FOcal Radiation for Oligometastatic Castration-rEsistant Prostate Cancer (FORCE): A Phase II Randomized Trial
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: University of Michigan Rogel Cancer Center

ID: UMCC 2017.163 
 
FOcal Radiation for Oligometastatic Castration-rEsistant Prostate Cancer (FORCE) 
 
 
NCT03556904 

 
 
UMCC 2017.163 
 
FOcal Radiation for oligometastatic Castration-rEsistant prostate cancer (FORCE): A phase II 
randomized trial 
 
 
Principal Investigator:  
Zachery Reichert 
 
 
 
 
University of Michigan, Department of Medical Oncology 
 
 
 
 
1500 East Medical Center Drive, SPC 5848 
 
 
 
 
Ann Arbor, MI 48109-5848 
 
 
 
 
(734)-764-3066  
 
 
 
 
(734)-647-8903 
 
 
 
 
zreiche@med.umich.edu  
 
Co-Principal Investigator: 
William Jackson 
  
 
 
 
 
University of Michigan, Department of Radiation Oncology 
 
 
 
 
1500 East Medical Center Drive 
 
 
 
 
Ann Arbor, MI 48109 
 
 
 
 
(269) 598-4616  
 
 
 
 
wcj@med.umich.edu 
 
  
Coordinating Center:  
University of Michigan 
 
 
 
 
Biostatistician:  
 
Thomas Braun, PhD 
 
 
 
 
University of Michigan 
 
 
 
 
M4063 SPH II 
 
 
 
 
1415 Washington Heights  
 
 
 
 
Ann Arbor, MI 48109-2029 
 
 
 
 
(734)-936-9844 
 
 
 
 
tombraun@umich.edu    
 
 
 
 
Initial version:  
 
06/07/2018, Version 4.0 
Amended: 
 
 
07/25/2018, Version 5.0 
 
 
 
01/16/2019, Version 6.0 
 
 
 
05/15/2020, Version 7.0 
 
 
 
11/11/2020, Version 8.0 
 
 
 
02/05/2021, Version 9.0 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
ABBREVIATIONS ............................................................................................................1 
STUDY SYNOPSIS ...........................................................................................................4 
1.0 
BACKGROUND AND RATIONALE ..................................................................6 
1.1 
Disease Background ........................................................................................................ 6 
1.2 
Study Agent(s) Background and Associated Known Toxicities ....................................... 6 
1.3 
Other Agents .................................................................................................................... 7 
1.4 
Rationale .......................................................................................................................... 8 
1.5 
Correlative Studies .......................................................................................................... 8 
2.0 
STUDY OBJECTIVES ...........................................................................................9 
2.1 
Primary Objectives ........................................................................................................... 9 
2.2 
Secondary Objectives .................................................................................................... 10 
2.3 
Exploratory Objectives ................................................................................................... 10 
3.0 
PATIENT ELIGIBILITY ....................................................................................10 
3.1 
Inclusion Criteria ............................................................................................................ 11 
3.2 
Exclusion Criteria ........................................................................................................... 12 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES ...............12 
4.1 
Screening, Enrollment and Randomization ................................................................... 12 
5.0 
TREATMENT PLAN ...........................................................................................13 
5.1 
Radiotherapy Treatment Dosage and Administration ................................................... 13 
5.3 
Systemic Therapy .......................................................................................................... 15 
5.4 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 16 
5.5 
Concomitant Medications/Treatments ........................................................................... 16 
5.6 
Duration of Radiotherapy ............................................................................................... 16 
5.7 
Off Radiotherapy Treatment Criteria ............................................................................. 16 

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5.8 
Duration of Systemic Therapy ....................................................................................... 16 
5.9 
Off Systemic Therapy Criteria ....................................................................................... 17 
5.10 
Duration of Follow-Up .................................................................................................... 17 
5.11 
Off Study Criteria ........................................................................................................... 17 
6.0 
STUDY PROCEDURES ......................................................................................18 
6.1 
Screening/Baseline Procedures .................................................................................... 18 
6.2 
Study Calendar: ............................................................................................................. 19 
7.0 
MEASUREMENT OF EFFECT .........................................................................21 
7.1 
Response Definitions and Evaluations .......................................................................... 21 
7.2 
Response Criteria .......................................................................................................... 24 
7.3 
Safety/Tolerability .......................................................................................................... 28 
8.0 
ADVERSE EVENTS ............................................................................................28 
8.1 
Adverse Event Reporting Requirements ....................................................................... 28 
8.2 
Definitions ...................................................................................................................... 28 
8.3 
Adverse Event Characteristics ...................................................................................... 30 
8.4 
Serious Adverse Event Reporting Guidelines ............................................................... 30 
8.5 
Routine Reporting of Non-Serious AE ........................................................................... 31 
8.6 
Reporting of Unanticipated Problems ............................................................................ 31 
9.0 
CORRELATIVE PROTOCOLS .........................................................................31 
9.1 
Laboratory Correlative Studies ...................................................................................... 31 
9.2 
Radiographic Correlative Study ..................................................................................... 32 
10.0 STATISTICAL CONSIDERATIONS ................................................................32 
10.1 
Statistical Design ........................................................................................................... 32 
10.2 
Statistical Analysis ......................................................................................................... 33 
10.3 
Sample Size and Accrual .............................................................................................. 34 
10.4 
Stratification Factors ...................................................................................................... 34 

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10.5 
Derived Variables .......................................................................................................... 34 
10.6 
Analysis Datasets .......................................................................................................... 35 
11.0 DATA AND SAFETY MONITORING ..............................................................36 
12.0 DATA MANAGEMENT ......................................................................................37 
13.0 QUALITY ASSURANCE AND AUDITS ...........................................................37 
14.0 CLINICAL MONITORING PROCEDURES ...................................................37 
15.0 REFERENCES ......................................................................................................38 
16.0 APPENDICES .......................................................................................................40 

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ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AR 
Androgen Receptor 
AR-V7 
Androgen Receptor Splice Variant 7 
AST 
Aspartate Aminotransferase 
ASTRO 
American Society for Radiation Oncology 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CRPC 
Castration Castration-Resistant Prostate Cancer 
CT 
Computed Tomography 
CTC 
Circulating Tumor Cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating Tumor DNA 
CTSU 
Clinical Trials Support Unit 
CTV 
Clinical Target Volume 
DSMC 
Data and Safety Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal Growth Factor Receptor 
ERG 
ETS-Related Gene 
FU 
Follow-up 
GTV 
Gross Tumor Volume 
Gy 
Gray 
HER2 
Human Epidermal Growth Factor Receptor 2 
HRPP 
Human Research Protections Program 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
LDH 
Lactate Dehydrogenase 
mCRPC 
Metastatic Castration-Resistant Prostate Cancer 
MRI 
Magnetic Resonance Imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
PTV 
Planning Target Volume 

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PR 
Partial Response 
PRC 
Protocol Review Committee 
PSMA 
Prostate Specific Membrane Antigen 
RP 
Radical Prostatectomy 
RT 
Radiotherapy 
RTOG 
Radiation Therapy Oncology Group 
SAE 
Severe Adverse Event 
SBRT 
Stereotactic Body Radiation Therapy 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
UaP 
Unanticipated Problem 
WBC 
White Blood Cells 
 
 
 
 
 

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STUDY SCHEMA 
 
 
 
 
 
 
 
 

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STUDY SYNOPSIS 
Title 
FOcal Radiation for oligometastatic Castration-rEsistant prostate cancer 
(FORCE): A phase II randomized trial 
Phase 
Phase II 
Methodology 
Randomized, non-blinded 
Study Duration 
6 years 
Study Center(s) 
University of Michigan, Ann Arbor Veterans Healthcare System 
Objectives 
To determine whether the addition of radiotherapy to standard of care 
systemic therapy improves objective progression-free survival, compared 
to systemic therapy alone. 
Number of Subjects 
36 
Inclusion Criteria 
1. Biopsy-proven adenocarcinoma of the prostate 
2. Discontinue any prior systemic therapies (excluding GnRH 
agonist/antagonists) without PSA withdrawal effects if using first 
generation anti-androgens 
- 
Patients who recently started systemic therapy for mCRPC are 
eligible to enroll if new therapy was started ≤ 14 days prior to 
consent (see section 3.1.2 for discussion) 
3. Progressive metastatic CRPC (progressive disease by PSA or 
radiographic progression defined in the same modality with 
testosterone <50 ng/dL)  
4. Oligometastatic prostate cancer defined as at least 1 and ≤5 treatment 
sites measured by conventional imaging with CT, bone scan or 68GA-
PSMA PET/CT scans.  Each metastatic tumor must be ≤5 cm in 
maximum cross section.  If the patient’s prostate itself has not been 
treated (radiation or surgery), it will be treated and count as 1 
treatment site. 
Any site treated with radiation in the preceding 4 weeks from 
registration are counted as a trial relevant treatment site toward the 5 
or less criteria.  The patient must have at least 1 non-irradiated site 
remaining though.  
5. Medically fit for radiation and medical therapy 
6. Age ≥18 years old 
7. ECOG ≤2 
8. No prior invasive malignancy in the past 3 years. Exceptions include 
non- melanomatous skin cancer or in situ cancers of bladder or head 
and neck which are permissible.  
9. Subjects must freely sign informed consent to enroll in the study. 
10. Subjects must use contraception up to 90 days after last drug dose. 
Exclusion Criteria 
1. Planned systemic therapy with Radium-223 dichloride or sipuleucel-T 
2. Tumor requiring emergent radiation in view of provider 
3. Life expectancy <3 months 
4. Presence of known parenchymal brain metastasis 
5. Uncontrolled intercurrent illness 
6. Inability to undergo radiotherapy, systemic therapy, CTs or bone 
scans. 
7. Biopsy proven pure small cell or neuroendocrine prostate cancer 

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Study Product(s), Dose, 
Route, Regimen 
External beam radiotherapy.  Dose will depend on lesion location and 
size, but eqd2(2) ranges of dose fractionation typically is between 30 Gy 
in 10 fractions and 50 Gy in 5 fractions. 
Duration of 
Administration 
Radiotherapy will be delivered based on lesion location.  Radiation will 
start within 8 weeks of randomization and complete by day 84. 
Reference Therapy 
Both study arms will receive a systemic therapy for mCRPC. 
Statistical Methodology 
Using prior studies, the disease control rate at 6 months for systemic 
therapy alone is approximately 50% when averaged over the various 
lines of therapy for prostate cancer. Assuming the experimental arm 
increases the median duration of disease control to 15 months, 16 
patients per arm provides 80% power assuming a 1-sided alpha of 0.1.  
This results in 32 total patients for randomization.  To accommodate a 
10% loss to follow-up rate, accrual will continue to a total study sample 
of 36.    
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Cancer is the second leading cause of death in the United States, chiefly from an inability 
to control metastatic disease. Similarly, prostate cancer is the second leading cause of 
death in men with cancer, accounting for nearly 30,000 deaths per year. Hormonal based 
therapies are the mainstay of treatment for men with recurrent and metastatic prostate 
cancer. Systemic therapy alone is not curative for these patients, and treatment resistance 
develops, termed castration-resistant prostate cancer (CRPC). One primary theory of 
progression is the development of resistance within a metastatic site that then seeds other 
sites to form new metastases. The uncontrolled progression of disease to a castration-
resistant state is uniformly fatal for men with prostate cancer with a limited number of 
durable systemic treatment options. 
 
