Individualisation of Management With Novel Upfront Therapies in Newly Diagnosed Metastasized Prostate Cancer Using (PSMA)PET/CT Imaging
Phase: NA
Conditions: Prostate Cancer
Sponsor: Roderick van den Bergh

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RESEARCH PROTOCOL 
Individualisation of management with novel upfront therapies in 
newly diagnosed metastasized prostate cancer using 
(PSMA)PET/CT imaging 
 
(August 18th 2021) 
 
Short title: 
PET-based MaNagement of Metastasized prostate cancer treated with Novel upfront 
therapies 
 
Acronym: 
PET-MaN 
 
 
 
 
 

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PROTOCOL TITLE: Individualisation of management with novel upfront therapies in 
newly diagnosed metastasized prostate cancer using (PSMA)PET/CT imaging 
 
Protocol ID 
NL77093.041.21 
Short title 
PET-based management of metastasized prostate 
cancer treated with novel upfront therapies 
Version 
2.0 
Date 
18-08-2021 
Coordinating investigator 
Prof. dr. Marnix G.E.H. Lam MD PhD 
UMC Utrecht, Utrecht, Dept. of Radiology and Nuclear 
Medicine 
Heidelberglaan 100, 3584 CX Utrecht 
m.lam@umcutrecht.nl 
Principal investigator(s 
Dr. Roderick C.N. van den Bergh 
UMC Utrecht, Utrecht, Department of Radiology and 
Nuclear Medicine 
Heidelberglaan 100, 3584 CX Utrecht 
R.C.N.vandenBergh-2@umcutrecht.nl 
 
Sub- investigator(s 
Dr. Roderick C.N. van den Bergh 
St. Antonius Hospital Nieuwegein-Utrecht, 
Department of Urology 
Koekoekslaan 1 
3430 EM Nieuwegein 
R.van.den.bergh@antoniusziekenhuis.nl  
 
Dr. Roderick C.N. van den Bergh 
UMC Utrecht, Utrecht, Department of Radiology and 
Nuclear Medicine 
Heidelberglaan 100, 3584 CX Utrecht 
R.C.N.vandenBergh-2@umcutrecht.nl 
 
Dr. André N. Vis 
Amsterdam UMC 
Department of Urology 
De Boelelaan 1117-1118 
1081 HV Amsterdam 
A.vis@amsterdamumc.nl 
 
Dr. Tom Arends 
Meander MC 
Department of Urology 
Maatweg 3 
3813 TX Amersfoort 
TJH.Arends@meandermc.nl 

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Sponsor  
UMC Utrecht 
 
 
Subsidising party 
Janssen-Cilag B.V. 
Independent expert (s) 
Dr. Jack Beck 
St. Antonius Hospital Nieuwegein-Utrecht, 
Department of Urology 
Koekoekslaan 1 
3430 EM Nieuwegein 
j.beck@antoniusziekenhuis.nl 
 
 
 
 
 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Manager Research 
Prof. Dr. H.M. Verkooijen 
 
 
18-08-2021 
Principle investigator 
Dr. Roderick C.N. van den Bergh 
 
 
18-08-2021 
 
 

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TABLE OF CONTENTS  
 
1. 
INTRODUCTION AND RATIONALE .............................................................................10 
2. 
OBJECTIVES ................................................................................................................12 
3. 
STUDY DESIGN ...........................................................................................................13 
4. 
STUDY POPULATION ..................................................................................................15 
4.1 
Population (base) ...................................................................................................15 
4.2 
Inclusion criteria .....................................................................................................15 
4.1 
Exclusion criteria ....................................................................................................15 
4.2 
Sample size calculation ..........................................................................................15 
5. 
METHODS ....................................................................................................................18 
5.1 
Study parameters/endpoints ...................................................................................18 
5.1.1 
Main study parameter/endpoint .......................................................................18 
5.1.2 
Secondary study parameters/endpoints ..........................................................19 
5.2 
PSMA-PET/CT .......................................................................................................19 
5.2.1 
PSMA-PET/CT imaging protocol .....................................................................19 
5.3 
Withdrawal of individual subjects ............................................................................20 
5.4 
Replacement of individual subjects after withdrawal ...............................................20 
5.5 
Follow-up of subjects withdrawn from treatment .....................................................20 
5.6 
Premature termination of the study .........................................................................20 
5.7 
Additional findings PSMA PET/CT ..........................................................................20 
6. 
SAFETY REPORTING ..................................................................................................20 
6.1 
Temporary halt for reasons of subject safety ..........................................................20 
6.2 
AEs, SAEs and SUSARs ........................................................................................21 
6.2.1 
Adverse events (AEs) ......................................................................................21 
6.2.2 
Serious adverse events (SAEs) .......................................................................21 
6.3 
Follow-up of adverse events ...................................................................................21 
6.4 
Data Safety Monitoring Board (DSMB) / Safety Committee ....................................21 
7. 
STATISTICAL ANALYSIS .............................................................................................22 
7.1 
Primary study parameter(s) ....................................................................................22 
7.2 
Secondary study parameter(s) ...............................................................................22 
8. 
ETHICAL CONSIDERATIONS ......................................................................................23 
8.1 
Regulation statement .............................................................................................23 
8.2 
Recruitment and consent........................................................................................23 
8.3 
Benefits and risks assessment, group relatedness .................................................23 
8.4 
Compensation for injury .........................................................................................23 
8.5 
Incentives ...............................................................................................................23 
9. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .............................24 
9.1 
Handling and storage of data and documents ........................................................24 
9.2 
Monitoring and Quality Assurance ..........................................................................24 
9.3 
Amendments ..........................................................................................................24 
9.4 
Annual progress report ...........................................................................................24 
9.5 
Temporary halt and (prematurely) end of study report ............................................24 

