A 2 Arm, Phase II Controlled Randomized Trial Comparing Efficacy and Safety of Abiraterone and Abiraterone Associated With of Ablative Radiation Therapy in Patients With Oligometastatic Castration Resistant Prostate Cancer (ARTO Trial)
Phase: NA
Conditions: Rate of PSA Response in Oligometastatic,CRPC Undergoing SBRT in Combination With Abiraterone Acetate (AA), Compared to Patients Treated With AA Alone
Sponsor: Lorenzo Livi

Protocol V.1 final 26.09.2017   
 
1 
 
 
A phase II randomized trial of Ablative Radiation 
Therapy in patients with Oligometastatic castration 
resistant prostate cancer (ARTO trial)  
 
 
Protocol Identifying Number: Arto Trial  
Protocol Version Number: 1 
ΕudraCT Number: 2016-005284-13 
 
Sponsor: Dipartimento di scienze biomediche sperimentali e cliniche "Mario 
Serio” 
Sponsor representative: Prof. Livi Lorenzo 
 
 
 
Dated: 26 September 2017 
 

Protocol V.1 final 26.09.2017   
 
2 
 
 
A phase II randomized trial of Ablative Radiation 
Therapy in patients with Oligometastatic castration 
resistant prostate cancer (ARTO trial)  
 
 
 
1. INTRODUCTION 
 
1.1. Background and overall rationale for the study. 
 
 
Prostate cancer (PCa) is one of the most common malignancies and main causes of 
cancer death in Western countries [1,2]. 
Metastatic castration resistant prostate cancer, defined by tumor growth despite a 
testosterone level of less than 50 ng per deciliter (1.7nmol per liter), causes 
approximately 258400 deaths annually worldwide[2,3]. Death of patients with this 
condition, which typically occurs within 24 to 48 months after the onset of castration 
resistance, is commonly preceded by a sequence of landmark events associated with 
deterioration of overall health and worsening symptoms. 
In the presence of metastatic disease, systemic treatment remains the main clinical 
option. However, since the introduction of highly sensitive imaging techniques, a new 
clinical entity of metastatic patients with a limited number of lesions has been defined: 
oligometastatic patients. 
In 1995, Hellman and Weichselbaum [4] first described oligometastatic disease as an 
intermediate state between local and widespread metastatic dissemination. Although a 
clear benefit has yet to be demonstrated in this group of patients, the use of 
stereotactic body radiotherapy (SBRT) or other local therapies directed against all active 
lesions has been suggested as a possible salvage treatment [5-8]. 
Irradiation of metastatic foci may delay the emergence of castration resistance because 
irradiation is effective against both ADT sensitive and ADT resistant prostate cancer cells 
as shown in re-biopsy studies [9]. Stereotactic body radiation therapy has been used in 
this setting to defer the initiation of ADT in patients with oligometastatic prostate cancer 
with notable results [10]. 
Abiraterone acetate is a first class inhibitor of cytochrome P 450c17, a critical enzyme in 
extragonadal and testicular androgen synthesis [11-13]. Abiraterone plus low dose 

Protocol V.1 final 26.09.2017   
 
3 
 
prednisone improves survival in patients with metastatic castration resistant prostate 
cancer who have already received docetaxel [14] and the combination therapy has 
received regulatory approval for this indication. Furthermore, Abiraterone acetate is 
approved also in patients who did not undergo to docetaxel chemotherapy, after the 
results from the COU-AA 302 study; Results from this phase III trial confirmed the 
benefit in chemo-naïve patients treated with abiraterone acetate both in terms of overall 
and radiological progression free survival, if compared to placebo [15-16]. 
In oligometastatic CRPC, the rationale to use SBRT is that the addition of a local ablative 
treatment could improve disease control in mCRPC patients treated with a systemic 
therapy. 
Furthermore, macroscopic disease control could affect metastatic behavior by interplay 
of growth factors or by modulate immune system, leading to an improvement of clinical 
benefit. 
The current phase II randomized trial,”Ablative Radiation Therapy in patients with 
Oligometastatic castration resistant prostate cancer (ARTO trial)” aims to evaluate the 
difference in PSA response rate between the experimental arm (AA+SBRT) and control 
arm (AA) in metastatic castration-resistant prostate cancer patients. 
 
1.2. Zytiga ® (Abiraterone Acetate) 
 
 
ZYTIGA® (abiraterone acetate) is a prodrug of abiraterone, an irreversible inhibitor of 
17α hydroxylase/C17, 20lyase (cytochrome P450c17 [CYP17]), a key enzyme required 
for testosterone synthesis. This enzyme is found in the testes, adrenal glands and 
prostate tumors. 
For the most comprehensive nonclinical and clinical information regarding the efficacy 
and safety of ZYTIGA, refer to the latest version of the summary of product 
characteristics for ZYTIGA. 
 
Hormonal effects have been observed at all doses (200 through 2000 mg) and no dose-
limiting toxicities were documented. A daily dose of 1000 mg was selected for Phase 2 
and 3 studies in the management of prostate cancer patients and for the routine use of 
the drug based on its consistent pharmacologic and endocrinologic effects. Abiraterone 
has been shown to be approximately 21-24 times more potent than ketoconazole in 
CYP17A1 inhibition [17]. 

Protocol V.1 final 26.09.2017   
 
4 
 
Abiraterone acetate is absorbed after oral administration and rapidly converted in 
abiraterone. At 1000 mg/die the terminal plasma half life is approximately 17 hours. 
After oral administration, maximum plasma concentration was reached between 2 to 4 
hours. Co administration with food appears to significantly increase both exposure and 
maximal plasma exposition. 
The maximum inhibition of CYP17A1 is achieved within 28 days of continuous dosing. 
 