 
Metastatic CRPC (mCRPC) is a disease spectrum that ranges from a limited burden of 
disease, termed oligometastatic mCRPC, to diffuse mCRPC. The presence of an 
oligometastatic state was originally proposed by Hellman who suggested oligometastatic 
patients would benefit from effective local therapy in addition to systemic therapy [1]. In 
agreement with this hypothesis, focal treatments for metastatic patients with renal cell 
carcinoma, non-small cell lung cancer, and small cell lung cancer have shown benefit in 
select circumstances [2-5].  The most prevalent example though is colorectal cancer, 
where chemotherapy combined with surgery (or other ablative therapies) is the standard 
of care for isolated hepatic or pulmonary metastases with 5-year survival rates of ~45% 
[6, 7]. 
 
Given the success of treating oligometastatic cancer with a combination of local and 
systemic therapy in other diseases, this approach may prove beneficial in prostate cancer 
for multiple reasons. First, patients with mCRPC often receive radiotherapy for the 
palliation of pain, or systemic radiotherapy with Radium-223 dichloride, which has 
demonstrated both pain palliation and also improved overall survival in a randomized 
phase III trial [8, 9]. Hence, the use of radiotherapy in these patients is routine and 
toxicities well-known.  Secondly, resistance to common treatments suppressing the 
androgen pathway (e.g. enzalutamide or abiraterone) is inevitable and patients with a 
higher volume of metastatic disease have shorter responses [10].  By depleting the viable 
mCRPC tumor volume, the stochastic nature of resistance may be exploited and 
sensitivity to therapy prolonged.   
1.2 
Study Agent(s) Background and Associated Known Toxicities 
The study agent in this trial is the use of external beam radiotherapy.  External beam 
radiotherapy is a standard treatment approach for the palliation of symptomatic metastatic 
sites in most cancers, and is commonly used in metastatic prostate cancer.  National 
guidelines from both NCCN and ASTRO support the use of palliative radiotherapy for 
bone metastasis in prostate cancer.  Over a dozen trials have been conducted and 
numerous meta-analyses have demonstrated the safety and tolerability of palliative 
radiotherapy.  Most of these trials included a 30 Gy in 10 fractions arm.  
 
Radiotherapy can be delivered in many ways and the dose, fractionation, and location of 
the tumor all dictate the potential side effects.  On this trial, radiotherapy can be delivered 

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in either moderate hypofractionation (examples could be 30 Gy in 10 fractions or 50 Gy 
in 20 fractions) or stereotactic body radiotherapy (SBRT). Ablative doses should be used, 
but as radiotherapy is a rapidly evolving field, flexibility in dose/schedule is offered to 
the delivering radiation oncologist.  SBRT reduces the overall time of radiation treatment 
and offers a greater potential for cell kill compared to standard fractionation schemas of 
1.8-3.0 Gy/Day. This technique allows for rapid delivery of tumoricidal doses of 
radiotherapy and provides ablative treatment to metastases not amenable to surgical 
intervention. Single studies have demonstrated that SBRT for ablative treatment of non-
symptomatic, solitary metastases is technically feasible, with acceptable toxicity and high 
rates of in-field cancer control [11]. SBRT or ablative RT approaches have been studied 
in four Radiation Therapy Oncology Group (RTOG) clinical trials: RTOG 0236, 
0813/0915, 0438 and 0613 for solitary lesions in lung, liver and spinal metastases 
respectively. These trials have provided a framework for successful delivery and quality 
assurance of complex radiotherapy in the cooperative group setting.   Regardless of the 
dose/fraction implemented, well established international dose constraints will be 
followed to ensure predictable and low rates of side effects from external beam 
radiotherapy. 
 
Table 1: A partial list from QUANTEC as to the dose constraints for well-established toxicity 
metrics and estimated rates of toxicity and toxicity endpoint.  
Critical Structure 
Volume Dose/Volume Max Dose 
Toxicity 
Rate 
Toxicity Endpoint 
Spinal cord 
  
  
50 Gy 
0.2% 
Myelopathy 
Larynx 
Mean 
<44 Gy 
  
<20% 
Edema 
Lung 
Mean 
7 Gy 
  
5% 
Symptomatic pneumonitis 
Esophagus 
V35 
<50% 
  
<30% 
Grade 2+ esophagitis 
Liver 
Mean 
<30-32 Gy 
  
<5% 
RILD (in normal liver 
function) 
Liver 
Mean 
<28 Gy 
  
<5% 
RILD (in Child-Pugh A or 
HCC) 
Kidney, bilateral 
Mean 
<15-18 Gy 
  
<5% 
Clinical dysfunction 
Stomach 
D100 
<45 Gy 
  
<7% 
Ulceration 
Small bowel (individual 
loops) 
V15 
<120 cc 
  
<10% 
Grade 3+ toxicity 
Rectum 
V75 
<15% 
  
<10% 
Grade 3+ toxicity 
Bladder  
  
  
<65 
<6% 
Grade 3+ toxicity 
1.3 
Other Agents 
All patients will be treated with standard of care systemic therapy, most commonly with a 
second generation androgen pathway inhibitor (e.g. enzalutamide or abiraterone), 
although other standard agents (e.g. docetaxel, cabazitaxel) are allowed.  These have 
known safety profiles from large phase III and IV trials.  Radium-223 dichloride is not 
allowed due to overlapping radiotoxicity.  Concurrent sipuleucel-T is not allowed as there 
is no safety data with concurrent radiation.  The use of palliative radiotherapy (for pain or 
urinary obstructive symptoms) is commonly delivered concurrently with some of these 
systemic agents (e.g. abiraterone or enzalutamide).  Radiotherapy, in combination with 

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many forms of hormonal based treatments, have been studied in over 15 randomized 
clinical trials and have not shown any enhanced toxicity from the combination, and 
delivery together is part of the standard of care for localized, recurrent, and node positive 
prostate cancer.  If other agents (e.g. docetaxel, cabazitaxel) are used, the dose of drug 
may be adjusted or held during radiation (or radiation adjusted) at the discretion of the 
medical and radiation oncologists.  This is done occasionally in standard practice for 
patient’s receiving docetaxel in mCRPC and requiring emergent radiation.   
1.4 
Rationale 
There are several studies supporting the use of ablative therapy in the setting of 
oligometastatic disease. Salama et al. performed a prospective study examining the 
results of radiation dose escalation in patients with one to five sites of metastatic disease 
with any histology, all with a life expectancy of >3 months [11]. The starting dose was 8 
Gy x 3 fractions, and the protocol-specified maximum dose was 20 Gy x 3 fractions. In 
an interim analysis of 29 patients with 56 metastatic lesions, the authors found a response 
rate of 59%, and 21% of patients did not have progression following treatment [12]. In 
those patients that did progress, this progression was amenable to further local treatment 
in 48% of patients. In the final analysis, the authors confirmed that patients with 1 to 5 
metastases could be safely treated to multiple body sites and could thus benefit from 
hypofractionated, “ablative” radiation doses in this setting.  
 
Recently, a trial in non-small cell lung cancer randomized patients who responded to 
initial systemic chemotherapy and had ≤ 3 lesions to continue chemotherapy or have 
oligometastatic radiation, then resume chemotherapy (although only 1 of 20 patients 
continued non-molecularly targeted systemic treatment).  They found a dramatic 
improvement in PFS; the median progression-free survival in the local consolidative 
therapy group was 11.9 months (90% CI 5.7–20.9) versus 3.9 months (2.3–6.6) in the 
maintenance chemotherapy group (hazard ratio 0.35 [90% CI 0.18–0.66], log-rank 
p=0.0054) [4]. 
 
Given that the systemic treatment in these patients is not curable, and that a greater 
burden of disease correlates to a more rapid development of treatment resistance, it is 
rational to provide radiotherapy to destroy macroscopic clonogens to decrease the 
probability of resistance formation and reduce the capacity for existing metastases to seed 
to form new metastasis.  If these theories hold true, this would manifest in a prolongation 
in progression-free survival on first/early line systemic therapy.  Oligometastatic 
treatment for prostate cancer in the earlier hormone-sensitive clinical space was just 
published [13].  This trial showed that oligometastatic radiation (3 or fewer sites as 
determined by choline PET), delayed the start of ADT (dictated by symptomatic 
progression, new radiographic sites or local progression of treated sites) from 13 months 
(80% CI, 12-17 months) to 21 months (80% CI, 14-29 months) with a hazard ratio of 0.6 
(80% CI, 0.4-0.9, log-rank P = 0.11).  Effects on survival or subsequent treatment 
response are unknown.  
1.5 
Correlative Studies 
1.5.1 
Circulating Analytes (CTC and ctDNA) 
Extensive work has been done on circulating analytes in mCRPC.  They have 
explored both molecular insights into disease and have the potential to 
inform treatment decisions (although none are in routine practice).  CTC’s 

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were shown to recapitulate ERG rearrangements seen in metastatic biopsies, 
simulate tumor heterogeneity by maintaining variable AR copy number 
gains, and also imply a role for HER2 and EGFR in bone metastases [14, 15].  
The predictive capacity for ctDNA or CTC is reflected by tumor AR-V7 
transcript presence (enzalutamide resistance), and CTC expression of EGFR 
or CTC count (docetaxel resistance) [16-19].  This work has never been 
explored uniquely in the oligometastatic state (which may have different 
molecular features then widely metastatic patients), nor with radiation in 
mCRPC.  
 
