is important that you answer all questions 
honestly and completely. 
 

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Appendix D – Expanded Prostate Cancer Index Composite (EPIC-26) (page 2/3) 
 

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Appendix D – Expanded Prostate Cancer Index Composite (EPIC-26) (page 3/3) 
 
Subject signature: ________________ 
Date: ________________
 
 

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Appendix E – Charlson Comorbidity Index 
 
 
Yes = 1 No = 0 
Myocardial infarction 
History of definite or probable MI (EKG changes and/or enzyme changes) 
 
 
Congestive Heart Failure 
Exertional or paroxysmal nocturnal dyspnea and has responded to 
digitalis, diuretics, or afterload reducing agents 
 
 
Peripheral vascular disease 
Intermittent claudication or past bypass for chronic arterial insufficiency, 
history of gangrene or acute arterial insufficiency, or untreated thoracic or 
abdominal aneurysm (≥6 cm) 
 
 
Cardiovascular Accident (CVA) or Transient Ischemic Attack (TIA) 
 
 
Dementia 
Chronic cognitive deficit 
 
 
Chronic Obstructive Pulmonary Disease 
 
 
Connective tissue disease 
 
 
Peptic ulcer disease 
Any history of treatment for ulcer disease or history of ulcer bleeding 
 
 
 
Yes = 2 No = 0 
Hemiplegia 
 
 
Moderate to severe CKD 
Severe = on dialysis, status post kidney transplant, uremia, moderate = 
creatinine >3 mg/dL (0.27 mmol/L) 
 
 
Leukemia 
 
 
Lymphoma 
 
 
 
Yes = 6 No = 0 
AIDS 
 
 
 
Score 
Liver disease 
• 0: None 
• +1: Mild = chronic hepatitis (or cirrhosis without portal 
hypertension) 
• +3: Moderate = cirrhosis and portal hypertension but no 
variceal bleeding history 
 
 

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• +3: Severe = cirrhosis and portal hypertension with variceal 
bleeding history 
Diabetes mellitus 
•   0: None or diet-controlled 
• +1: Uncomplicated 
• +2: End-organ damage 
 
Solid tumor 
•   0: None 
• +2: Localized 
• +6: Metastatic 
 
Age 
•   0: < 50 years 
• +1: 50-59 years 
• +2: 60-69 years 
• +3: 70-79 years 
• +4: ≥ 80 years 
 
Total Score ______________ 
 
 
 

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Appendix F- Prostate Cancer Clinical Trials Working Group 3 (PCWG3) 
The PCWG3 was created to more accurately assess bone lesions and to describe PSA based 
progression. PCWG3 rules were designed to be used in conjunction with radionuclide (90mTc) 
bone scintigraphy and therefore should be used for all bone response assessments. Only bone 
lesions seen on bone scans will be followed for assessment of response.  
Bone Assessments 
Baseline Assessment 
All bone lesions may be recorded as non-target lesions only and the number of lesions 
should be noted. 
Response Assessment 
While on treatment, follow-up scans should be assessed for progressive disease (PD), 
progressive disease unconfirmed (P Du), no progressive disease (Non-PD), no evidence 
of disease (NED), or non-evaluable (NE). 
Table 1: Bone response assessment categories 
Bone Response 
Definition 
PD 
2 new lesions, not flare, persistent 
P Du 
2 new lesions, but confirmation is required by the second scan. The 
temporary marker of PD should be updated to PD or non-PD upon 
subsequent scans. 
If P Du is determined on the last scan, sponsor should update to PD upon 
analysis. 
Non-PD 
At least 1 bone lesion present, but not enough to trigger PD. 
NE 
Status of bone lesions cannot be determined. 
NED 
No lesions are seen on bone scan (either none at baseline or all have 
resolved). 
Rules of Progressive Disease 
• 2+2 Rule: If 2 new lesions appear on the first scan after the initiation of treatment, 
the response is classified as P Du and another scan is performed ≥ 6 weeks. 
o If the next scans show at least 2 new bone lesions in addition to those seen 
in the prior scan, the prior scan is to be considered confirmed PD. 
o If the next scan does not show at least 2 additional new bone lesions the 
lesions seen on the prior scan are considered pre-existing lesions. The 
bone response on the prior scan is updated to non-PD and new lesions 
seen on the first scan are ignored. 
• Once outside of the flare window (the first 12 weeks of treatment) the appearance 
of new lesions must be confirmed with a second scan ≥ 6 weeks after the first 
scan. 
o If ≥ 2 new lesions appear on a scan the scan will be classified as P Du 
until a second scan confirms lesion persistence.  

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 If lesions are persistent on the second scan, the prior response will 
be updated to PD. 
 If the lesions disappeared on the second scan, the prior response is 
updated to non-PD. 
• If 1 new bone lesion is seen on one scan classifying the scan as non-PD, but the 
following scan shows an additional new lesion (2 new lesions total between 
subsequent scans) the second scan will be classified as PD. 
• Diffuse skeletal tumor involvement may result in a superscan. In this case, 
distinguishing between individual new bone lesions may be impossible. If a 
superscan occurs after baseline, the response will be considered PD and no further 
confirmation scans are required. 
PSA Progression 
PSA should be monitored at the beginning of every cycle. Any rise in PSA during the first 12 
weeks of treatment should be monitored but should not be deemed evidence of progression. 
Record the percent change from baseline at 12 weeks. After a decline from baseline: record time 
from start of therapy to first PSA increase that is ≥ 25% and ≥ 2 ng/mL above the nadir, and 
which is confirmed by a second value ≥ 3 weeks later (i.e., a confirmed rising trend). 
Nodal and Soft Tissue Progression 
Nodal and soft tissue documentation, tracking, and determination of progression will follow 
RECIST 1.1.