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10. 
REFERENCES ..........................................................................................................25 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
General Assessment and Registration form (ABR form), the application 
form that is required for submission to the accredited Ethics Committee; in 
Dutch: Algemeen Beoordelings- en Registratieformulier (ABR-formulier) 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials  
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
(S)AE 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics; in Dutch: officiële productinformatie 
IB1-tekst 
Sponsor 
The sponsor is the party that commissions the organisation or performance 
of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A party 
that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
UAVG 
Dutch Act on Implementation of the General Data Protection Regulation; in 
Dutch: Uitvoeringswet AVG 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
68Ga 
Gallium-68 
AE 
Adverse Event 
AR 
Adverse Reaction 
CT 
Computed Tomography 
IB 
Investigator’s Brochure 
METC  
Medical research ethics committee (MREC); in Dutch: medisch ethische 
toetsing commissie (METC) 
MRI 
Magnetic Resonance Imaging 
mSv 
MilliSievert 
PCa 
Prostate Cancer 

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PERCIST PET Response Evaluation Criteria In Solid Tumours 
PET 
Positron Emission Tomography 
PET-
MaN 
PET-based MaNagement of Metastasized prostate cancer treated with 
Novel therapies 
PSA 
Prostate-Specific Antigen. 
PSMA 
Prostate-Specific Membrane Antigen 
RECIST 
Response Evaluation Criteria in Solid Tumours 
(S)AE 
(Serious) Adverse Event  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 

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SUMMARY 
 
Rationale: Men, newly diagnosed with metastasized prostate cancer on PSMA PET/CT, who 
start on standard hormonal therapy, are additionally treated with either upfront chemotherapy 
or upfront extra androgen-receptor targeted agents (‘ARTA’), as per guidelines’ 
recommendations. The benefit in overall survival of these two options is similar, but important 
differences exist in patient-specific efficacy, costs, side-effects, and impact on quality of life. 
No predictive factors are available to individualize treatment choice. Currently, a one-size-
fits-all strategy with hormonal therapy plus chemotherapy is usually followed. 
Objective: To assess the predictive value of early response measurements on PSMA-
PET/CT for therapy success, defined as time to development of castration-resistant prostate 
cancer (CRPC), in order to personalize treatment choice. 
Study design: Prospective, single arm, open label, non-interventional, non-therapeutic 
observational cohort study. 
Study population: Patients >18 years with newly diagnosed, histologically proven prostate 
cancer with >3 skeletal or visceral metastatic lesions on the PSMA-PET/CT, who are 
considered eligible for upfront therapy (chemotherapy or ARTA) in addition to standard 
hormonal therapy. 
Main study parameters/endpoints: 
Primary parameter: Predictive value of early response on PSMA-PET/CT to upfront therapy, 
according to PERCIST criteria. Primary endpoint: Time to development of CRPC. Secondary 
parameters: Predictive value of early response on PSMA-PET/CT to hormonal therapy; 
predictive value of baseline PSMA-PET/CT, analysis of response in different subgroups of 
patients: e.g. high versus low tumour load, high versus low PSA, high versus low Gleason 
score. Secondary endpoint: Time to initiation of second line therapy after castration-resistant 
disease has been found.  
Nature and extent of the burden and risks associated with participation, benefit, and 
group relatedness:  
Patients will be treated according to standard of care, including baseline PSMA-PET/CT. The 
timing of follow-up PSMA-PET/CT imaging will be standardized. Instead of imaging at 
biochemical or clinical signs of disease progression, one PSMA-PET/CT will be performed 
after two months of hormonal therapy, one PSMA-PET/CT will be performed after two 
months of upfront therapy. Each PSMA-PET/CT scan will require an extra visit (2-3 hours) 
and a limited radiation burden after intravenous injection of PSMA. The additional information 
from the standardized follow-up PSMA-PET/CT scans will not be used for clinical decision-
making. 