As discussed above, the hypothesis that ablating the bulk of disease may 
eliminate resistant clones which can be queried through circulating analytes.  
If radiation (while we know oral therapy does not) converts a patient with 
positive circulating signatures for androgen pathway resistance (AR-V7 
positive or AR copy number/mRNA amplification) into a negative one, and 
the trial’s outcome is positive, that theory would be reinforced.  Also, if the 
number of CTCs are eliminated, and development of new metastatic sites 
prolonged, this would support the hypothesis that metastases may seed other 
metastases, and radioablation delays it.    
1.5.2 
Radiographic Correlative Study 
If any patients have undergone previous nuclear imaging prior to enrolment 
those images will be collected and may be used for enrolment (if obtained 
within mCRPC state) and therapy designation.  As there is no data supporting 
the superiority of these newer radiologic techniques in regards to treatment 
decision designation, patients without molecular imaging will not undergo 
them for treatment designation.  Patients in Arm 2 who have not undergone 
prior molecular imaging will be offered (patients may accept or refuse this 
extra study) nuclear imaging towards prostate specific membrane antigen 
(PSMA).  This 68Ga-PSMA PET/CT analysis will be done before starting 
radiation therapy as a research scan. The results will be sequestered and not 
disclosed to provider until after that patient has completed the therapeutic 
study (so does not play a role in eligibility or treatment planning).  This will 
allow the evaluation of whether patients who received radiation progress in 
lesions that were undetectable by standard imaging, but present on 68Ga-
PSMA PET/CT.  It will create a knowledge foundation to support or refute 
whether a 68Ga-PSMA PET/CT guided study oligometastatic mCRPC should 
be pursued exclusively.  
2.0 
STUDY OBJECTIVES 
The purpose of this study is to assess if the addition of radiotherapy to systemic treatment for men 
with oligometastatic CRPC improves outcomes over systemic therapy alone. 
2.1 
Primary Objectives 
To determine whether the addition of radiotherapy to standard of care early systemic 
therapy improves objective progression-free survival, compared to systemic therapy 
alone. 

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2.2 
Secondary Objectives  
2.2.1 
To compare PSA PFS between arms. 
2.2.2 
To compare radiographic PFS between arms. 
2.2.3 
To compare PSA response rates (≥90% and ≥50% decline from baseline) and 
rate of undetectable PSA (≤ 0.2 ng/mL) between arms. 
2.2.4 
To compare measurable disease response rate between arms. 
2.2.5 
To compare non-irradiated distant metastasis free survival between arms.  
2.2.6 
To compare patient-reported outcomes based on NCCN-FACT FPSI-17. 
2.2.7 
To compare overall survival between arms 
2.2.8 
To compare prostate cancer specific survival between arms 
2.2.9 
To describe the adverse events associated with radiotherapy when 
administered in combination with systemic therapy. 
 
2.3 
Exploratory Objectives 
2.3.1 
Circulating analytes (circulating tumor DNA (ctDNA) and circulating tumor 
cells (CTC)) will be evaluated alone and in combination with standard 
laboratory measures for biologic insights and predictive/prognostic 
capacities.   
2.3.2 
If patients were on continuous treatment with second generation androgen 
inhibitors (e.g. abiraterone or enzalutamide) in the metastatic hormone-
sensitive phase, the ctDNA and CTC cells will be investigated before and 
after radiation and at ~3 months post-radiotherapy to measure eradication 
and/or relapse of resistance signatures (AR-V7 presence, androgen receptor 
mRNA copy number). 
2.3.3 
68Ga-PSMA PET/CT will be offered to patients in ARM 2 (unless already 
done in routine care) to evaluate if areas of subsequent relapse were present 
on the molecular study compared to standard imaging.  
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria to be enrolled to the study. Study 
treatment may not begin until a subject is enrolled. 

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3.1 
Inclusion Criteria 
3.1.1 
Subjects must have biopsy-confirmed adenocarcinoma of the prostate (pure 
small cell or pure neuroendocrine prostate cancer are not allowed). 
3.1.2 
Subjects must discontinue any prior systemic therapies (excluding GnRH 
agonist/antagonists) without PSA withdrawal effects if using first generation 
anti-androgens. LHRH analogues (agonist or antagonist) must be continued 
if they have not undergone orchiectomy.  
  
 
 
 
- Patients who recently started systemic therapy for mCRPC are eligible  
  
 
 
 
   to enroll if new therapy was started ≤ 14 days to consent date.  No  
  
 
 
 
   washout or new PSA rise is required.  Labs and/or imaging prior to  
  
 
 
 
   starting the new therapy are used for disease progression criteria (see  
  
 
 
 
   3.1.3).  Scans may be obtained after consent if PSA progression was  
  
 
 
 
  deemed cause of mCRPC designation (within 28 days). 
3.1.3 
Subjects must have progressive metastatic castration-resistant prostate cancer 
based on at least one of the following criteria while having castrate levels 
(<50 ng/dL) of testosterone: 
A) PSA progression defined as a 25% increase over baseline 
value with an increase in the absolute value of at least 2.0 
ng/mL that is confirmed by another PSA level with a 
minimum of a 1-week interval.  
B) Progression of bidimensionally measurable soft tissue or 
nodal metastasis by CT scan or MRI based on RECIST v1.1 
criteria (see section 7.0 for definitions). Note, new lesions 
diagnosed by 68Ga-PSMA PET/CT alone are insufficient for 
enrolment in absence of PSA progression. 
C) Progression of bone disease on bone scan as defined by two 
new lesions arising 
3.1.4 
Subjects must have oligometastatic prostate cancer, defined as between 1 and 
≤5 treatment sites that can be treated within a radiotherapy treatment field.  
All sites must be ≤5 cm in maximum cross section. If the patient’s prostate 
itself has not been treated (radiation or surgery), it will be treated and count 
as 1 treatment site.   
Any site treated within 4 weeks of registration counts as a trial relevant 
treatment site toward the 5 or less criteria.  The patient must have at least 1 
non-irradiated site remaining though. Treatment sites are designated by 68Ga-
PSMA PET/CT or CT/MRI/NM bone imaging, whatever is available. 
 
 
 
The radiation oncologist should designate the number or treatment sites.   
-Examples: 2 adjacent vertebral bodies would count as 1 treatment site, 
multiple contiguous external iliac LNs would count as 1 treatment site, and 

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untreated/intact prostate would count as 1 site.  Also, a single symptomatic 
lesion that required treatment before enrollment would count as 1 site.   
3.1.5 
Subjects must be medically fit to undergo radiotherapy and systemic therapy 
as determined by the treating physician.  
3.1.6 
Age ≥ 18  
3.1.7 
ECOG ≤ 2. 
3.1.8 
No prior invasive malignancy in the past 3-years. Exceptions include non-
melanomatous skin cancer and in situ cancers of the bladder or head and 
neck are permissible.  
3.1.9 
Subjects must freely sign informed consent to enroll in the study. 
3.1.10 Subjects must use contraception up to 90 days after last drug dose. 
3.2 
Exclusion Criteria 
3.2.1 
Planned systemic therapy with Radium-223 dichloride or sipuleucel-T 
3.2.2 
Tumor requiring emergent radiation in view of provider 
3.2.3 
Life expectancy estimate of <3 months 
3.2.4 
Presence of known parenchymal brain metastasis 
3.2.5 
Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina 
pectoris, or psychiatric illness/social situations that would limit compliance 
with study requirements. This will be determined by one of the study PIs if in 
question. 
3.2.6 
Inability to undergo radiotherapy, systemic treatment, CTs or bone scans 
3.2.7 
Biopsy proven pure small cell or neuroendocrine prostate cancer 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
4.1 
Screening, Enrollment and Randomization 
 
Patients who are identified by medical oncology and are candidates for a systemic therapy 
will be discussed with radiation oncology.  Radiation oncology will review the imaging 
and confirm radiographic candidacy.       
 
If a patient is identified by radiation oncology as a candidate, they will refer to medical 
oncology.  Medical oncology will meet (virtual or in person) and evaluate the patient for 
systemic candidacy.  
 
Only when both radiation oncology (at minimum by radiography assessment) and medical 
oncology (in person or virtual visit) have deemed the patient a candidate for their 
respective therapies, will the patient be registered.  
 

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Patient registration and randomization for this trial will be centrally managed by the Coordinating 
Center of The University of Michigan Rogel Cancer Center as described below: 
 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on a Screening and 
Enrollment Log.  
 
It is the responsibility of the local site investigator to determine patient eligibility prior to 
submitting patient registration request to the Coordinating Center. After patient eligibility has 
been determined, a copy of the completed Eligibility Worksheet together with all the pertinent 
redacted source documents will be submitted by the requesting site to the Coordinating Center, by 
email to CTSU-Oncology-Multisite@med.umich.edu.  
 
The Multi-Site Coordinator (MSC) of the Coordinating Center will review the submitted 
documents and process the registration. Sites should inform the Multi-Site Coordinator of a 
potential registration by 5 p.m. on the day prior to registration.  Same day registrations cannot be 
guaranteed.   
 
An email will be sent by the MSC to the requesting site registrar to confirm patient registration 
and randomization and to provide the study identification number and randomization number that 
has been assigned to the patient. In addition, a copy of the completed Eligibility Worksheet 
signed and dated by the MSC, will be sent back to the requesting site registrar. 
 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in a Screening and Enrollment Log. These patients will not have 
study identification number assigned to them, and will not receive study treatment. 
 
All patients who are treatment candidates will be stratified by the number of metastatic sites (1-2 
or 3-5 treatment sites) and prior lines of mCRPC like therapy (1-2 or 3+ lines of therapy). Note, a 
patient who receives a second-generation anti-androgen (e.g. enzalutamide, apalutamide, 
darolutamide) or abiraterone or docetaxel in mHSPC or non-metastatic CRPC and progresses 
while ON the treatment, it counts as one line of mCRPC therapy. Next generation mCRPC 
directed therapies also count as lines of therapy. They will be enrolled 1:1 between Arms 1 and 2.  
Randomization will be performed at the University of Michigan. 
5.0 
TREATMENT PLAN 
5.1 
Radiotherapy Treatment Dosage and Administration 
Arm 1 patients should begin systemic treatment within 3 weeks of randomization.  Arm 2 
patients should start systemic therapy within 3 weeks of randomization and receive 
radiotherapy within 8 weeks of randomization. For Arm 2, systemic therapy (if not safe 
to do concurrently with radiation) may be held at provider’s discretion until after 
radiation completes if radiation begins within 3 weeks of randomization.  Sites of disease 
are designated by prior 68Ga-PSMA PET/CT and CT/MRI/NM bone scan- whatever are 
available. 
 
 
Radiotherapy will typically be delivered to a total EQD2 (alpha/beta 2) that ranges 
between conventional 30 Gy in 10 fractions, to SBRT with 50 Gy in 5 fractions.  Use of 
3D conformal radiotherapy (3DCRT), Intensity-Modulated Radiation Therapy (IMRT), 
or SBRT will be used as needed to meet dose constraints for tumor coverage and organs 

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at risk. Some flexibility is given to radiation oncology to allow newer techniques to be 
accounted for as long as goal remains ablative radiation dosing.  
 
 
Simulation, Treatment planning, Set-up and Localization 
 
Computed Tomography (CT) Simulation and Treatment Planning  
CT will be the primary image platform for simulation and treatment planning.  The 
simulation should be performed in the supine treatment position if possible. Axial 
cuts of ≤3 mm will be acquired to encompass the relevant tumor sites and organs at 
risk. Oral and IV contrast are allowed but not required.  
Patient Set-up 
Patients will be positioned usually supine depending on the target sites in a 
comfortable posture. The minimum immobilization apparatus will be a pillow or 
knee fix under the knees and the feet taped or rubber-banded together. More 
complex immobilization devices are allowed, as per the discretion of the treating 
physician. 
 