 
2. OVERVIEW OF STUDY DESIGN 
 
2.1. Hypothesis: 
 
This phase II randomized trial was designed to evaluate the difference in PSA response 
rate between the experimental arm (AA+SBRT) and control arm (AA). PSA response will 
be defined as a post-treatment decrease > 50% from baseline measured within 6 
months. 
 
 
 
2.2 Study design 
 
 
This is a phase II randomized multicenter study in patients affected by oligo mCRPC, 
treated with standard of care (GnRH agonist or antagonist plus abiraterone acetate and 
prednisone) and randomized to receive SBRT to all sites of disease. Patients will be 
randomly assigned in a 1:1 ratio to both treatment, stratified by Centre, Performance 
Status, and number of metastases. 
Randomization will be performed the same day of the baseline evaluation (+/-3 days). 
Planned size of the overall study population is 174 patients, 87 for each arm. 
The study will include a screening phase and a treatment phase. 
 
The screening phase allows for assessment of subject eligibility, demographics, PSA, 
testosterone, comorbidities and current drug therapies up to 45 days prior to 
randomization.  
The treatment phase consists of systemic treatment with abiraterone acetate 1000 mg 
daily and prednisone 10 mg daily, plus GnRH agonist or antagonist (control arm). 
Furthermore, the patients in the experimental arm will receive SBRT to all metastatic 
lesions. 

Protocol V.1 final 26.09.2017   
 
5 
 
SBRT will be delivered in 1 to 5 fractions, and the dose and fractionation schedule will 
depend on the size and location of the lesion and the surrounding normal tissue 
constraints in accordance with AAPM Task Group 101 recommendations 
 [19]. Considering an Alfa/beta of 3, a BED3 > 100 Gy  is recommended. 
The total planned duration of the study is 40 months, consisting in 28 months 
enrollment period, during which patients will perform the screening and will begin 
standard of care treatment with or without SBRT and later phase of 12 months in which 
patients will continue the treatment with standard of care and will be submitted to 
periodic checks every 3 months. 
 
2.3. Study design rationale 
 
 
Abiraterone acetate is a treatment option in mCRPC patients [15]. Data in literature 
demonstrated the emerging role of metastasis directed therapy (surgery or 
radiotherapy) in the management of oligometastatic prostate cancer [20-21]. In 
particular, stereotactic body radiotherapy (SBRT) seems to be a safe and effective 
treatment, and has a positive impact on progression free survival. Thus, the association 
of SBRT to systemic treatment with ADT and abiraterone acetate may have a role in the 
management of oligometastatic castration resistant prostate cancer patients. 
A Phase II study is suitable to investigate the interaction of systemic therapy (ADT and 
abiraterone) with locoregional therapy (SBRT). The duration of the study equal to 40 
months was defined taking into account both the expected time of occurrence of 
investigated endpoints and feasibility considerations related to patient availability. 
 
3. STUDY OBJECTIVES 
 
 
3.1. Primary objectives 
 
Primary objective of the study will be to compare the rate of PSA response in nodal 
and/or bone oligometastatic (⩽3 lesions), castration resistant prostate cancer patients 
undergoing SBRT in combination with AA (experimental arm), compared  to patients 
treated with AA (control arm). PSA response will be defined as a post-treatment 
decrease > 50% from baseline measured within 6 months. 
 
3.2.Secondary objectives 
 

Protocol V.1 final 26.09.2017   
 
6 
 
-To describe SBRT+AA safety. 
 
-To compare PSA trend in the two treatment arms during the observation period.  
 
-To compare the overall survival (OS) in the two treatment arms. 
 
-To describe quality of life (QoL) data, as measured by EORTC QLQ-C30 during the 
observation period. 
-To describe the use of analgesic drugs and pain experience by means 
presence/absence of symptoms assessed by the Brief Pain Inventory Short Form (BPI 
SF) 
-To compare the radiographic progression free survival (rPFS) and/or biochemical PFSin 
experimental vs control arm 
rPFS is defined as the time from random assignment to the first occurrence of either 
progression by bone scan, progression by computed tomography/ (PET/CT) or death 
resulting from any cause.  
Definition of bone scan progression was adapted from PCWG2 consensus [18], with the 
following criteria: 
 
● If the first bone scan with new lesions compared with baseline is observed within 12 
weeks from treatment beginning, a confirmatory bone scan is required, taken 6 weeks 
or more later, showing additional new lesions if compared to first follow-up scan  
 
● If the first bone scan with new lesions compared with baseline was observed after 12 
weeks from treatment beginning (ie, outside of flare window), or at following bone 
scans, a confirmatory second bone scan is not required  
 
CT or magnetic resonance imaging progression are defined as a 20% increase from 
nadir in target lesion sum of long diameters, appearance of new soft tissue or visceral 
lesions, and/or unequivocal progression of baseline target lesions.  
According to PCWCG2 consensus, a sequence of rising values at a minimum of 1-week 
intervals is requested to define biochemical progression, establishing a minimum starting 
value of 2.0 ng/ml for PSA progression. 

Protocol V.1 final 26.09.2017   
 
7 
 
 
 
4. STUDY POPULATION 
 
4.1. Inclusion Criteria 
 
 
Each potential subject must satisfy all of the following criteria to be enrolled in the 
study. 
 
 
1. Metastatic disease and only <3 metastatic sites recorded (irrespective if nodal or 
bone). 
2. Patients should have received abiraterone acetate for 30 days before eventual 
start of radiotherapy in the experimental arm (+/– 3 days) 
3. Asymptomatic or mildly symptomatic patients according to clinical judgement. 
 