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1. INTRODUCTION AND RATIONALE 
 
In men with newly diagnosed metastasized prostate cancer (i.e. metastatic hormone-
sensitive prostate cancer; M+HSPC) who start on androgen deprivation therapy, a 
personalized approach towards choosing upfront additional therapy is required. PSMA-
PET/CT early response has the potential to stratify patients who will best respond to 
chemotherapy or androgen-receptor targeted agents (ARTA). 
 
In 2019, 15% of 13,000 prostate cancer (PCa) diagnoses in The Netherlands was already in 
the metastasized stage at first detection (~1,950 cases/year).(IKNL 2020) In M+HSPC, 
palliative androgen-deprivation therapy (ADT) is the backbone of therapy, usually a LHRH 
agonist.(Cornford 2019) The condition and associated treatments have a detrimental impact 
on quality of life (QoL).(Holm 2018) In recent years, different therapies have been found to 
have a favourable impact on overall survival (OS) when initiated directly upfront (which 
should be started <3 months after diagnosis) in combination with ADT, revolutionizing 
treatment for M+HSPC. These options include very different types of agents; chemotherapy 
(i.e. docetaxel) or novel androgen-receptor targeted agents (ARTA; such as: CYP-17 
inhibitor: abiraterone, or competitive inhibitors of the androgen-receptor: apalutamide, 
enzalutamide).(James 2016, Sweeney 2015, James 2017, Fizazi 2017, Chi 2019, Davis 
2019, Armstrong 2019). Although the favourable effect on OS of these drugs when added to 
ADT monotherapy is similar in the M+HSPC setting on a group level (docetaxel 
chemotherapy: hazard ratio OS 0.61-0.78; ARTA: hazard ratio 0.62-0.67), there are 
important differences in costs, treatment burden, side-effects, and impact on QoL.(Hird 2020) 
Also, the choice for a specific therapy in first line for M+HSPC influences the effectiveness of 
treatments when the castration-resistant phase of PCa (CRPC) is reached (after median 18 
months).(deWit 2020) Currently, docetaxel chemotherapy is mostly used as a first line 
treatment in addition to ADT.(Kuppen 2019) 
 
For the individual M+HSPC patient, the response to chemotherapy or ARTA is highly 
variable. A possible explanation may be the heterogeneity in androgen-receptor mutations. 
(Bostwick 1998, Evans 2011) One man may benefit more from ADT plus upfront 
chemotherapy, the other may be better off with ADT plus additional hormonal manipulation 
with an ARTA. Basic research on biomarkers for response in this setting (e.g. AR-V7; 
androgen receptor variant 7) have failed to translate to use in clinical practice.(Antonarakis 
2014) Thus, there is a lack of predictive factors providing individualized guidance (e.g. which 
first line upfront therapy and in which order). Currently, a blind, one-size-fits-all strategy is 
usually attempted first. Furthermore, there is no standard approach regarding imaging 
(skeletal scintigraphy, CT, and/or PET-imaging) at diagnosis or follow-up of M+HSPC 
patients. This is highly variable, depending on hospital and physician preference.(Mottet 
2017) 
 
Prostate-specific membrane antigen (PSMA)-PET/CT imaging has revolutionized PCa nodal 
and distant metastasis staging, initially in the recurrent disease setting after local surgery or 
radiation therapy, but also increasingly in the primary setting.(Hofman 2020, Perera 2020) 
This type of PET imaging is specific for PCa. PSMA tracer uptake may be associated with 
the same tumour features that are related to the susceptibility of disease to ADT and 
additional upfront chemotherapy, or additional androgen receptor manipulation with an 
ARTA.(Bostwick 1998, Evans 2011) In other tumour types (e.g. lymphoma or bladder 

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cancer), PET imaging is used to assess treatment response to (neo-adjuvant) 
chemotherapy.(Witjes 2020) Essential decisions on continuation, early discontinuation, or 
switch of treatment are made based on these imaging results. Currently, the type (e.g. 
CT/MRI, skeletal scintigraphy or PET-imaging) and timing of imaging in M+HSPC patients is 
not standardized, but variable dependent on hospital and physician preference.(Cornford 
2017)  
 
With the current availability of a PCa specific imaging modality, access to very different types 
of upfront therapy (chemotherapy versus ARTA) added to standard ADT, the potential of 
imaging-based early treatment response to individualise treatment in M+HSPC patients, 
needs to be explored. Risk stratification may improve timing and sequencing of the available 
upfront therapy options, reducing unnecessary therapies and concomitant impact on QoL. 
 