Localization 
Daily MV, KV or cone-beam CT can be used as required for appropriate 
localization.   
 
Treatment Planning/Target Volumes 
 
1. The definition of volumes will be in accordance with the ICRU Report #50: 
Prescribing, Recording, and Reporting Photon Beam Therapy. 
2. Gross tumor volume (GTV) delineation will be performed based on the CT simulation 
and any relevant additional diagnostic imaging. 
3. The Clinical Target Volume (CTV) is defined by the physician as the GTV plus any 
necessary margin to account for microscopic disease.  This margin will typically be 
between 0-5 mm depending on the location of the tumor. If lymph nodes are involved, 
the entire nodal chain should be included in the CTV.  
4. The planning target volume (PTV) will be defined as the CTV plus a 3-5 mm margin 
based on immobilization and image guidance utilized.  
 
Dosimetry 
 
1. Axial or non-axial beam arrangements may be utilized.  
2. The prescription isodose line must encompass at least 95% of the PTV with a maximal 
differential between the prescription isodose line and the maximum dose to the PTV 
of 20%. Thus, PTV coverage will be within the range of +19% to -1%. Maximal dose 
to the PTV is defined as to a single point or voxel within the PTV.  In addition, <15% 
of the PTV or < 10 cc (whichever is smaller) should be treated to >115% of the 
prescription dose.  
 
Critical Structures 
   
 
Critical Organ Dose-Volume Limits 
1. The normal tissue volume to be contoured will include any organ at risk that is within 
2 cm superior or inferior to each PTV.  Structures that have mean volume constraints 
must be contoured in their entirety.  
2. The normal tissues will be contoured and considered as solid organs.  

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Dose limits should be followed by either SBRT criteria or 3DCRT/IMRT criteria as listed 
below:  
 
DVH Criteria  
 
Table 2: SBRT dose constraints in 1, 3, or 5 fractions: 
Normal Structures 
& Goals:  
Measure 
Limit (5 
Fx) 
Limit (3 
Fx) 
Limit (1 
Fx)* 
SpinalCord 
D0.1cc 
<28 Gy  
<22 Gy 
<14 Gy 
Brainstem 
D0.1cc 
<20 Gy 
<18 Gy 
<14 Gy 
BrachialPlex 
D0.1cc 
<30 Gy 
<24 Gy 
<17.5 Gy 
Esophagus 
D0.1cc 
D5cc  
<35 Gy 
<19 Gy 
<27 Gy 
<16.5Gy 
<16 Gy 
<12 Gy 
Heart 
D0.1cc 
<38 Gy 
<30 Gy  
<22 Gy 
Great Ves 
D0.1cc 
V47Gy 
<52.5Gy 
<10 cc 
<30 Gy 
N/A 
<18 Gy 
Trachea 
D0.1cc 
V32Gy 
<52.5Gy 
<5 cc   
<30 Gy 
N/A 
<20 Gy 
 
Chestwall / Rib 
V30Gy 
<70 cc 
<30 cc 
N/A 
Liver 
NTCP 
>700 cc 
<15% 
N/A 
N/A 
<15 Gy 
N/A 
<9.6 Gy 
Stomach 
D0.5cc 
<30 Gy 
<22.5Gy 
<16 Gy 
Kidneys 
D35.0% 
<15 Gy 
<12 Gy  
<8 Gy 
Kidney_R 
D67.0% 
<15 Gy 
<12 Gy  
<8 Gy 
Kidney_L 
D67.0% 
<15 Gy 
<12 Gy  
<8 Gy 
Duodenum 
D0.1cc  
<30 Gy 
<24 Gy  
<10 Gy 
Bowel_Small 
D0.1cc 
<30 Gy 
<24 Gy  
<11 Gy 
Colon 
D0.5cc 
<32 Gy 
<24 Gy 
<16 Gy 
Rectum 
D0.1cc 
D2cc 
<39.3Gy 
<37 Gy  
<28 Gy  
N/A 
<18 Gy  
N/A 
CaudaEquina 
D0.1cc 
<32 Gy  
<24 Gy  
<16 Gy 
SacralPlex 
D0.1cc 
<32 Gy  
<24 Gy  
<18 Gy 
 
*Other organs at risk that investigators identify not provider should contact the study PI to 
determine the appropriate dose constraint based on the most recent national clinical trials. 
 
3DCRT and IMRT constraints: 
Should follow QUANTEC for estimated risks of grade 3 toxicity of ≤10%. 
  
5.3 
Systemic Therapy   
Current systemic therapies include second generation androgen pathway agents 
(enzalutamide or abiraterone) and chemotherapies (docetaxel, cabazitaxel), all which are 
FDA approved in mCRPC.  Radium-223 dichloride and sipuleucel-T are not allowed (see 
section 1.3 for discussion).  The choice of agent will be up to the treating medical 
oncologist and is not the study intervention.  Treatment holds or adjustments to 
accommodate radiation are up to the treating oncologist (see section 5.1 for timing).  
Otherwise, normal use, dose reductions and discontinuation of therapy for toxicity will be 
executed as described in the package inserts and provider discretion. If there is any 

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question on appropriate holds or discontinuation, please contact the Principal 
Investigator(s). 
5.4 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
Table (Section 6.5). Toxicity will be assessed according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03. Dose adjustments 
should be made according to the system showing the greatest degree of toxicity.  
 
 
Table 3. Non-Hematological Toxicity Dose Reductions for Radiation 
Event 
Action 
Name of Toxicity 
Grade 1-2 
No action. 
Grade 3 
Grade 3 toxicity during radiotherapy, consider 
holding radiotherapy until reduced to grade 2 
toxicity, or reduce dose of radiotherapy as 
deemed appropriate by the PI.   
Grade 4 
If any grade 4 event attributed during 
radiotherapy then radiotherapy should be 
discontinued. 
5.5 
Concomitant Medications/Treatments 
Only systemic therapy with radiation is allowed concurrently at discretion of providers in 
arm 2. 
5.6 
Duration of Radiotherapy 
In the absence of treatment delays due to adverse events, radiotherapy treatment may 
continue unless one of the following criteria apply: 
 
Intercurrent illness that prevents further administration of radiotherapy 
 
Unacceptable adverse event(s); grade 4. 
 
Patient voluntarily withdraws from treatment OR 
 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
5.7 
Off Radiotherapy Treatment Criteria  
Patients will be removed from radiotherapy when any of the criteria listed in Section 5.5 
apply. Document in the source the reason for ending radiotherapy and the date the patient 
was removed from radiotherapy.  The only exception to this requirement is when a 
subject withdraws consent for all study procedures or loses the ability to consent freely. 
5.8 
Duration of Systemic Therapy 
In the absence of treatment toxicities, systemic therapy may continue unless one of the 
following criteria apply: 
 
Disease progression as defined in Section 7 
 
Intercurrent illness that prevents further administration of systemic treatment 
 
Unacceptable adverse event(s); grade 4. 
 
Patient voluntarily withdraws from treatment OR 

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 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 
Note, patient whose therapy is held for toxicity and no new therapy is started, will remain 
on study if they have not clinically or radiographically progressed.  If a new therapy is 
started, they will be defined as having progressed.  
5.9 
Off Systemic Therapy Criteria  
Patients will be removed from systemic therapy treatment when any of the criteria listed 
in Section 5.8 apply. Document in the source the reason for ending systemic therapy 
treatment and the date the patient was removed from treatment. All patients who 
discontinue treatment should comply with protocol specific follow-up procedures. The 
only exception to this requirement is when a subject withdraws consent for all study 
procedures or loses the ability to consent freely. 
5.10 
Duration of Follow-Up 
After treatment discontinuation, patients should return for an End of Treatment Visit 30 
days (±14 days) after last treatment dose.  
 
If off treatment for reasons other than progression, patient should be followed for disease 
status every 6 months (± 31 days) via telephone, virtual visit or office visit 
documentation for up to 2.5 years from treatment discontinuation or until death, objective 
progression, or initiation of another prostate cancer directed therapy (excluding 
bisphosphonates or RANKL inhibitors), whichever comes first. 
 
If off treatment for progression, patients should be followed for survival and initiation of 
any other prostate cancer directed therapy (excluding bisphosphonates or RANKL 
inhibitors) every 6 months (± 31 days) via telephone or office visit documentation for up 
to 2.5 years from treatment discontinuation or until death, whichever comes first.  
5.11 
Off Study Criteria 
Patients can be taken off study at any time at their own request, or they may be removed 
at the discretion of the investigator for safety, behavioral or administrative reasons. The 
reason(s) for discontinuation from study will be documented and may include: 

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5.11.1 Patient withdraws consent (termination of treatment and/or follow-up); 
5.11.2 Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment; 
5.11.3 Patient is unable to comply with protocol requirements; 
5.11.4 Treating physician judges continuation on the study would not be in the patients 
best interest; 
5.11.5 Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.11.6 Lost to Follow-up. If a research subject cannot be located to document survival 
after a period of 2.5 years, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during the 2.5 years must be documented. 
5.11.7 Termination of the study by The University of Michigan; 
5.11.8 Patient completes protocol treatment and follow-up criteria. 
6.0 
STUDY PROCEDURES 
6.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done 
only after obtaining informed consent. Assessments performed for clinical indications 
(not exclusively to determine study eligibility) may be used for baseline values even if 
the studies were done before informed consent was obtained. 
 
 All screening procedures must be performed within 28 days prior to 
registration unless otherwise stated 
 

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6.2 
Study Calendar:   
Note: a cycle is 42 days. 
 