4. Age ≥ 18 years. 
 
5. Subject must have signed an informed consent document indicating that they 
understand the purpose of procedures required for the study and are willing to 
participate in the study. 
 
 
 
4.2. Exclusion Criteria 
 
 
1. More than 3 metastatic lesions. 
 
2. Visceral involvement. 
 
3. Known or suspected contraindications or hypersensitivity to Abiraterone, GnRH 
agonist/antagonist or Radiotherapy. 
4. Comorbidities that contraindicate Abiraterone, GnRH agonist/antagonist or 
Radiotherapy. 
5. Any condition for which, in the option of the investigator, participation would not 
be in the best interest of subject. 
6. Patients who received previous therapies for mCRPC (excluded hormonal 
therapy) 
 

Protocol V.1 final 26.09.2017   
 
8 
 
 
5. STUDY EVALUATIONS 
 
 
5.1. PreTreatment Evaluation 
 
Baseline evaluations include: 
 
 
● demographics data; 
 
● staging, PSA value and Gleason Score at the time of prostate cancer diagnosis; 
 
● previous treatments for prostate cancer; 
 
● active comorbidities and current medical treatments; 
 
● assessment of Performance Status with the Eastern Cooperative Oncology Group 
(ECOG) Score; 
● presence/absence of symptoms assessed by the Brief Pain Inventory Short Form 
(BPI SF) and the quality of life assessment by EORTC QLQ-C30  (baseline 
evaluation should be performed before radiotherapy beginning); 
● complete haematological and biochemical exams [including Lactate 
Dehydrogenase (LDH)], PSA value and testosterone before randomization 
(baseline assessment should be performed within 15 days(+/-3) 
● Imaging procedures (baseline assessment should be performed within 45 days 
before randomization): 
 
○ Tomography/Computed Tomography (PET/CT), or 
○ Bone Scan and Computed Tomography thorax-abdomen pelvis (CT) with 
contrast. 
 
5.2. Evaluation During Treatment 
 
 
Patients will be evaluated as follows: 
 
● every 3 months from start of Abiraterone therapy with ECOG Score; PSA value 
and testosterone; Blood count and LDH. 
● every 3 months from start of Abiraterone the feedback of BPISF and EORTC 
QLQ-C30 questionnaire will also be carried out. 
● every 6 months from randomization or in case of suspected clinical or 
biochemical progression, with the same radiological exams used at the beginning 

Protocol V.1 final 26.09.2017   
 
9 
 
(PET/CT or Bone Scan and CT Computed Tomography thorax-abdomen pelvis 
(CT) with contrast). 
 
Furthermore, in baseline evaluation as well as in case of disease progression, the use of 
additional diagnostic exams (such as magnetic resonance imaging, MRI) is allowed 
according to clinical judgement. 
 
 
 
5.3. Statistical Analysis 
 
Continuous variables will be presented as mean values  standard deviation (SD) and 
categorical variables as numbers and percentages. Comparisons between groups will be 
performed using a two-sided Student’s t-test, after checking data are normally 
distributed (based on the Shapiro-Wilk statistic) for continuous variables and a two-
sided Wilcoxon’s rank-sum test otherwise. Categorical data will be analysed using the 
contingency table analysis with the Chi-square or Fisher’s test, as appropriate.  
Time-to-event data will be analyzed using Kaplan-Meier product-limit survival curve 
estimates and log-rank tests for comparison between groups. 
Data-analysis will be performed on intention to treat population (ITT) and safety data-
analysis will be performed on all patients receiving at least one dose of study treatment 
(the full analysis set). p-values of 0.05 or less will be considered statistically significant 
and all tests will be two-sided. 
Assuming that the proportion of patients achieving a ≥50% PSA level decline in control 
arm is equal to 62% [15,16], with a 5% type 1 error rate and a power of 80%, a total 
of 156 patients are required to show an absolute improvement in proportion of patients 
in the experimental arm of +21%. Considering a 10% rate of drop out during follow-up, 
the final sample size needed is 174 patients (87 for each arm). 
 

Protocol V.1 final 26.09.2017   
 
10 
 
 
 
 
 
 
6.0 ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical 
studies are crucial for the protection of subjects, investigators, and the sponsor, and are 
mandated by regulatory agencies worldwide. 
 
6.1 Adverse Event Definitions and Classifications 
Adverse Event 
An adverse event is any untoward medical occurrence in a clinical study subject 
administered a medicinal (investigational or non-investigational) product. An adverse 
event does not necessarily have a causal relationship with the treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal 
finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational or non-investigational) product, whether or not related to that medicinal 
(investigational or non-investigational) product (Definition per International Conference 
on Harmonisation [ICH]). 
This includes any occurrence that is new in onset or aggravated in severity or frequency 
from the baseline condition, or abnormal results of diagnostic procedures, including 
laboratory test abnormalities. 
 
Serious Adverse Event 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death should it have been more severe.) 
 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 

Protocol V.1 final 26.09.2017   
 
11 
 
 Is a suspected transmission of any infectious agent via a medicinal product 
 Is medically important* 
*Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in other situations, such as important medical events that 
may not be immediately life threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above. These should usually be considered serious. 
 
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An adverse event is considered unlisted when the nature or severity is not consistent 
with the applicable product reference safety information. For an investigational product, 
the expectedness of an adverse event will be determined by whether or not it is listed in 
the Investigator's Brochure. 
 