Results of the study can be used to move from the current paradigm of using biochemical 
(PSA) and clinical (symptoms) parameters to guide imaging and treatment decisions, to a 
standardized imaging-based follow-up strategy in order to individualize treatment timing and 
sequencing. Future options for this study approach include a randomized setting for upfront 
treatment options.  

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2. OBJECTIVES 
 
The primary objective of the current research proposal is to assess whether PSMA-PET/CT 
early response assessment (between start of upfront therapy and after 2 months of upfront 
therapy) is associated with treatment success (defined as time to development of CRPC). 
This may allow for individualized treatment planning in newly diagnosed M+ HSPC patients, 
who have started on ADT and receive additional upfront therapy (Figure 1). 
 
By performing PSMA PET/CT at fixed time points during ADT and upfront therapy treatment, 
information is collected on the imaging–based response to treatment. Analysis of the value of 
PSMA-PET/CT will be assessed by predictive modelling, taking the following predictive 
factors into account: PET findings, PSA at diagnosis, pathological Gleason score, tumour 
load, and PSA early response. 
 
The secondary objectives include: 
- Predictive value of baseline PSMA-PET/CT imaging on time to development of CRPC. 
- Predictive value of early response to ADT only (which is standard of care during first 2-3 
months of therapy; upfront therapy needs to be started within this timeframe) on time to 
development of CRPC. 
- Analysis of response in different subgroups of patients: high versus low tumour load, high 
versus low PSA, high versus low Gleason score, <median versus >median age at diagnosis.   
 
 
Fig. 1 PET-MaN study design. (SOC = standard of care) Imaging will include PSMA-PET/CT 
at standardized time points (instead of at progression / on indication only): 1st baseline, 2nd 
after 2 months of hormonal therapy (ADT), and 3rd after 2 months of upfront therapy (for 
docetaxel, this is between 3rd and 4th cycle (out of 6)). 

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3. STUDY DESIGN 
 
The study is a prospective open-label, non-interventional, non-therapeutic observational 
cohort study. The study is performed in an outpatient setting. Total study duration will be 48 
months. 
 
Multicenter (Netherlands):  
- UMC Utrecht, Utrecht (lead);  
- St Antonius Hospital, Utrecht / Nieuwegein (external inclusion);  
- Meander MC, Amersfoort (external inclusion); 
- Amsterdam UMC, Amsterdam (external inclusion). 
 
Patients will be treated with hormonal therapy plus upfront therapy. Indication for upfront 
therapy and the choice for specific combination will be made at a multidisciplinary meeting. 
Patients are elected for study participation after prostate cancer has been histologically 
confirmed and signs of multiple metastases have been confirmed on PSMA-PET/CT-
imaging. The definition of multiple / high volume metastasis is: >3 metastatic lesions (any 
combination of either lymph node metastasis outside of pelvis, bone metastasis, or visceral 
metastasis). Participating centers will standard use PSMA PET/CT as first imaging choice at 
suspicion of metastasized disease. 
 
Standardized imaging (Figure 1): 
 
PSMA-PET/CT: 
1. Standard of care PSMA PET/CT: At diagnosis (hormonal therapy needs to be 
started <4 weeks). 
2. Additional PSMA PET/CT: 2 months after start hormonal therapy (+/- 1 week). 
3. Additional PSMA PET/CT: 2 months after start of chemotherapy (+/- 1 week). 
 
Patients continue hormonal therapy plus upfront therapy according to standard of care. 
Follow-up of standard of care consists of monthly outpatient checks, including standard lab 
tests (i.e. PSA, AF, testosterone, electrolytes, full blood count).  
 
The results of the additional PSMA-PET/CT scans will not be blinded to patients or 
physicians and will not be used in clinical decision-making.  
 