 
Screening (Day 
-28 to 
registration) 
Day 1 of Cycle 1 
and 2  
Day 1 of Cycle 3l 
and 4 
Day 1s of Cycle 
5+a 
End of 
Treatmentm 
Follow-upg 
Informed Consent, HIPAA Form 
X 
 
 
 
 
 
Medical/Surgical Historyh, Demographics, 
Histologic Confirmation 
 
X 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
PEi, Vitalsi, Weight, Heighti 
X 
X 
X 
X 
X 
 
Performance Status (Appendix A) 
X 
X 
X 
X 
X 
 
Adverse Event, Toxicity Evaluations 
 
X 
X 
X 
X 
 
Medication Review including Systemic 
Therapy 
 
X 
X 
X 
X 
X 
 
Radiotherapy Administration 
 
Xd 
 
 
 
 
Systemic Therapy 
 
X 
X 
X 
 
 
Radiologic evaluations and measurementsb 
 
X 
Radiologic tests are performed every 12 weeks (± 7 days) for 
the first 2 years.  Radiologic tests then are performed every 6 
months (± 2 weeks) while in the treatment phase of the study. 
Xe 
 
Serum Chemistry, LDHc 
X 
X 
 X 
X 
X 
 
CBC with Differential 
X 
X 
X 
X 
X 
 
PSA 
X 
X 
X 
X 
X 
 
Testosterone 
X 
 
 
 
 
 
PROj 
X 
Within 30 days (±7 days) after radiation completion and 
every 3 months (± 4 weeks) from randomization for the first 
24 months. 
X 
 
Circulating Correlativesf 
 
X 
X 
 
X 
 
Radiologic Correlativesk 
X 
 
 
 
Follow-up 
 
 
 
 
 
X 
a. Patients will have a clinical and laboratory evaluation every 42 days (±14 days) for 24 weeks. At the discretion of the oncologist, it can be extended to 
a maximum of 12 weeks (±14 days) at week 25.  All patients remaining on study at 18 months (±14 days), should be evaluated at that time. Starting at 

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Cycle 3 of treatment, remote monitoring virtual clinic visits will be allowed at the discretion of the provider, but will not be allowed for the End of 
Treatment visit.   
b. Radiographic evaluation will include radionuclide bone scan, CT or MRI of abdomen and pelvis, and CT, CXR or MRI of the chest as appropriate.  All 
disease sites must be assessed using the same methodology as performed at baseline.  At the discretion of the investigator, additional radiological 
evaluations may be performed at an unscheduled time point.  A patient must have a valid standard radiographic evaluation within screening window, 
even if disease is visible only on 68Ga-PSMA PET/CT scan. 
c. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT (AST), SGPT 
(ALT), sodium 
d. Radiotherapy must be delivered during Cycles 1 and 2. 
e. If radiographic evaluations were completed within 30 days of End of Treatment, they do not need to be repeated. 
f. Circulating correlatives are collected if available at the local lab at Cycle 1 Day 1 (-14 days), Cycle 3 Day 1 (±14 days), Cycle 4 Day 1 (±14 days) and 
EOT (±14 days). Any missed time points due to lab closure will be recorded as protocol deviations.  
g. Follow-up: If off treatment for reasons other than progression, patient should be followed for disease status every 6 months (± 31 days) via telephone 
or office visit documentation for up to 2.5 years from treatment discontinuation or until death, objective progression, or initiation of another prostate 
cancer directed therapy (excluding bisphosphonates or RANKL inhibitors), whichever comes first.  If off treatment for progression, patients should be 
followed for survival and initiation of any other prostate cancer directed therapy (excluding bisphosphonates or RANKL inhibitors) every 6 months (± 
31 days) via telephone or office visit documentation for up to 2.5 years from treatment discontinuation or until death, whichever comes first. 
h. Complete medical and surgical history (especially in regards to prior treatments for prostate cancer), history of infections, history of bowel/bladder 
problems, history of seizures 
i. 
Vitals: should include temperature, pulse, respirations, blood pressure, height (baseline only), and weight. Vitals. PE, Weight will NOT be required 
when a remote monitoring virtual clinic visit is determined at the discretion of the provider. 
j. 
PRO: Patient reported outcome measure: NCCN-FACT FPSI-17 (Appendix B) 
k. For patients in Arm 2 and undergoing the correlative 68Ga-PSMA PET/CT scan, this needs to be completed before the start of radiation.  It may be done 
after systemic therapy begins though, but within 4 weeks of treatment start date. 
l. 
Starting at Cycle 3 of treatment, remote monitoring virtual clinic visits are allowed at the discretion of the provider.  
m. Virtual remote monitoring clinic visit will not be allowed for the End of Treatment visit. This must be completed in-person.  

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7.0 
MEASUREMENT OF EFFECT 
7.1 
Response Definitions and Evaluations 
Response and progression definitions contain various parts of the criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee and the Prostate 
Cancer Working Group 3 [20, 21]. Changes in only the largest diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST v1.1 criteria.    
7.1.1 
Definitions 
Evaluable for toxicity: all patients will be evaluable for toxicity from the time of 
their first treatment with radiation or oral drug. 
 
Evaluable for progression-free survival: only patients who begin treatment will 
be evaluable for progression-free survival 
 
Evaluable for measurable disease response: Only those patients with measurable 
disease present at entry (as defined below), have received at least 7 weeks of 
therapy from randomization, and have had their disease radiographically re-
evaluated at 7 weeks or beyond will be considered evaluable for measurable 
disease response.  Patients who are removed from study prior to 7 weeks or prior 
to any follow-up imaging (regardless of response) are censored. 
 
Non-measurable, non-target disease response: Patients who have non-
measurable/non-target disease will be evaluated for non-measurable/non-target 
disease resolution, stability or unequivocal progression. 
 
7.1.2 
Disease Parameters 
All disease parameters noted below are based on CT, MRI or bone scan.  Patients 
that enter the trial with a negative CT, MRI and bone scan, but positive 68Ga-
PSMA PET/CT, will be deemed as having no “radiographic disease” at baseline.  
If a patient has a combination of 68Ga-PSMA PET/CT and CT/MRI/bone scan 
disease, only the lesions noted in CT/MRI/bone scan are utilized per below.   
 
Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) 
as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with CT scan, 
MRI, or calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters).  A previously untreated, intact 
prostate primary is NOT considered measurable.  
 
 
Note: Measurable tumor lesions on the baseline scan that are irradiated 
should be measured for measurable disease response/progression.  In Arm 2, all 
target lesions on the baseline scan should be irradiated.  
 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed.  

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For existing pathologic adenopathy (≥15 mm), progression is defined per 
RECIST v1.1. 
 
 
Note:  All measurable malignant lymph nodes on the baseline scan 
should be irradiated in Arm 2 and followed for response/progression.  Whether 
indeterminate lymph nodes (between 10 and <15 mm in short axis) on the 
baseline scan represent prostate cancer is up to the radiation oncologist’s 
discretion and may be discussed with medical oncology.  Any irradiated site, 
should be documented and followed.   
 
 
Previously normal (<10 mm) lymph nodes must have grown to ≥ 10 mm 
in the short axis to be considered to have progressed.  Nodes that have progressed 
between 10 and <15 mm are pathologic, subject to clinical discretion, and non-
measurable. 
 
Non-measurable disease: All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 
mm short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions (neither measurable 
nor non-measurable) since they are simple cysts. 
 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described 
above. However, if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
 
Target lesions: All measurable lesions should be identified as target lesions and 
recorded and measured at baseline.  All target lesions should receive radiation in 
Arm 2.  A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters. If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum. The baseline sum diameters will be used as reference 
to further characterize any objective tumor regression in the measurable 
dimension of the disease.  
 
Non-target lesions: All non-measurable lesions (or sites of disease) should be 
identified as non-target lesions and should also be recorded at baseline.  
Measurement of these lesions are not required, but the presence, absence, or in 
rare cases unequivocal progression of each should be noted throughout follow-
up.  In Arm 2, all non-target lesions at baseline should receive ablative therapy.  
7.1.3 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler 
or calipers. All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 6 weeks before the beginning of 
the treatment. 

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The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
Clinical lesions.  Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm 
diameter as assessed using calipers (e.g., skin nodules).  In the case of skin 
lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, CT is 
preferable.  
 
Conventional CT and MRI.  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  If 
CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in 
certain situations (e.g., for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables 
involved in MRI, which greatly impact image quality, lesion conspicuity, and 
measurement. Furthermore, the availability of MRI is variable globally.  As with 
CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up should be the 
same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence. It is beyond the scope of the RECIST guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, 
and diseases. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. 
Body scans should be performed with breath-hold scanning techniques, if 
possible.   
 
68Ga-PSMA PET/CT.  This modality does NOT define lesions as target, non-
target or measurable. See section 7.1.2.   A patient with disease ONLY visible by 
68Ga-PSMA PET/CT is designated as having no target or measurable lesions at 
baseline for measurement purposes.  Sites of disease presence are noted in the 
record, but visualization on CT, MRI, bone scan (when previously negative) are 
deemed new lesions- thus potential progression.     
 
7.1.4 
Methods of Evaluation of Bone disease 
Bone disease will be evaluated using radionuclide bone scan. 

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7.2 
Response Criteria 
7.2.1 
Response Evaluation of Target/Measurable Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduced in short axis to 
<10 mm.  There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions, taking as reference the baseline sum LD. There 
can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded since the treatment 
started, or the appearance of one or more new lesions.  The sum must also 
demonstrate an absolute increase of at least 5 mm.  The appearance of one or 
more new target lesions is also considered progression. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum LD since the 
treatment started. 
7.2.2 
Response Evaluation of Non-Measurable/Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis).  
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new non-measurable 
lesions and/or unequivocal progression of existing non-target lesions.  
Unequivocal progression should not normally trump target lesion status.  It must 
be representative of overall disease status change, not a single lesion increase.  
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed with a Principal Investigator.  
 
If there are no non-target lesion, it is described as none. 
7.2.3 
Response Evaluation of Radionuclide Bone Scans for Bone Metastases 
The subjectivity in interpreting serial changes in a radionuclide bone scan is well 
recognized.  Thus, the primary outcome will be whether the scan is stable or 
improved, vs. progression.  Changes in intensity will not be used as an outcome 
measure.  Bone scans can be altered from non-oncologic changes as well.  If 
there is evidence of trauma or infection by history of exam to explain a bone scan 
finding, that site shall not be counted as a new lesion at the provider’s discretion 
and documented appropriately.  Bone metastases without accompanying 
measurable soft tissue component should only use radionuclide bone scans to 
classify lesion. 
 

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Stable Bone Disease: A stable classification requires that no more than 1 new 
lesion appears compared to the screening bone scan.   
 
Progression (Non-Response): Appearance of two or more new skeletal lesions 
compared to the screening bone scan. An increase in the size or intensity of 
known skeletal lesions will not be considered progression. 
7.2.4 
Response Evaluation Based on Post-Therapy PSA Changes 
These definitions are intended to characterize the PSA changes on study for the 
purpose of reporting of results.    
 
Complete Response (CR): Undetectable PSA (≤0.2 ng/ml) that is confirmed by 
another PSA level at no less than 4 weeks interval. 
 
Partial Response 50 (PR50): Decrease in PSA value by ≥ 50% that is confirmed 
by another PSA level at no less than 4 weeks interval. 
 
Partial Response 90 (PR90): Decrease in PSA value by ≥ 90% that is confirmed 
by another PSA level at no less than 4 weeks interval. 
 
Stabilization (SD): Patients who do not meet the criteria for PR50 or PD for at 
least 90 days on study will be considered stable. 
 
Progression (PD): 25% increase over baseline or nadir whichever is lower and an 
increase in the absolute value of PSA level by 2 ng/ml that is confirmed by 
another PSA level at no less than 4 weeks interval. 
 
7.2.5 
Response Evaluation Based on Disease Symptoms (Including Pain) 
Stable/Improved: Absence of progression of symptoms. 
 
Progression: Progression by disease symptoms is based on the interpretation of 
the provider that a patient is having progressive disease-related symptoms (e.g. 
urinary obstruction, pain).  Death is considered a progressive symptom. 
 