Adverse Event Associated With the Use of the Drug (Adverse Drug Reaction) 
An adverse event is considered associated with the use of the drug when the attribution 
is possible, probable, or very likely by the definitions listed below. 
 
6.2 Attribution Definitions 
Not Related: An adverse event that is not related to the use of the drug. 
Doubtful: An adverse event for which an alternative explanation is more likely, eg, 
concomitant drug(s), concomitant disease(s), or the relationship in time suggests that a 
causal relationship is unlikely. 
Possible: An adverse event that might be due to the use of the drug. An alternative 
explanation, eg, concomitant drug(s), concomitant disease(s), is inconclusive. The 
relationship in time is reasonable; therefore, the causal relationship cannot be excluded. 
Probable: An adverse event that might be due to the use of the drug. The relationship in 
time is suggestive (eg, confirmed by dechallenge). An alternative explanation is less 
likely, eg, concomitant drug(s), concomitant disease(s). 
Very Likely: An adverse event that is listed as a possible adverse reaction and cannot be 
reasonably explained by an alternative explanation, eg, concomitant drug(s), 
concomitant disease(s). The relationship in time is very suggestive (eg, it is confirmed 
by dechallenge and rechallenge). 

Protocol V.1 final 26.09.2017   
 
12 
 
 
6.3 Severity Criteria 
The NCI-CTCAE v4.0 will be used to grade the severity of adverse events. Any AE not 
listed in the CTCAE will be graded as follows: 
Grade 1, Mild: Awareness of symptoms that are easily tolerated, causing minimal 
discomfort and not interfering with everyday activities. 
Grade 2, Moderate: Sufficient discomfort is present to cause interference with normal 
activity. 
Grade 3, Severe: Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities. 
Grade 4, Life-threatening: Urgent intervention indicated. 
Grade 5, Death: Death. 
The investigator should use clinical judgment in assessing the severity of events not 
directly experienced by the subject (eg, laboratory abnormalities). 
 
6.4 Special Reporting Situations 
Safety events of interest on an investigational medicinal product  that may require 
expedited reporting or safety evaluation include, but are not limited to: 
 Overdose of an  investigational medicinal product 
 Suspected abuse/misuse of an investigational medicinal product 
 Accidental or occupational exposure to an  investigational medicinal product 
 
Any failure of expected pharmacologic action (ie, lack of effect) of an investigational 
medicinal product 
 
Unexpected therapeutic or clinical benefit from use of an investigational medicinal 
product 
 
Medication error involving a sponsor product (with or without subject/patient 
exposure to the sponsor study drug, eg, name confusion) 
 
Special reporting situations should be recorded in the CRF. Any special reporting 
situation that meets the criteria of a serious adverse event should be recorded on the 
serious adverse event page of the CRF. 
 
 
6.5 Procedures 

Protocol V.1 final 26.09.2017   
 
13 
 
 
6.5.1 All Adverse Events 
All adverse events and special reporting situations, whether serious or non-serious, will 
be reported from the time a signed and dated informed consent form is obtained until 
completion of the subject's last study-related procedure, which may include contact for 
follow-up of safety.. Serious adverse events, including those spontaneously reported to 
the investigator within 30 days after the last dose of study drug, must be reported using 
the Serious Adverse Event Form. The sponsor will evaluate any safety information that 
is spontaneously reported by an investigator beyond the time frame specified in the 
protocol. 
All adverse events, regardless of seriousness, severity, or presumed relationship to 
study therapy, must be recorded using medical terminology in the source document and 
the CRF. Whenever possible, diagnoses should be given when signs and symptoms are 
due to a common etiology (eg, cough, runny nose, sneezing, sore throat, and head 
congestion should be reported as "upper respiratory infection"). Investigators must 
record in the CRF their opinion concerning the relationship of the adverse event to study 
therapy. All measures required for adverse event management must be recorded in the 
source document and reported according to sponsor instructions. 
 
6.5.2 Serious Adverse Events 
All serious adverse events occurring during clinical studies must be reported to the 
appropriate sponsor contact person by investigational staff within 24 hours of their 
knowledge of the event: Prof. Lorenzo Livi, AOU Careggi, SODc Radioterapia. 
Information regarding serious adverse events will be transmitted to the sponsor using 
the Serious Adverse Event Form, which must be completed and signed by a physician 
from the study site , and transmitted to the sponsor within 24 hours. The initial and 
follow-up reports of a serious adverse event should be made by facsimile (fax). 
All serious adverse events that have not resolved by the end of the study, or that have 
not resolved upon discontinuation of the subject's participation in the study, must be 
followed until any of the following occurs: 
 The event resolves 
 The event stabilizes 
 The event returns to baseline, when a baseline value/status is available 

Protocol V.1 final 26.09.2017   
 
14 
 
 The event can be attributed to agents other than the study drug or to factors 
unrelated to study conduct 
 It becomes unlikely that any additional information can be obtained (subject or 
health care practitioner refusal to provide additional information, lost to follow-up 
after demonstration of due diligence with follow-up efforts)  
Suspected transmission of an infectious agent by a medicinal product will be reported as 
a serious adverse event. Any event requiring hospitalization (or prolongation of 
hospitalization) that occurs during the course of a subject's participation in a clinical 
study must be reported as a serious adverse event, except hospitalizations for the 
following: 
 Hospitalizations not intended to treat an acute illness or adverse event (eg, social 
reasons such as pending placement in long-term care facility) 
 Surgery or procedure planned before entry into the study (must be documented in 
the CRF). 
Disease progression should not be recorded as an adverse event or serious adverse 
event term; instead, signs and symptoms of clinical sequelae resulting from disease 
progression/lack of efficacy will be reported when they fulfill the serious adverse event 
definition. 
During the follow-up phase of the study, deaths regardless of causality and serious 
adverse events thought to be related to blinded study drug will be collected and 
reported within 24 hours of discovery or notification of the event and documented. 
 