The primary endpoint is time from start of ADT to CRPC. CRPC is defined by EAU guidelines 
(Cornford 2020) as: 
Castrate serum testosterone <50 ng/dL or 1.7 nmol/L plus either:  
a. Biochemical progression: Three consecutive rises in PSA at least one week apart resulting 
in two 50% increases over the nadir, and a PSA >2 ng/mL, or: 
b. Radiological progression: The appearance of new lesions: either two or more new bone 
lesions on skeletal scintigraphy or a soft tissue lesion on CT using RECIST (Response 
Evaluation Criteria in Solid Tumours) or on (PSMA-)PET/CT-imaging using PERCIST (PET 
Response Evaluation Criteria In Solid Tumours) (Fanti 2020, Boellaard 2015).  
(Symptomatic progression alone must be questioned and subject to further investigation. It is 
not sufficient to diagnose CRPC.) 

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In case of biochemical, radiological, or clinical progression indicating development of 
castration-resistant disease (CRPC), next line therapy will be considered at a 
multidisciplinary meeting, according to standard of care.  

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4. STUDY POPULATION 
4.1 Population (base)  
 
Patients with newly diagnosed prostate cancer, who have proven synchronous metastatic 
disease on PSMA PET/CT. Recruitment will take place in the urologist outpatient clinics. 
Patients will be approached for participation in the study at their first outpatient contact. 
They will sign informed consent after their diagnosis and management has been 
discussed at a multidisciplinary meeting.  
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
- 
Men >18 years of age. 
- 
Mentally competent and understanding of benefits and potential burden of the study. 
- 
Written and signed informed consent. 
- 
Histological confirmed diagnosis of adenocarcinoma of the prostate. 
- 
Indicated to start on hormonal therapy (any LHRH agonist or antagonist). 
- 
Indicated to start on upfront therapy (i.e. docetaxel, abiraterone, apalutamide, or 
enzalutamide). 
- 
Any initial PSA. 
- 
Any Gleason score. 
- 
Any T-stage. 
- 
Any N-stage. 
- 
Stage M1, with multiple / high volume metastasis:More than three (>3) metastatic 
lesions (any combination of either lymph node metastasis outside of pelvis, bone 
metastasis, or visceral metastasis), as seen on PSMA-PET/CT-imaging. As these 
patients are treated with palliative intent.  
 
4.1 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
- 
Concomitant malignancy (except from BCC of the skin). 
- 
History of prior diagnosed or treated PCa. 
- 
Any unrelated illness (e.g. active infection, inflammation or laboratory abnormalities) 
that in the judgment of the investigator will significantly affect patient’s clinical status 
and/or outcome of the study. 
- 
Any known allergy for the upfront therapy. 
- 
Any known allergy for LHRH agonist or antagonist. 
 
4.2 Sample size calculation 
Predictive modelling will be used. Besides the parameter of main interest:PSMA-PET/CT 
response to upfront therapy based on PERCIST (i.e. Complete response (CR), Partial 
response (PR), Progressive disease (PD), Stable disease (SD)) see also chapter 5.1.1 
table 1, the following potential predictive factors will be taken into account (these variables 
have been included in subgroup analyses in earlier M+HSPC studies):  
- PSA at diagnosis. 
- Pathological Gleason score (ISUP Gleason grades 1-3 versus 4-5). 

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- Metastasis volume load (defined as ‘Charteed’-study criteria; high volume defined as 
>5 skeletal lesions with 1 or more outside pelvis or vertebrae or visceral metastasis, 
low volume defined as all others).(Sweeney 2015) 
- PSA response (defined as PSA nadir). 
- Type of upfront therapy used. 
- PSMA response to hormonal therapy as continues variable in percentage based 
onPERCIST (see 5.1.1). 
 
Estimation of proportion of variation in PERCIST PSMA response was based on preliminary 
case series on PSMA response in M+HSPC patients.(Seitz 2018).  
 
Sample size estimation was performed in SAS (version 9.4) PROC POWER, using a score 
test for a Cox proportional hazards model.  
 
Considerations (Figure 2):  
- Expected median time to CRPC: 24 months. 
- Power 80%. 
- Type I error (alpha) 5%, two-sided. 
- Probability of event within 24 months: 0.5. 
- Estimation of proportion of variation in PERCIST PSMA response (R2): 0.75 (based 
on linear regression of data from Seitz et al.). 
- Standard deviation PERCIST PSMA response: 3.5 - 4 (per 10 percentage points). 
- Small to medium effect (hazard ratio 1.2-1.3 per 10 percentage points PERCIST 
PSMA). 
 
Assuming a standard deviation of 4, an R2 of 0.75, and a hazard ratio of 1.2-1.3, the number 
needed to include is 150. 
 
Around 1750 new diagnoses of M+HSPC are made in The Netherlands yearly. The 
collaborating centres cover ~12.5% of new diagnoses in The Netherlands (~200 cases). 
Assuming a study acceptance rate of 50% (low estimation), patient accrual (N=150) is 
expected to cover ~18 months.  
 