Progression by pain due to prostate cancer requires evidence of disease at the site 
of pain and one or more of the following palliative interventions: 
- 
Opioid Therapy: Intravenous, intramuscular or subcutaneous opioid 
therapy administered as a single dose; oral or transdermal opioid analgesic 
use administered for 10 out of 14 consecutive days 
- 
Radionuclide Therapy 
- 
Radiation Therapy   
7.2.6 
Outcomes Based on Response Evaluations 
A patient’s designated response at any one time is a combination of the 
assessment of target lesions, non-target lesions, bone lesions and disease 
symptoms.  
 

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Table 4: For Patient’s with Measurable Disease (i.e. Target Disease) 
  
 
Target 
Lesions 
Non-Target 
Lesions 
New Non-Bone 
Lesion(s) or Bone 
Metastases 
Progression* 
Disease 
Symptom 
Progression** 
Overall 
Response 
CR 
CR 
No 
No 
CR 
CR 
Non-CR/ 
Non-PD 
No 
No 
PR 
CR 
None 
No 
No 
PR 
PR 
Any 
No 
No 
PR 
SD 
Non-CR/ 
Non-PD, 
None 
No 
No 
SD 
PD 
Any 
Yes or No 
Yes or No 
PD 
Any 
PD*** 
Yes or No 
Yes or No 
PD 
Any 
Any 
Yes  
Yes or No 
PD 
Any 
Any 
Yes or No 
Yes 
PD 
* See RECIST 1.1 manuscript for details on what is evidence of a new non-bone 
lesion and see section 7.1.5.3 for definition of bone metastases progression. 
** See section 7.1.5.5 for definition of disease symptom progression. 
** In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression. 
 
Table 5: For Patients with Non-Measurable Disease/Non-Target Disease, Bone 
Metastases Only or exclusive 68Ga-PSMA PET/CT disease at baseline. 
  
Non-Target 
Lesions 
New Non-Bone 
Lesion(s) or Bone 
Metastases Progression* 
Disease Symptom 
Progression**  
Overall 
Response 
CR 
No 
No 
CR 
Non-CR, 
Non-PD 
No 
No 
Non-CR, 
Non-PD*** 
None 
No 
No 
Stable Bone 
Disease 
Unequivocal 
PD 
Yes or No 
No 
PD 
Any 
Yes 
No 
PD 
Any 
Yes or No 
Yes 
PD 
* See RECIST 1.1 manuscript for details on what is evidence of a new non-bone 
lesion and see section 7.1.5.3 for definition of bone metastases progression. 
** See section 7.1.5.5 for definition of disease symptom progression. 
*** Non-CR/Non-PD is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is misleading. 
 

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7.2.7 
Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented.  Patients with initiation of a different prostate cancer directed 
therapy (excluding bisphosphonates or RANKL inhibitors) are deemed to have 
progressed.  Patients lost-to-follow-up before progression will be censored at the 
date of last scan respectively. 
 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  
 
Patients with initiation of a different prostate cancer directed therapy (excluding 
bisphosphonates or RANKL inhibitors) are deemed to have progressed.  Patients 
lost-to-follow-up before progression will be censored at the date of last scan 
respectively. 
. 
7.2.8 
Progression-Free Survival  
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to date of progression or death (whichever is first).  Patients with 
initiation of other prostate directed therapies (excluding bisphosphonates or 
RANKL inhibitors) are progressors.  Those lost-to-follow-up before progression 
will be censored at the last scan date respectively. 
7.2.9 
Prostate Cancer Specific Survival 
Prostate Cancer Specific Survival is defined as the duration of time from start of 
treatment to death from prostate cancer.  Patients who have not died will be 
censored at the last known alive date and patients who died of other causes will 
be censored at the date of death. 
7.2.10 Overall Survival 
Overall survival (OS) is defined as the duration of time from start of treatment to 
death.  Patients who have not died will be censored at the last known alive date. 
7.2.11 Non-irradiated Distant Metastases Free Survival 
Non-irradiated metastases free survival is defined as the duration of time from 
start of treatment to the date of progressive disease of a new target lesion (as 
defined in section 7.2.1, progressive disease description), a new non-
measurable/non-target lesion (as defined in section 7.2.2) or emergence of 2 or 
more new skeletal lesions on a bone scan (as defined in section 7.2.3). Patients 
lost-to-follow-up before progression will be censored at last known scan date 
respectively. 
 

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7.3 
Safety/Tolerability 
Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the CTCAE version 4.03 for reporting of non-hematologic 
adverse events (http://ctep.cancer.gov/reporting/ctc.html). 
8.0 
ADVERSE EVENTS 
8.1 
Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and 
is done to ensure the safety of subjects enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Data on adverse events will be collected 
from the time of the initial study treatment through 30 days after the last dose of study 
treatment or study intervention. Any serious adverse event that occurs more than 30 days 
after the last study treatment or intervention and is considered related to the study 
treatment or intervention must also be reported. Serious Adverse Events (SAEs) will 
continue to be followed until: 
 
Resolution or the symptoms or signs that constitute the serious adverse event 
return to baseline; 
 
There is satisfactory explanation other than the study treatment or intervention 
for the changes observed; or  
 
Death. 
The investigator is responsible for the detection, documentation, grading and assignment 
of attribution of events meeting the criteria and definition of an AE or SAE. The 
definitions of AEs and SAEs are given below. It is the responsibility of the principal 
investigator to ensure that all staff involved in the trial is familiar with the content of this 
section. 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment administration or intervention is considered to be pre-existing in nature. Any 
known pre-existing conditions that are ongoing at time of study entry should be 
considered medical history. 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 8.2, 
occurring from the initial study treatment administration or intervention through 30 days 
following the last dose of the study treatment or study intervention must be recorded as 
an adverse event in the patient’s source documents and on the CRF regardless of 
frequency, severity (grade) or assessed relationship to the study treatment or intervention.  
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) 
of a pre-existing condition that occurs after the patient begins study treatment or 
intervention is also considered an adverse event. 
8.2 
Definitions 
8.2.1 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can be any unfavorable and unintended sign (including an 

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abnormal laboratory finding), symptom, or disease temporally associated with 
the use of an experimental intervention, whether or not related to the 
intervention.  
8.2.2 
Serious Adverse Event 
An adverse event is considered “serious” if, in the view of the investigator, it 
results in any of the following outcomes: 
  
o Death 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
 
o A life-threatening adverse event 
An adverse even is considered ‘life-threatening’ if, in the view of the 
investigator, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event that, had it occurred in a more 
severe form, might have caused death.  
 
o Inpatient hospitalization or prolongation of existing hospitalization for > 24 
hours. 
 
o A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
o A congenital anomaly/birth defect 
 
o Important medical event 
Any event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this 
definition of “Serious Adverse Event”. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; convulsions that do not result in inpatient hospitalization or 
the development of drug dependency or drug abuse. 
 
Previously planned (prior to signing the informed consent form) surgeries should 
not be reported as SAEs unless the underlying medical condition has worsened 
during the course of the study. Preplanned hospitalizations or procedures for 
preexisting conditions that are already recorded in the patient’s medical history at 
the time of study enrollment should not be considered SAEs. Hospitalization or 
prolongation of hospitalization without a precipitating clinical AE (for example, 
for the administration of study therapy or other protocol-required procedure) 
should not be considered SAEs. However, if the preexisting condition worsened 
during the course of the study, it should be reported as an SAE. 
 

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8.2.3 
Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
 
It relates to a common side effect associated with radiotherapy to the 
region of interest.  All grade 3 or higher expected side effects should be 
discussed with the study PI and Dr. Daniel Spratt to determine if it is an 
expected radiotherapy associated AE. 
 
It is described in the approved Package Insert for the systemic therapy 
being given. 
8.2.4 
Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it occurs outside of the 
radiotherapy treatment field and both is not reported in the published medical 
literature to be associated with radiotherapy and is not in the patient’s systemic 
therapy Package Insert.   
8.3 
Adverse Event Characteristics 
8.3.1 
CTCAE Term 
(AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will 
be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.03. A copy of the CTCAE version 4.03 can be 
down loaded from the CTEP web site. (http://ctep.cancer.gov) 
8.3.2 
Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the study treatment/intervention. 
Probable – The AE is likely related to the study treatment/intervention. 
Possible – The AE may be related to the study treatment/intervention. 
Unlikely – The AE is doubtfully related to the study treatment/intervention. 
Unrelated – The AE is clearly NOT related to the study treatment/intervention. 
8.4 
Serious Adverse Event Reporting Guidelines 
All serious adverse events (SAEs) and unanticipated problems (UPs), regardless of 
causality to study treatment, will be reported to the Principal Investigator and also to the 
Coordinating Center.  All SAEs and UPs must be reported to the Coordinating Center 
within 48 hours of first awareness of the event.  Events should be reported using the 
Coordinating Center’s SAE form as available in the study database.  A copy of the SAE 
form should be sent to the Coordinating Center via fax at 734-232-0744 or via email to 
CTSU-Oncology-Multisite@med.umich.edu within 48 hours of the site’s knowledge of 
the event.  
 
Follow-up information should also be reported within 48 hours of receipt of the 
information by the investigator. 
 
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The Coordinating Center will disseminate information regarding SAEs and UPs to the 
participating sites within 5 days of review of the information by the Coordinating 
Center’s Principal Investigator (or designee in the event of extended absence) only in the 
case that the event(s) is believed to be related (i.e., possibly, probably, or definitely) to 
the study intervention. 
8.5 
Routine Reporting of Non-Serious AE 
All other adverse events (e.g. not meeting criteria for SAE), such as those that are 
expected, or are unlikely or definitely not related to the study participation- are to be 
reported annually as part of regular data submission.  
8.6 
Reporting of Unanticipated Problems 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse 
event) that may represent an unanticipated problem, the investigator should assess 
whether the incident, experience, or outcome represents an unanticipated problem. The 
incident, experience or outcomes is considered unanticipated if it meets all of the 
following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency); 
2. Related or possibly related to participation in the research; and 
3. Suggests that the research places subjects or others at a greater risk of harm than 
was previously known or recognized. 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the IRB per local institutional 
standards. 
 
9.0 
CORRELATIVE PROTOCOLS 
For the biologic rationale of all correlative studies, see section 1.5. 
9.1 
Laboratory Correlative Studies  
Refer to Section 6.2 for correlative study collection time points and the Lab Manual for 
collection and processing details. 