6.5.3 Pregnancy 
All initial reports of pregnancy in  in partners of male subjects included in the study 
must be reported to the Sponsor-Investigator by investigational staff within 24 hours of 
their knowledge of the event using the pregnancy notification form. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events and 
must be reported using the Serious Adverse Event Form.  
 
Unforeseeable risks to the embryo or fetus (for both maternal and paternal exposure): 
There may be risks with the use of abiraterone acetate that are not yet known, and 
these may cause unforeseeable risks to the embryo or fetus and on sperm (i.e. for both 
maternal and paternal exposure). Because of this, the subjects included should not 
become father of a baby while participating in this study. 

Protocol V.1 final 26.09.2017   
 
15 
 
Pregnancies in partners of male subjects included in the study will be reported by the 
investigational staff within 24 hours of their knowledge of the event using the pregnancy 
notification form. Follow-up information regarding the outcome of the pregnancy and 
any postnatal sequelae in the infant will be required. 
 
6.5.4 SUSAR Reporting 
The sponsor assumes responsibility for appropriate reporting of adverse events to the 
regulatory authorities. The sponsor will also report to investigators (and the head of the 
investigational institute where required) all suspected unexpected serious adverse 
reactions (SUSARs). The investigator (or sponsor where required) must report SUSARs 
to the appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
that approved the protocol unless otherwise required and documented by the IEC/IRB. 
A SUSAR will be reported to regulatory authorities unblinded. Participating investigators 
and IEC/IRB will receive a blinded SUSAR summary, unless otherwise specified. 
 
6.5.5 Annual Safety Reports 
An annual report for each trial must be submitted by the sponsor to the competent 
authorities and the ethics committees, taking into account all new available safety 
information received during the reporting period. 
The aim of the annual safety report is to describe concisely all new safety information 
relevant to the IMP, providing with a listing of all suspected serious adverse reactions 
which have occurred over this period and a report of the subjects' safety. 
 
6.5.6 Adverse Drug Reactions Associated with Abiraterone Acetate 
(ZYTIGA®) 
Infections and infestations  
- 
very common: urinary tract infection 
Endocrine disorders  
- 
uncommon: adrenal insufficiency 
Metabolism and nutrition disorders  
- 
very common: hypokalaemia 
- 
common: hypertriglyceridaemia 
Cardiac disorders  
- 
common: cardiac failure (a), angina pectoris, , atrial fibrillation, tachycardia 

Protocol V.1 final 26.09.2017   
 
16 
 
- 
uncommon: arrhythmia 
Vascular disorders  
- 
very common: hypertension 
 
Respiratory, thoracic and mediastinal disorders 
- 
Rare: Allergic alveolitis (c) 
Gastrointestinal disorders  
- 
common: dyspepsia 
Hepatobiliary disorders  
- 
very common: alanine aminotransferase increased, aspartate aminotransferase 
increased (d) 
- 
Rare: Acute hepatic failure (c), Hepatitis fulminant (c) 
- 
Musculoskeletal and connective tissue disorders 
- 
Uncommon: Myopathy/rhabdomyolysis (c) 
Renal and urinary disorders  
- 
common: haematuria 
General disorders and administration site conditions  
- 
very common: oedema peripheral 
Injury, poisoning and procedural complications  
- 
common: fractures (b) 
 
(a) Cardiac failure also includes congestive heart failure, left ventricular dysfunction and 
ejection fraction decreased 
(b) Fractures includes osteoporosis and all fractures with the exception of pathological 
fracture 
(c) ADR is based on spontaneous reports from post-marketing experience 
(d) Alanine aminotransferase increased and/or aspartate aminotransferase increased 
includes ALT increased, AST increased, and hepatic function abnormal. 
 
Frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 
to <1/100); rare (≥1/10,000 to <1/1,000); 
very rare (<1/10,000). 
 
 

Protocol V.1 final 26.09.2017   
 
17 
 
 
7.0 PRODUCT QUALITY COMPLAINT HANDLING 
A product quality complaint (PQC) is defined as any suspicion of a product defect 
related to manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the 
identity, quality, durability, or reliability of a product, including its labeling or package 
integrity. PQCs may have an impact on the safety and efficacy of the product. Timely, 
accurate, and complete reporting and analysis of PQC information from clinical studies 
are crucial for the protection of subjects, investigators, and the manufacturing company, 
and are mandated by regulatory agencies worldwide. 
 
7.1 Procedures 
All initial PQCs must be reported to the company by the investigational staff as soon as 
possible after being made aware of the event. 
If the defect is combined with a serious adverse event, then the investigational staff 
must report the PQC to the sponsor according to the serious adverse event reporting 
timelines. A sample of the suspected product should be maintained for further 
investigation if requested by the company. 
 
 
8. STUDY LIMITATIONS 
 
 
Study results have to be interpreted considering that participant sites constitute a 
convenience sample of all centers. In each site, investigators are recommended to enroll 
patients in a consecutive manner. Characteristics of enrolled patients will be described in 
order to provide all necessary information. 
No formal associations will be assessed, but some patients and treatment characteristics 
could have an impact on investigated outcomes. Thus, age, relevant concomitant 
disease and therapies, Gleason score, ECOG PS, previous and subsequent treatment for 
mCRPC will be collected in order to be considered in the analysis. 
Finally, target sample size is considered to be achievable during the enrolment period on 
the basis of feasibility considerations. 
 