 

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Fig. 2 Considering small effect HR 1.2 – 1.3, SD 4, R-square 0.75 – 0.80 leads to sample 
size 130 – 150.  
 
 
 
 

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5. METHODS 
 
5.1 Study parameters/endpoints 
5.1.1 Main study parameter/endpoint 
Main parameter: 
- Response to upfront therapy on PSMA-PET/CT based on PERCIST (PET 
Response Criteria In Solid Tumours). 
 
PERCIST consists of a set of rules to interpretate solid tumor response on the 
PET/CT originally based on the FDG-PET/CT (O 2016, Fanti 2019). It looks at the 
tumor uptake of the PET tracer also expressed as the standardized uptake value 
(SUV). It divides tumor response based on the perceptual change in SUV between 
two (in our case) PSMA PET/CT’s and the change in the amount of tumor lesions 
(see table 1). For the notation you also need to include the amount of time between 
the two PET scans. For example (35% increase, 4 weeks, five new lesions). 
 
Table 1 
Response 
PSMA PET/CT interpretation 
Complete response (CR) 
Complete resolution of PSMA-tracer uptake in all 
lesions 
Partial response (PR) 
More than or equal to 30% reduction of SUV and an 
absolute drop of 0.8 SUV units 
Progressive disease (PD) 
More than or equal to 30% increase in SUV and 
absolute increase of 0.8 SUV units, or appearance of 
new lesions with PSMA-tracer uptake 
Stable disease (SD) 
Not quality for CR, PR, or PD 
 
NB: lesions with prior radiation treatment (e.g. symptomatic bone metastasis) will not be 
accounted for in the PERCIST response evaluation. 
 
Main endpoint: 
- Time since start ADT to development of castration-resistant disease (CRPC). 
CRPC is defined by EAU guidelines (Cornford 2020) as: 
 
 
Castrate serum testosterone <50 ng/dL or 1.7 nmol/L plus either: 
 
a. Biochemical progression: Three consecutive rises in PSA at least one 
week apart, resulting in two 50% increases over the nadir, and a PSA >2 
ng/mL, or: 
b. Radiological progression: The appearance of new lesions: either two or 
more new bone lesions on skeletal scintigraphy or a soft tissue lesion on 
CT using RECIST (Response Evaluation Criteria in Solid Tumours) or on 
(PSMA-)PET/CT-imaging using PERCIST (PET Response Evaluation 
Criteria In Solid Tumours) (Fanti 2020, Boellaard 2015).  
  
Symptomatic progression alone must be questioned and subject to further 
investigation. It is not sufficient to diagnose CRPC. 

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5.1.2 Secondary study parameters/endpoints 
- Predictive value of baseline PSMA-PET/CT imaging on time to development of 
CRPC. 
- Predictive values of early response to ADT therapy on PSMA PET/CT (i.e. 
response between first and second PSMA PET/CT) according to PERCIST (PET 
Response Criteria In Solid Tumours).  
- Predictive values of response to upfront therapy on PSMA-PET/CT (i.e. response 
between second and third PSMA PET/CT) according to PERCIST (PET Response 
Criteria In Solid Tumours).  
- Analysis of response in different subgroups of patients: e.g. high versus low 
tumour load, high versus low PSA, high versus low Gleason score. 
-Time to initiation of second line therapy after castration-resistant disease has been 
found.  
 
 
5.2 PSMA-PET/CT 
Conform standard of care, PSMA-PET/CT will be performed before hormonal 
therapy is started. As part of this study, PSMA-PET/CT will be the method of imaging 
of first choice and repeated at standardized time-points: after 2 months (+/- 1 week) 
of hormonal therapy and after 2 months (+/- 1 week) of upfront therapy.  
5.2.1 PSMA-PET/CT imaging protocol  
PSMA-PET/CT will be performed according to standard of care, with low-dose CT 
using 1.5-2.0 MBq/kg of PSMA-tracer (68-Gallium PSMA and 18 Fluor PSMA are 
allowed). Image reconstruction will be performed according to EARL 
accreditation.(Boellaard 2015) The used PSMA tracer may vary between 
participating centers, but in each center the same tracer will be used at baseline and 
during follow-up. Image acquisition starts 60 minutes (+/- 15 minutes is acceptable) 
after injection from head to upper thigh. Effective absorbed dose is approximately 6 
mSv, which is similar to a full-dose CT scan of the abdomen. IV drip is necessary to 
inject the tracer. 
 