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9.1.1 
Laboratory Protocol for CTC Analysis 
 
For the CTC-based evaluation, blood collected will be processed using an 
immunomagnetic bead enrichment approach.  Briefly, whole blood is incubated 
with anti-EpCAM microbeads (Dynabeads, Life Technologies) and washed 
multiple times. Lysis buffer is then added and the supernatant containing pooled 
cell lysateis collected for expression analysis. Oligo(dT)25 mRNA Dynabeads 
(Life Technologies) are used for mRNA capture, and cDNA prepared using the 
Superscript III One-Step RT-PCR system (Life Technologies). Following pre-
amplification and library establishment, multiplex qPCR will be performed for a 
total of 48 prostate cancer-related genes, including AR, AR-V7, Schlap1, PSMA, 
PSA, cytokerratins (8, 18, 19), and CD45 as well as actin and tubulin as internal 
controls. Quantitative RT-PCR will be performed using SYBR Green Mastermix 
(Life Technologies) on the ABI 7900 real time PCR machine. Gene expression 
signatures associated with response/resistance to therapy will be identified. 
9.1.2 
Laboratory Protocol for CTC Analysis 
Circulating tumor DNA (ctDNA) will be isolated from plasma using the QIAamp 
Circulating Nucleic Acid Kit. Low quantities of genomic ctDNA from each 
sample will be subjected to whole genome amplification using the ThruPlex-FD 
Prep Kit for Ion Torrent, and all samples will be sequenced on an Ion Proton 
sequencer with 10-20 samples loaded per chip (to at least 0.05x depth). Whole-
genome copy number profiles will be generated using a read-binning, circular 
binary segmentation method optimized for low-input DNA to yield genome wide 
copy number profiles. Additionally, we will profile ctDNA using the DNA 
component of the Oncomine Comprehensive Assay (OCP), to assess for 
prioritized mutations, insertions/deletions and copy number alterations in ~135 
recurrently altered oncogenes and tumor suppressors.  Sequencing to >1000x will 
be performed. 
9.1.3 
Excess Sample Banking 
With optional patient permission, excess blood specimens may be stored long-
term for potential use not outlined in the protocol.  This is to answer questions 
not identified a priori or future hypothesis.   These are subject to University 
Policy Governing Tissue Sample Collection, Ownership, Usage, and Disposition 
within all UMMS Research Repositories. 
9.2 
Radiographic Correlative Study 
Any patient who is undergoing 68Ga-PSMA PET/CT (see section 1.5.2), will have the 
scan done at the University of Michigan Rogel Cancer Center.  The data will be labeled 
with the subject’s coded study number and study date.  The results will not be made 
available to any of the providers until that patient has completed the study.   
10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Statistical Design 
This is a phase II randomized clinical trial in men with oligometastatic castration-
resistant prostate cancer to determine if the addition of radiotherapy to standard of care 
systemic therapy improves duration of response compared to systemic therapy alone 
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systemic treatment (Arm 1) versus systemic treatment plus radiotherapy (Arm 2).  The 
primary endpoint is objective duration of response.     
10.2 
Statistical Analysis 
10.2.1 Analysis of the Primary Endpoint 
The primary endpoint of the study is duration of response to therapy.  As this 
study includes all lines of systemic therapy within mCRPC, progression on 
therapy is related to prior lines which is stratified for.  Progression is defined a 
worsened pain or new sites of disease on imaging. The time to changing therapy 
will be collected for use in survival analysis.  The primary analysis will use 
Kaplan-Meier methods to estimate the median duration of response and 
associated 90% confidence intervals and compare groups using a stratified log-
rank test. We will also include 12 months and 18 months proportions with 90% 
confidence intervals by treatment arm. Patients who are lost to follow-up prior to 
changing therapies will be censored at the time they are lost-to-follow-up.   
  
10.2.2 Analysis of Secondary Endpoints 
See section 7 for endpoint descriptions 
 
- 
Objective PFS, PSA PFS, Radiographic PFS, OS, PCSS, Non-irradiated DMFS 
Each time-to-event endpoint will be presented with a Kaplan-Meier figure and corresponding 
estimates, including median, 12 months’, and 24 months’ proportions with 95% confidence 
intervals will be reported by treatment arm.  Stratified log-rank tests will be used for testing. 
 
- 
PSA Response Rate 
The PSA response rate (CR, PR50, PR90) will be calculated and proportion of responders by arm 
reported with the corresponding 95% exact binomial confidence intervals.  A Cochran-Mantel-
Haenszel statistic will be used for testing treatment differences.  
 
- 
Measurable Disease Response Rate 
The measurable disease response rate (CR + PR) will be calculated for patients evaluable for 
measurable disease response.  The proportion of responders by arm will be reported with 
corresponding 95% exact binomial confidence intervals.  A Cochran-Mantel-Haenszel statistic 
will be used for testing treatment differences. 
 
- 
Patient-reported outcomes  
Patient-reported outcomes (PROs) will be described using means or medians with associated 
measures of variability by treatment arm at each time collected.  A cumulative logistic model or 
general linear model with repeated measures throughout treatment with a primary test of the 
treatment arm fixed effect will be used to assess PROs.  
 
- 
Adverse events  
AE summaries will be reported by treatment arm and organized by body system, frequency of 
occurrence, intensity (e.g. severity, grade), and causality or attribution.  Treatment exposure will 
be summarized for all patients, including dose administration, number of cycles, dose 
modification or delays, and duration of therapy.  
 

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10.2.3  Analysis of Correlative Objectives 
Many correlative biomarkers are described in the correlative objectives. A 
general statistical analysis plan is described here to provide a skeleton for the 
known correlatives planned: 
Continuous correlative biomarkers will be described using means and standard 
deviations or medians with percentiles. Categorical covariates will be described 
with counts and frequencies. These descriptors will be provided by classifications 
by arm and/or by outcome.  Change from baseline and percent change will be 
described for biomarkers collected at post-baseline time points.  Prognostic or 
predictive associations of correlative biomarkers with response will be assessed 
using logistic models with response as the outcome and the correlative covariates 
and the independent predictors.  Cox models will be used when the outcome is 
time-to-event (PFS/OS).  Correlations of liquid assays to each other and/or 
clinical data will be reported using Pearson or Spearman correlation coefficients 
as is appropriate.  
 
68Ga-PSMA PET/CT comparisons to standard imaging will be descriptive only. 
10.3 
Sample Size and Accrual 
Sample Size 
This is a two-arm randomized, open-label phase II study in men with oligometastatic 
mCRPC.  36 patients with oligometastatic disease who are candidates for systemic and 
local therapy will be randomized 1:1 to each arm.   
 
Arm 1: standard of care  
Arm 2: standard of care with ablation of all metastatic sites 
 
Using prior studies, the median duration of response for systemic therapy alone is 
approximately 6 months (e.g. AFFIRM with enzalutamide, COU-AA-301 with 
abiraterone).  There is no clear data for oligometastatic patients.  Assuming the 
experimental arm increases this median duration of response to 15 months and 
exponential distribution of duration of response for both groups, with a 1 sided alpha of 
0.1 and power of 0.8 allows for 16 patients per arm. This results in 32 total patients for 
randomization.  To accommodate a 10% loss to follow-up rate, the total study sample is 
36.     
 
Accrual 
Accrual of 36 subjects with 1 subject per month (as now allowing multiple lines of prior 
therapy) results in complete accrual in 28 months.  3 years of follow-up will result in a 
total trial time of approximately ~6 years.  
 
10.4 
Stratification Factors 
There will be two stratification factors: 1-2 vs 3-5 treatment sites and line of therapy (1/2 
or 3+). Block randomization will be completed by stratification group. 
10.5 
Derived Variables 
- 
Change from baseline will be calculated as the rating after baseline minus the rating 
at baseline 

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- 
Percent change from baseline will be calculated as the rating after baseline minus the 
rating at baseline quantity divided by the baseline. 
- 
Duration of treatment will be defined as the number of days from the first day of 
protocol assigned intervention to the last day of protocol treatment. If the last day of 
protocol treatment is missing, the date of the last visit will be substituted for the missing 
value. 
 
10.6 
Analysis Datasets 
10.6.1 Survival Populations 
All patients who meet eligibility criteria and receive at least 1 dose of radiation or 
study medication will be included in the analysis of duration of response even if 
there are major protocol deviations (e.g., incorrect treatment schedule or drug 
administration). Primary conclusions are to be based on the population of all 
eligible treated patients with an intent-to-treat analysis. Sub-analyses will be 
performed on various subsets of patients, such as those with no major protocol 
deviations or those who continued in the study for the entire treatment period 
(i.e., did not withdraw prematurely by patient choice) as these sub-analyses will 
be important for designing future trials. However, sub-analyses will not serve as 
the basis for drawing conclusions concerning treatment efficacy. 
10.6.2 Response Rates 
All patients who meet eligibility criteria and receive at least one dose of study 
medication or radiation and undergo one response evaluation will be included in 
the main analysis of the response rate, even if there are major protocol deviations 
(e.g., incorrect treatment schedule or drug administration). Each patient will be 
assigned to one of the following categories for each response outcome: 
 
          Table 6: Categories for Response to Treatment 
Category 
Response 
1 
Complete Response 
2 
Partial Response 
3 
Stable Disease 
4 
Progressive Disease 
5 
Early Death from Malignant Disease 
6 
Early Death from Toxicity 
7 
Early Death from Other Causes 
8 
Unknown (not assessable/insufficient data) 
Note: By arbitrary convention, category 8 designates unknown 
status in a clinical database.  Patients in response categories 4-8 
will be considered to have treatment failure (disease progression).  
 
Conclusions are to be based on the population of all eligible patients. Sub-
analyses will be performed on various subsets of patients, such as those with no 
major protocol deviations or those who continued in the study for the entire 
treatment period (i.e., did not withdraw prematurely). Sub-analyses will not serve 
as the basis for drawing conclusions concerning treatment efficacy. 

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10.6.3 Patient-Reported Outcome 
All patients enrolled in the study who receive at least one dose of standard of 
care or radiation will be included in patient-reported outcome assessments. 
10.6.4 Safety Population 
All patients enrolled in the study who receive at least one dose of study or 
radiation treatment will be included in the safety analysis population and 
considered evaluable for toxicity and safety from the time of their first dose. 
Analysis will be completed by treatment received rather than treatment assigned.  
Demographic and baseline characteristics for the safety population will be 
summarized by number and percent for categorical data (e.g., race/ethnicity) and 
by descriptive statistics for continuous data (e.g., weight, vital signs, EKG 
readings, disease status). 
11.0 
DATA AND SAFETY MONITORING 
This study will be monitored in accordance with the NCI approved University of Michigan Rogel 
Cancer Center Data and Safety Monitoring Plan, with oversight by the Rogel Cancer Center Data 
and Safety Monitoring Committee (DSMC). 
 
The Sponsor Investigator (S-I)/Study Principal Investigator and/or the Project Manager/Delegate 
will review data and patient safety issues with participating sites per a defined quarterly meeting 
cadence. Depending on the protocol activity, the meeting cadence may be more frequent. This 
data review meeting may be achieved via a teleconference or another similar mechanism to 
discuss matters related to: 
 
Enrollment rate relative to expectations, characteristics of participants 
 
Safety of study participants (SAE reporting, unanticipated problems) 
 
Adherence to protocol (protocol deviations) 
 
Completeness, validity and integrity of study data 
 
Retention of study participants 
 
Participating sites are required to ensure all pertinent data for the review period are available in 
the database at the time of the discussion.  
 