 
 
9. STUDY SPECIFIC MATERIALS 
 
 

Protocol V.1 final 26.09.2017   
 
18 
 
The investigator will be provided with the following supplies: 
 
● Final protocol and, if applicable, amendments/addenda. 
 
● Independent Ethics Committee or Institutional Review Board (IEC/IRB)-
approved informed consent form (and any other written materials to be 
provided to the subjects). 
● Independent Ethics Committee or Institutional Review Board (IEC/IRB)-
approved subject recruiting materials. 
● Applicable recruiting materials. 
 
● Applicable questionnaires. 
 
● Information regarding funding, contact name of the promoter, institutional 
affiliations, other potential conflicts of interest. 
● Any other documents that the IEC/IRB requests to fulfill its obligation. 
 
● Pharmaco vigilance guideline for the interventional study session. 
 
● All material needed for data collection according to this protocol in order to 
strictly avoid any additional cost for the Investigator Structure and/or 
patients. 
 
10 .Regulatory Ethics Compliance 
 
 
10.1. Investigator Responsibilities 
 
The investigator is responsible for ensuring that this phase II study is performed in 
accordance with the protocol, concurrent ICH guidelines on Good Clinical Practice (GCP) 
and applicable regulatory and country specific requirements. 
 
In Italy the clinical trials are regulated by regulated by a ,entered into force in January 
2004 (Decreto legislativo 24 giugno 2003, n.211).This decree transposes the concerning 
the implementation of in the conduct of clinical trials on medicinal products for human 
use. 
Good Clinical Practice is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve the participation of 
human subjects. Compliance with this standard provides public assurance that the 
rights, safety, and well being of study subjects are protected, consistent with the 

Protocol V.1 final 26.09.2017   
 
19 
 
principles that originated in the Declaration of Helsinki, and that the clinical study data 
are credible.

Protocol V.1 final 26.09.2017   
 
20 
 
 
 
 
10.2. Independent Ethics Committee or institutional Review Board 
(IEC/IRB) 
 
Before the start of the study, the investigator (or promoter where required) will provide 
the IEC/IRB with concurrent and complete copies of the following documents (as 
required by local organisation): 
 
● Final protocol and, if applicable, amendments/addenda 
 
● Promoter approved informed consent form (and any other written materials to 
be provided to the subjects) 
● Investigator’s brochure for Zytyga (or equivalent information) and 
amendments/addenda 
● Promoter approvedsubjectrecruitingmaterials 
 
● Information regarding funding, institutional affiliations, other potential conflicts 
of interest 
● Any other documents that the IEC/IRB requests to fulfill its obligation 
 
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the informed consent and privacy 
form, applicable recruiting materials, and subject compensation programs, and the 
promoter has received a copy of this approval. 
This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved. Approval for the collection of optional samples for research 
and for the corresponding ICF must be obtained from the IEC/IRB. 
During the study the investigator (or promoter where required) will send the following 
documents and updates to the IEC/IRB for their review and approval, where 
appropriate: 
 
● Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct) 

Protocol V.1 final 26.09.2017   
 
21 
 
● Revision(s) to informed consent form and any other written materials to be 
provided to subjects 
● If applicable, new or revised subject recruiting materials approved by the 
promoter 
 
● New edition(s) of the Investigator's Brochures and amendments/addenda 
 
● Summaries  of  the  status  of  the  study  at  intervals stipulated in guidelines of 
theIEC/IRB 
 
● Reports of adverse events that are serious, unlisted/unexpected, and associated 
with treatments in study 
● New information that may adversely affect the safety of the subjects or the 
conduct of the study 
● Deviations from or changes to the protocol to eliminate immediate hazards to 
the subjects 
● Report of deaths of subjects under the investigator's care 
 
● Notification if a new investigator is responsible for the study at the site 
 
● Any other requirements of the IEC/IRB 
 
● Paper CRF 
 
 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable 
informed consent form revisions must be submitted promptly to the IEC/IRB for review 
and approval before implementation of the change(s).
At the end of the study, the investigator (or promoter where required) will notify the 
IEC/IRB about the study completion. 
 
 
10.3. Informed Consent 
 
 
The process of obtaining informed consent should be documented in the patient source 
documents. Each subject (or a legally acceptable representative) must give written 
consent according to local requirements after the nature of the study has been fully 
explained. The informed consent form [ICF(s)] must be signed before performance of 
any study-related activity. The ICF(s) that is/are used must be approved by both the 

Protocol V.1 final 26.09.2017   
 
22 
 
promoter and by the reviewing IEC/IRB and be in a language that the subject can read 
and understand. The informed consent should be in accordance with principles that 
originated in the Declaration of Helsinki, current ICH and GCP guidelines, applicable 
regulatory requirements, and sponsor policy. 
Before enrollment in the study, the investigator or an authorized member of the 
investigational staff must explain to potential subjects (or their legally acceptable 
representative) the aims, methods, reasonably anticipated benefits, and potential 
hazards of the study, and any discomfort participation in the study may entail. Subjects 
will be informed that their participation is voluntary and that they may withdraw consent 
to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive for the treatment of his disease. Subjects will be 
told that alternative treatments are available if they refuse to take part and that such 
refusal will not prejudice future treatment. Finally, they will be told that the investigator 
will maintain a subject identification register for the purposes of long term follow up if 
needed and that their records may be accessed by health authorities and authorized 
sponsor stuff without violating the confidentiality of the subject, to the extent permitted 
by the applicable law(s) or regulations. By signing the ICF the subject (or legally 
acceptable representative) is authorizing such access, including permission to obtain 
information about his survival status, and agrees to allow his or her study physician to 
recontact the subject for the purpose of obtaining consent for additional safety 
evaluations, if needed, and subsequent disease-related treatments, or to obtain 
information about his survival status. 
The subject (or a legally acceptable representative) will be given sufficient time to read 
the ICF and the opportunity to ask questions. After this explanation and before entry 
into the study, consent should be appropriately recorded by means of the subject's (or 
his/her legally acceptable representative’s ) personally dated signature. After having 
obtained the consent, a copy of the ICF must be given to the subject. 
Written assent should be obtained from subjects who are able to write. 