The scans will be examine by the local nuclear medicine physician and afterwards 
two experienced nuclear medicine physicians will examine all PSMA-PET/CT 
images. The following parameters will be assessed:  
- TNM stage. 
- Response according to PERCIST (in follow-up scans). 
- PiP-RADS scores.  
- Location and number of prostate lesions, lymph node metastases and distant 
metastases. 
- Activity (SUVlbm-mean, SUVlbm-peak, SUVlbm-max) of all lesions. 
 
 
 
5.2.1.1 Timing first PSMA-PET/CT – baseline 
First PSMA-PET/CT needs to be performed <4 weeks before start ADT. 
 
5.2.1.2 Timing second PSMA-PET/CT – hormonal therapy response 

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Second PSMA-PET/CT needs to performed 2 months after start of 
hormonal therapy (+/- 1 week). As per guidelines recommendations, upfront 
therapy needs to be started <3 months after start of hormonal therapy. 
 
5.2.1.3 Timing third PSMA-PET/CT – upfront therapy response 
Third PSMA-PET/CT needs to be performed 2 months after start of upfront 
therapy (+/- 1 week). 
 
5.3 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without 
any consequences.  
 
5.4 Replacement of individual subjects after withdrawal 
. Patients who drop out before acquisition of baseline and two response PSMA-
PET/CT scans will be replaced. If the endpoint CRPC is not reached due to lost-to-
follow-up, patients will be censored at the time of last follow-up. 
 
5.5 Follow-up of subjects withdrawn from treatment 
Not applicable. Patients, who drop out of the study, will receive standard of care. 
 
5.6  Premature termination of the study 
Treatment and follow-up will proceed as per standard of care in case of study 
termination. 
 
5.7  Additional findings PSMA PET/CT 
 
Before patients are included in this study they already received a PSMA PET/CT, 
according to standard of care. During this study two additional standard of care PSMA 
PET/CT’s will be given performed within  ±4 months (see also figure 1).  
The chance that there will be additional findings ±4 months after the first PSMA PET/CT is 
very low. If there will be additional findings on the study PSMA PET/CT’s, unrelated to 
prostate cancer, these will be communicated to the treating physician/head 
practitioner/general practitioner.  
 
6. SAFETY REPORTING 
 
6.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardize subject 
health or safety. The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 

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6.2 AEs, SAEs and SUSARs 
6.2.1 
Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to the study procedures. All 
adverse events reported spontaneously by the subject or observed by the investigator 
or her staff will be recorded. 
6.2.2 
Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalization or prolongation of existing inpatients’ hospitalization; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgment by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
PSMA PET/CT has not been reported to cause any side effects and is one of the 
accepted routine imaging options for prostate cancer diagnostics. Since this study 
concerns an observational study with two standardized PSMA PET/CT examinations, 
it is not expected that AEs or SAEs occur due to these additions. Only (S)AEs that 
occur during the PSMA PET/CT procedure will be reported.  
The local principal investigator or an authorized delegate will report the SAE to the 
sponsor without undue delay after obtaining knowledge of the events.  
The sponsor will report the recorded SAEs to the accredited METC through line listing 
at the annual progress report.  
 
6.3 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow-up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
protocol. 
 
6.4 Data Safety Monitoring Board (DSMB) / Safety Committee 
This study is assessed as having a minimal risk for the subject by the principal 
investigator and is therefore classified as ‘low risk, similar to usual care’. Therefore, a 
DSMB / Safety Committee will not be necessary. 
 

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7. STATISTICAL ANALYSIS 
 
7.1 Primary study parameter(s) 
The collected data will include nominal, categorical, ordinal and continuous variables.  
 
A predictive model will be constructed. Main parameter is PERCIST PSMA response to 
upfront therapy. Main outcome is time since diagnosis to development of CRPC. 
Primary analysis will be the comparison of two Cox proportional hazards models for time 
to development of CRPC: the first including the six predictive factors (PSA at diagnosis, 
pathological Gleason score, metastasis volume load, PSA early response, type of upfront 
therapy, PSMA response to hormonal therapy only), mentioned in section 4.4, and the 
second including those six variables plus PERCIST PSMA-PET/CT response after start of 
upfront therapy. The models will be compared using a likelihood ratio test, and the c-
statistic will be calculated to estimate the added benefit of PERCIST PSMA response 
above the known predictors of CRPC. 
 
An intention-to-treat analysis will be performed (i.e. all subjects who actually receive 
baseline and two follow-up PSMA PET/CT scans.) will be included for analysis, even 
when treatment is changed early. 
 