Participating sites unable to participate in the data review meeting are required to provide written 
confirmation that their site has reviewed the relevant data and patient safety issues for the review 
period and their site’s data are in alignment with the data reported in the database. Written 
confirmation is to be provided to the Project Manager/Delegate within the timeline requested to 
retain compliance with monitoring timelines. 
 
Documentation of the teleconference or alternate mechanism utilized to review items above is to 
be retained in the Trial Master File. 
 
The Project Manager/Delegate is responsible for collating the data from all participating sites and 
completing the Protocol Specific Data and Safety Monitoring Report (DSMR) form to document 
the data review meeting discussion. 
 
The DSMR will be signed by the Sponsor-Investigator (S-I)/Study Principal Investigator or 
designated Co-Investigator and submitted to the DSMC on a quarterly basis for independent 
review. 

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12.0 
DATA MANAGEMENT 
All information will be recorded locally and entered into Case Report Forms (CRFs) on the web-
based electronic data capture (EDC) system of the University of Michigan. Online access will be 
provided to each site by the Coordinating Center.  
 
CRFs will be reviewed and source verified by the MSC during annual monitoring visits and prior 
to and between visits. Discrepant, unusual and incomplete data will be queried by the MSC. The 
investigator or study coordinator will be responsible for providing resolutions to the data queries, 
as appropriate. The investigator must ensure that all data queries are dealt with promptly.  
 
The data submission schedule is as follows:  
 
At the time of registration   
o Subject entry into EDC 
 
Subject Status 
 
Demographics 
 
During study participation 
o All data should be entered online within 10 business days of data acquisition. 
Information on Serious Adverse Events must be entered within the reporting 
timeframe specified in Section 8 of the protocol.  
 
All study information should be recorded in an appropriate source document (e.g. clinic chart). 
13.0 
QUALITY ASSURANCE AND AUDITS 
The Data and Safety Monitoring Committee can request a ‘for cause’ quality assurance audit of 
the trial if the committee identifies a need for a more rigorous evaluation of study-related issues.  
 
A regulatory authority may also wish to conduct an inspection of the study, during its conduct or 
even after its completion. If an inspection has been requested by a regulatory authority, the site 
investigator must immediately inform the Coordinating Center that such a request has been made. 
14.0 
CLINICAL MONITORING PROCEDURES 
Clinical studies coordinated by University of Michigan Rogel Cancer Center must be conducted 
in accordance with the ethical principles that are consistent with Good Clinical Practices (GCP) 
and in compliance with other applicable regulatory requirements. 
 
This study will be monitored by a representative of the Coordinating Center of the University of 
Michigan Rogel Cancer Center. Monitoring visits will be made during the conduct of the study 
and at study close-out. 
 
Prior to subject recruitment, a participating site will undergo site initiation meeting to be 
conducted by the Coordinating Center. This will be done as an actual site visit; teleconference, 
videoconference, or web-based meeting after the site has been given access to the study database 
and assembled a study reference binder.  The site’s principal investigator and his study staff 
should make every effort in attending the site initiation meeting. Study–related questions or issues 
identified during the site initiation meeting will be followed-up by the appropriate University of 
Michigan Rogel Cancer Center personnel until they have been answered and resolved. 
 
Monitoring of this study will include both ‘Centralized Monitoring’, the review of source 
documents at the Coordinating Center and ‘On-site Monitoring’, an actual site visit.  The first 
‘Centralized’ visit should occur after the first subject enrolled completes first treatment cycle.  

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The study site will send the redacted source documents to the Coordinating Center for 
monitoring.  ‘Centralized’ monitoring may be requested by the Coordinating Center if an 
amendment requires changes to the protocol procedures. The site will send in pertinent redacted 
source documents, as defined by the Coordinating Center for monitoring.  
 
The first annual ‘On-site’ monitoring visit should occur after the first five study participants are 
enrolled or twelve months after a study opens, whichever occurs first.  The annual visit may be 
conducted as a ‘Centralized’ visit if less than three subjects have enrolled at the study site.  The 
type of visit is at the discretion of the Coordinating Center.  At a minimum, a routine monitoring 
visit will be done at least once a year, or once during the course of the study if the study duration 
is less than 12 months. The purpose of these visits is to verify: 
 
 
Adherence to the protocol 
 
Completeness and accuracy of study data and samples collected 
 
Proper storage, dispensing and inventory of study medication 
 
Compliance with regulations 
 
During a monitoring visit to a site, access to relevant hospital and clinical records must be given 
by the site investigator to the Coordinating Center representative conducting the monitoring visit 
to verify consistency of data collected on the CRFs with the original source data.  While most 
patient cases will be selected from patients accrued since the previous monitoring visit, any 
patient case has the potential for review.  At least one or more unannounced cases will be 
reviewed, if the total accruals warrant selection of unannounced cases.  
 
The Coordinating Center expects the relevant investigational staff to be available to facilitate the 
conduct of the visit, that source documents are available at the time of the visit, and that a suitable 
environment will be provided for review of study-related documents. Any issues identified during 
these visits will be communicated to the site and are expected to be resolved by the site in a 
timely manner.  For review of study-related documents at the Coordinating Center, the site will 
be required to ship or fax documents to be reviewed.   
 
Participating site will also undergo a site close-out upon completion, termination or cancellation 
of a study to ensure fulfillment of study obligations during the conduct of the study, and that the 
site Investigator is aware of his/her ongoing responsibilities. In general, a site close-out is 
conducted during a site visit; however, site close-out can occur without a site visit. 
15.0 
REFERENCES 
 
1. 
Hellman, S. and R.R. Weichselbaum, Oligometastases. J Clin Oncol, 1995. 13(1): p. 8-
10. 
2. 
Kavolius, J.P., et al., Resection of metastatic renal cell carcinoma. J Clin Oncol, 1998. 
16(6): p. 2261-6. 
3. 
Ashworth, A.B., et al., An individual patient data metaanalysis of outcomes and 
prognostic factors after treatment of oligometastatic non-small-cell lung cancer. Clin 
Lung Cancer, 2014. 15(5): p. 346-55. 
4. 
Gomez, D.R., et al., Local consolidative therapy versus maintenance therapy or 
observation for patients with oligometastatic non-small-cell lung cancer without 
progression after first-line systemic therapy: a multicentre, randomised, controlled, 
phase 2 study. Lancet Oncol, 2016. 17(12): p. 1672-1682. 

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5. 
Jeremic, B., et al., Role of radiation therapy in the combined-modality treatment of 
patients with extensive disease small-cell lung cancer: A randomized study. J Clin Oncol, 
1999. 17(7): p. 2092-9. 
6. 
Morris, E.J., et al., Surgical management and outcomes of colorectal cancer liver 
metastases. Br J Surg, 2010. 97(7): p. 1110-8. 
7. 
Gonzalez, M. and P. Gervaz, Risk factors for survival after lung metastasectomy in 
colorectal cancer patients: systematic review and meta-analysis. Future Oncol, 2015. 
11(2 Suppl): p. 31-3. 
8. 
Parker, C., et al., Alpha emitter radium-223 and survival in metastatic prostate cancer. N 
Engl J Med, 2013. 369(3): p. 213-23. 
9. 
Nilsson, S., et al., A randomized, dose-response, multicenter phase II study of radium-
223 chloride for the palliation of painful bone metastases in patients with castration-
resistant prostate cancer. Eur J Cancer, 2012. 48(5): p. 678-86. 
10. 
Van Praet, C., et al., Which Factors Predict Overall Survival in Patients With Metastatic 
Castration-Resistant Prostate Cancer Treated With Abiraterone Acetate Post-Docetaxel? 
Clin Genitourin Cancer, 2017. 15(4): p. 502-508. 
11. 
Salama, J.K., et al., Stereotactic body radiotherapy for multisite extracranial 
oligometastases: final report of a dose escalation trial in patients with 1 to 5 sites of 
metastatic disease. Cancer, 2012. 118(11): p. 2962-70. 
12. 
Salama, J.K., et al., An initial report of a radiation dose-escalation trial in patients with 
one to five sites of metastatic disease. Clin Cancer Res, 2008. 14(16): p. 5255-9. 
13. 
Ost, P., et al., Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate 
Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. J Clin 
Oncol, 2017: p. Jco2017754853. 
14. 
Attard, G., et al., Characterization of ERG, AR and PTEN gene status in circulating 
tumor cells from patients with castration-resistant prostate cancer. Cancer Res, 2009. 
69(7): p. 2912-8. 
15. 
Day, K.C., et al., HER2 and EGFR Overexpression Support Metastatic Progression of 
Prostate Cancer to Bone. Cancer Res, 2017. 77(1): p. 74-85. 
16. 
Antonarakis, E.S., et al., AR-V7 and resistance to enzalutamide and abiraterone in 
prostate cancer. N Engl J Med, 2014. 371(11): p. 1028-38. 
17. 
Okegawa, T., et al., Epidermal Growth Factor Receptor Status in Circulating Tumor 
Cells as a Predictive Biomarker of Sensitivity in Castration-Resistant Prostate Cancer 
Patients Treated with Docetaxel Chemotherapy. Int J Mol Sci, 2016. 17(12). 
18. 
Thalgott, M., et al., Categorical versus continuous circulating tumor cell enumeration as 
early surrogate marker for therapy response and prognosis during docetaxel therapy in 
metastatic prostate cancer patients. BMC Cancer, 2015. 15: p. 458. 
19. 
Goldkorn, A., et al., Circulating tumor cell counts are prognostic of overall survival in 
SWOG S0421: a phase III trial of docetaxel with or without atrasentan for metastatic 
castration-resistant prostate cancer. J Clin Oncol, 2014. 32(11): p. 1136-42. 
20. 
Scher, H.I., et al., Trial Design and Objectives for Castration-Resistant Prostate Cancer: 
Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. 
J Clin Oncol, 2016. 34(12): p. 1402-18. 
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Therasse, P., et al., New guidelines to evaluate the response to treatment in solid tumors. 
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of the United States, National Cancer Institute of Canada. J Natl Cancer Inst, 2000. 
92(3): p. 205-16. 
 
 
16.0 
APPENDICES 
Appendix A: PERFORMANCE STATUS CRITERIA 
Appendix B: NCCN-FACT FPSI-17 (Version 2) 
 
 
 
 
 
 

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Appendix A 
 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Grade Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory and able 
to carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry out any 
work activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair. 
5 
Dead. 
 
 
 

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Appendix B:   
NCCN-FACT FPSI-17 (Version 2) 
 
 
DRS-P=Disease-Related Symptoms Subscale – Physical 
DRS-E=Disease-Related Symptoms Subscale – Emotional 
TSE=Treatment Side Effects Subscale 
FWB=Function and Well-Being Subscale 
 
English (Universal) 
03 March 2010 
Copyright 2001 
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