Protocol V.1 final 26.09.2017   
 
23 
 
 
 
10.4. Privacy of Personal Data 
 
 
Confidentiality of patient records will be maintained at all times. The collection and 
processing of personal data from subjects enrolled in this study will be limited to those 
data that are necessary to fulfill the objectives of the study. These data must be 
collected and processed with adequate precautions to ensure confidentiality and 
compliance with applicable data privacy protection laws and regulations. 
The informed consent obtained from the subject includes explicit consent for the 
processing of personal data and for the investigator/institution to allow direct access to 
his or her original medical records (source data/documents) for study related 
monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries. The subject 
has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. 
Reasonable steps will be taken to respond to such a request, taking into consideration 
the nature of the request, the conditions of the study, and the applicable laws and 
regulations. 
 
11. ADMINISTRATIVE REQUIREMENTS 
 
11.1. Protocol Amendments 
 
 
Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for nonacceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case 
the amendment must be promptly submitted to the IEC/IRB and relevant competent 
authority. When the change(s) involves only logistical or administrative aspects of the 
study, the IRB (and IEC where required) only needs to be notified.

Protocol V.1 final 26.09.2017   
 
24 
 
 
 
11.2. Subject Identification, Enrollment, and Screening Logs 
 
 
The investigator agrees to complete a subject identification and enrollment log to permit 
easy identification of each subject during and after the study. This document will be 
reviewed by the promoter studysite contact for completeness. The subject identification 
and enrollment log will be treated as confidential and will be filed by the investigator in 
the study file. All reports and communications relating to the study will identify subjects 
by subject identification and date of birth. The investigator must also complete a subject 
screening log, which reports on all subjects who were seen to determine eligibility for 
inclusion in the study. 
 
 
11.3 Source Documentation 
 
At a minimum, source documentation must be available to substantiate subject 
identification, eligibility, and participation; proper informed consent procedures;dates of 
visits;adherence to protocol procedures;results of safety and efficacy parameters as 
required by the protocol;record of all AEs and followup of AEs;concomitant 
medication;drug receipt/dispensing/return records;and date of subject completion or 
withdrawal from the study, and the reason if appropriate. In addition, the author of an 
entry in the source documents should be identifiable. 
At a minimum, the type and level of detail of source data available for a subject should 
be consistent with that commonly recorded at the study site as a basis for standard 
medical care. Specific details required as source data for the study will be reviewed with 
the investigator before the study and will be described in the monitoring guidelines (or 
other equivalent document). 
Data from medical records of each enrolled patient will be collected uscing a paper CRF. 
CRF’s will be sent through e-mail or fax to the promoter of the study at baseline and 
every 3 months. 
 
11.4 
Record Retention 
 

Protocol V.1 final 26.09.2017   
 
25 
 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all 
CRFs and all source documents that support the data collected from each subject, as 
well as all study documents as specified in ICH/GCP Section. The investigator/institution 
will take measures to prevent accidental or premature destruction of these documents. 
Essential documents must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These 
documents will be retained for a longer period if required by the applicable regulatory 
requirements or by an agreement with the promoter. It is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer 
need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person 
who will accept the responsibility. Under no circumstance shall the investigator relocate 
or dispose of any study documents before having obtained written approval from the 
promoter.If it becomes necessary for the promoter or the appropriate regulatory 
authority to review any documentation relating to this study, the investigator/institution 
must permit access to such reports. 
 
 
 
11.5 Study Completion 
 
The final data from the study site will be sent to the promoter (or designee) after 
completion of the final subject assessment at that study site, in the time frame specified 
in the Clinical Trial Agreement. 
 
11.6. Study Termination 
 
Study sites will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected and a study site closure 
visit has been performed. The investigator may initiate study site closure at any time, 
provided there is reasonable cause and sufficient notice is given in advance of the 

Protocol V.1 final 26.09.2017   
 
26 
 
intended termination. Reasons for the early closure of a study site by the sponsor or 
investigator may include but are not limited to: 
 
● Failure of the investigator to comply with the protocol, the requirements of the 
IEC/IRB or local health authorities, the sponsor's procedures, or GCP guidelines 
● Inadequate recruitment of subjects by the investigator 
 
● Discontinuation of further study drug development 
 
 
11.7. On Site Audits 
 
Representatives of the promoter's clinical quality assurance department may visit the 
study site at any time during or after completion of the study to conduct an audit of the 
study in compliance with regulatory guidelines and company policy. These audits will 
require access to all study records, including source documents, for inspection and 
comparison with the CRFs. Subject privacy must, however, be respected. The 
investigator and studysite personnel are responsible for being present and available for 
consultation during routinely scheduled studysite audit visits conducted by the promoter 
or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, 
either as part of a national GCP compliance program or to review the results of this 
study in support of a regulatory submission. The investigator should immediately notify 
the promoter if he or she has been contacted by a regulatory agency concerning an 
upcoming inspection. 
 