 
7.2 Secondary study parameter(s)  
 
 
- Predictive value of baseline PSMA-PET/CT imaging on time to development of CRPC. 
- Predictive value of early response to ADT only on time to development of CRPC. 
- Predictive value of early response to ADT combined with upfront therapy on time to 
development of CRPC. 
- Analysis of response in different subgroups of patients: e.g. high versus low tumour 
load, high versus low PSA, high versus low Gleason score, low versus high age.   

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8. ETHICAL CONSIDERATIONS 
 
8.1 Regulation statement 
This study will be conducted in accordance with the principles of the Declaration of 
Helsinki (version 10, amended in October 2013 by the 64th WMA General Assembly) and 
in accordance with the Medical Research Involving Human Patients Act (WMO) and this 
research protocol. The handling of personal data will be in accordance with the Dutch 
Personal Data Protection Act (In Dutch: Wet Bescherming Persoonsgegevens (WPB)). 
 
8.2 Recruitment and consent 
Patients matching the inclusion criteria will be informed at the urological outpatient clinic. 
Patients will only be included in the present study after written informed consent. Written 
informed consent will be obtained by the investigators or treating physician. Patients will 
be given at least two days to consider participation. After written informed consent, 
patients will get an invitation to visit the outpatient clinic for acquisition of a PSMA-
PET/CT at baseline, if not already performed. Hormonal therapy is then started by the 
treating physician. Upfront therapy will be monitored in shared follow-up between 
oncologist and urologist. PSMA-PET/CT response after hormonal therapy and PSMA-
PET/CT response after upfront therapy will be planned. 
 
8.3 Benefits and risks assessment, group relatedness 
Standard introduction of PSMA-PET/CT into the diagnostic and follow-up process may 
result in more accurate visualization of true tumour and metastasis status and 
assessment of disease response, but will not impact therapy choice or other disease 
management changes in this study. Participating patients will not benefit from the results 
of this study. 
 
For the PSMA PET/CT an IV need to be placed to administer the radioligand. The whole 
procedure will take 1,5 hours and patients will be exposed to 6,4 mSV effective dose 
each time. Therefore, subjects in this study will have an additional radiation exposure of a 
total of 12,8 mSV. This amount can be considered negligible and the burden can be 
considered minimal as we aim to plan the PSMA PET/CT during regular follow-up 
moments at the clinic and thereby minimize the amount of travel.  
 
8.4 Compensation for injury 
The sponsor/investigator has a liability insurance that is in accordance with article 7 of the 
WMO. The sponsor (also) has an insurance that is in accordance with the legal 
requirements in the Netherlands (Article 7 WMO). This insurance provides cover for 
damage to research subjects through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
 
8.5  Incentives  
The subject will receive a reimbursement for the extra visits' travel costs.  
 

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9. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
9.1 Handling and storage of data and documents 
All baseline and follow-up PSMA-PET/CT examinations are stored in the hospital 
archives under the patient’s own name, following routine clinical practice. For the 
purposes of analysis and storage, images need to be coded for pseudo-anonymization in 
Research Imaging Architecture (RIA) (in compliance with the trial office). All study data 
will be stored for at least 15 years.  An electronic paper Case Report Form (CRF) will be 
used to collect all necessary patient data. Data will be coded, and the local principal 
investigator will have access to this code. As such, the handling of personal data will be in 
accordance with the Dutch Personal Data Protection Act (In Dutch: Wet Bescherming 
Persoonsgegevens (WPB)). Only pseudomized data will be shared with the subsidizing 
party Janssen-Cilag B.V if an independent audit is requested. For details see K6. 
‘Datamanagement plan’. 
 
9.2 Monitoring and Quality Assurance  
The study will be risk based monitored according to ICH GCP. This study has been 
classified as low risk for toxicity. Source data verification of the eCRFs will be performed 
by an independent Clinical Research Monitor from Julius Clinical.  
A detailed monitoring plan specific to the study and describing the nature and frequency of 
the monitoring can be found in K6. ‘Monitorplan’.  
 
9.3 Amendments  
All substantial amendments will be notified to the METC that gave a favourable opinion. 
Non-substantial amendments will not be notified to the accredited METC, but will be 
recorded and filed by the sponsor.  
 
9.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the study to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and number of subjects that have completed 
the trial, other problems, and amendments.  
 
9.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of eight weeks. The end of the study is defined as the last patient’s last visit. The 
sponsor will notify the METC immediately of a temporary halt of the study, including the 
reason of such an action. In case the study is ended prematurely, the sponsor will notify 
the accredited METC within 15 days, including the reasons for the premature termination. 
Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC.  
 
 

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