 
 
12.REFERENCES 
 
1. Boyle P, Ferlay J: Cancer incidence and mortality in Europe, 2004. AnnOncol 
2005;16:481–488. 
2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer 
statistics. CA Cancer J Clin 2011;61:6990 [Erratum, CA Cancer J Clin 
2011;61:134.] 
3. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for 
patients with progressive prostate cancer and castrate levels of testosterone: 

Protocol V.1 final 26.09.2017   
 
27 
 
recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin 
Oncol2008;26:11481159 
4. Hellman S, Weichselbaum RR: Oligometastases. J ClinOncol 1995;13:8–10 
 
5. Decaestecker K, De Meerleer G, Lambert B, Delrue L, Fonteyne V, Claeys T, De 
Vos F, Huysse W, Hautekiet A, Maes G, Ost P: Repeated stereotactic body 
radiotherapy for oligometastatic prostate cancer recurrence. RadiatOncol 
2014;9:135. 
6. Tree AC, Khoo VS, Eeles RA, Ahmed M, Dearnaley DP, Hawkins MA, Huddart RA, 
Nutting CM, Ostler PJ, van As NJ: Stereotactic body radiotherapy for 
oligometastases. Lancet Oncol 2013;14:e28–37.
7. Berkovic P, De Meerleer G, Delrue L, Lambert B, Fonteyne V, Lumen N, 
Decaestecker K, Villeirs G, Vuye P, Ost P: Salvage stereotactic body radiotherapy 
for patients with limited prostate cancer metastases: deferring androgen 
deprivation therapy. ClinGenitourinCancer 2013;11:27–32. 
8. Ahmed KA, Stauder MC, Miller RC, Bauer HJ, Rose PS, Olivier KR, Brown PD, 
Brinkmann DH, Laack NN: Stereotactic body radiation therapy in spinal 
metastases. Int J RadiatOncolBiolPhys 2012;82:e803–809 
9. MartinezFernandez MI, Perez Gracia JL, GilBazoI, MartinezMonge R:Stereotactic 
body radiation therapy (SBRT) delays the emergence of castration resistance in 
patients with oligometastatic prostate cancer. ClinTranslOncol 2016;18: 743. 
10. Berkovic P, De Meerleer G, Delrue L, Lambert B, Fonteyne V, Lumen N, et al. 
Salvage stereotactic body radiotherapy for patients with limited prostate cancer 
metastases: deferring androgen deprivation therapy. ClinGenitourin Cancer. 
2013;11:27–32 
11. Attard G, Belldegrun AS, de Bono JS. Selective blockade of androgenic steroid 
synthesis by novel lyase inhibitors as a therapeutic strategy for treating 
metastatic prostate cancer. BJU Int2005;96:12411246 
12. Molina A, Belldegrun A. Novel therapeutic strategies for castration resistant 
prostate cancer: inhibition of persistent androgen production and androgen 
receptor mediated signaling. J Urol2011;185:787794[Erratum, J Urol 
2011;186:762.] 
13. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral 
androgens in metastatic prostate cancer: a mechanism for castration resistant 
tumor growth. Cancer Res2008;68:44474454 

Protocol V.1 final 26.09.2017   
 
28 
 
14. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in 
metastatic prostate cancer. N Engl J Med2011;364:19952005 
15. Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, 
Logothetis CJ, Shore ND, Small EJ, Carles J, Flaig TW, Taplin ME, Higano CS, de 
Souza P, de Bono JS, Griffin TW, De Porre P, Yu MK, Park YC, Li J, Kheoh T, 
Naini V, Molina A, Rathkopf DE; COU-AA-302 Investigators.. Abiraterone acetate 
plus prednisone versus placebo plus prednisone in chemotherapy-naive men 
with metastatic castration-resistant prostate cancer (COU-AA-302): final overall 
survival analysis of a randomised, double-blind, placebo-controlled phase 3 
study. Lancet Oncol. 2015 Feb;16(2):152-60. 
 
16. Morris MJ, Molina A, Small EJ, de Bono JS, Logothetis CJ, Fizazi K, de Souza P, 
Kantoff PW, Higano CS, Li J, Kheoh T, Larson SM, Matheny SL, Naini V, 
Burzykowski T, Griffin TW, Scher HI, Ryan CJ. Radiographic progression-free 
survival as a response biomarker in metastatic castration-resistant prostate 
cancer: COU-AA-302 results. J Clin Oncol. 2015 Apr 20;33(12):1356-63.  
 
17. Ang JE, Olmos D, de Bono JS. CYP17 blockade by abiraterone: Further evidence 
for frequent continued hormonedependence in castrationresistant prostate 
cancer. Br J Cancer2009; 100:671–675.  
18. Scher HI, Halabi S, Tannock I, et al: Design and end points of clinical trials for 
patients with progressive prostate cancer and castrate levels of testosterone: 
Recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin 
Oncol 26:1148-1159, 2008] 
19. 
Benedct SH, Yenice KM, Followill D, et al. Stereotactic body radiation 
therapy: the report of AAPM task group 101. Med Phys. 2010;37(8):5047–101.  
20. Ost P, Bossi A, Decaestecker K, De Meerleer G, Giannarini G, Karnes RJ, Roach 
M 3rd, Briganti A. Metastasis-directed therapy of regional and distant 
recurrences after curative treatment of prostate cancer: a systematic review of 
the literature. Eur Urol. 2015 May;67(5):852-63. 
21. Ost P, Jereczek Fossa BA, As NV et al. Progression free Survival Following 
Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Treatment 
naive Recurrence: A Multi-institutional Analysis. Eur Urol. 2016 Jan;69(1):912