A Randomized Phase II Study of Sequencing Abiraterone Acetate and Enzalutamide in Metastatic Castration-Resistant Prostate Cancer
Phase: PHASE2
Conditions: Metastatic Castration-Resistant Prostate Cancer
Sponsor: British Columbia Cancer Agency

 
 
 
 
 
 
 
 
A RANDOMIZED PHASE II STUDY OF SEQUENCING ABIRATERONE 
ACETATE AND ENZALUTAMIDE IN METASTATIC CASTRATION-
RESISTANT PROSTATE CANCER 
GUTG-001 
 
PROTOCOL VERSION: 6.0 
 
PROTOCOL VERSION DATE: 16Jul2018 
 
 
 
STUDY CHAIR: DR. KIM N. CHI 
 
 
COGNITIVE STUDY CO-CHAIR: DR. BERNHARD EIGL 
 
STUDY COORDINATOR: MS. LEANNE SETO 
 
BCCA – VCC PI: Dr. Kim N. Chi 
 
BCCA – AC PI: Dr. Muhammad Zulfiqar 
 
BCCA – CN PI: Dr. Christian Fibich 
 
BCCA – CSI PI: Dr. Daygen Finch 
 
BCCA – FVC PI: Dr. Conrad Oja 
 
BCCA – VIC PI: Dr. Joanna Vergidis 
 
Vancouver Prostate Centre – PI: Dr. Martin Gleave 
 

Version 6.0 – July 16, 2018 
i
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................... I 
1.0  
PROTOCOL SUMMARY ............................................................................................... 1 
2.0  
BACKGROUND AND RATIONALE .......................................................................... 10 
2.1  
PROSTATE CANCER ................................................................................................ 10 
2.2  
ABIRATERONE ACETATE AND ENZALUTAMIDE ............................................. 10 
2.3 
RESISTANCE MECHANISMS TO ABIRATERONE ACETATE AND 
ENZALUTAMIDE ................................................................................................................... 11 
2.4  
CIRCULATING CELL-FREE TUMOUR DNA ......................................................... 11 
2.5  
COGNITIVE EFFECTS OF ABIRATERONE ACETATE AND ENZALUTAMIDE 11 
3.0 
BACKGROUND THERAPEUTIC INFORMATION ................................................ 12 
3.1 
PHARMACOLOGY .................................................................................................... 12 
3.2 
CLINICAL EFFICACY DATA ................................................................................... 13 
3.3 
CLINICIAL TOXICITY DATA .................................................................................. 14 
3.3.1 
Abiraterone acetate + prednisone ............................................................................ 14 
3.3.2 
Enzalutamide ........................................................................................................... 14 
4.0  
STUDY OBJECTIVES .................................................................................................. 15 
4.1 
PRIMARY OBJECTIVES ........................................................................................... 15 
4.2 
SECONDARY OBJECTIVES ..................................................................................... 15 
5.0 
STUDY DESIGN AND ENDPOINTS .......................................................................... 15 
5.1 
DESCRIPTION OF STUDY DESIGN ........................................................................ 15 
5.2 
SCREENING PHASE .................................................................................................. 15 
5.3 
RANDOMIZATION AND TREATMENT ALLOCATION ....................................... 16 
5.4 
FIRST-LINE THERAPY ............................................................................................. 16 
5.4.1 
Cycle 1 ..................................................................................................................... 16 
5.4.2 
Cycle 2 and subsequent cycles ................................................................................ 16 
5.5 
CROSS-OVER FROM FIRST-LINE TO SECOND-LINE THERAPY ...................... 16 
5.6 
SECOND-LINE THERAPY ........................................................................................ 16 
5.6.1 
Cycle 1 ..................................................................................................................... 16 
5.6.2 
Cycle 2 and subsequent cycles ................................................................................ 17 
5.7 
END OF SECOND-LINE THERAPY ......................................................................... 17 
6.0 
STUDY POPULATION ................................................................................................. 17 
6.1 
PATIENT POPULATION ........................................................................................... 17 
6.2 
INCLUSION CRITERIA ............................................................................................. 17 
6.3 
EXCLUSION CRITERIA ............................................................................................ 18 
7.0 
TREATMENT ................................................................................................................ 19 
7.1 
STUDY TREATMENT ............................................................................................... 19 
7.1.1 
Dosing ...................................................................................................................... 19 
7.1.2 
Dose modification .................................................................................................... 19 
7.1.3 
Compliance .............................................................................................................. 19 
7.1.4 
Treatment duration................................................................................................... 19 
7.2 
PRIOR TREATMENT ................................................................................................. 19 
7.3 
PROHIBITED CONCOMITANT TREATMENT ....................................................... 19 
7.4 
PERMITTED CONCOMITANT MEDICATIONS AND TREATMENT .................. 20 
8.0 
VISIT SCHEDULE ........................................................................................................ 20 
8.1 
SCREENING ............................................................................................................... 20 

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8.2 
FIRST-LINE THERAPY ............................................................................................. 20 
8.2.1  Cycle 1 (Day 1 – Baseline) ...................................................................................... 20 
8.2.2  Cycles 2 - 4 .............................................................................................................. 21 
8.2.3 
Subsequent Cycles ................................................................................................... 21 
8.3 
SECOND-LINE THERAPY ........................................................................................ 21 
8.3.1 
Cycle 1 (Day 1 – Baseline) ...................................................................................... 21 
8.3.2 
Cycle 2 - 4 ................................................................................................................ 22 
8.3.3 
Subsequent Cycles ................................................................................................... 22 
8.4 
END OF SECOND-LINE THERAPY ......................................................................... 23 
9.0 
ASSESSMENTS ............................................................................................................. 23 
9.1 
EFFICACY .................................................................................................................. 23 
9.1.1 
PSA response ........................................................................................................... 23 
9.1.2 
PSA progression ...................................................................................................... 23 
9.1.3 
Radiological Tumour Assessments .......................................................................... 24 
9.2 
COGNITIVE, DEPRESSION, AND FUNCTIONAL TESTING ................................ 24 
9.3 
SAFETY AND TOLERABILITY ............................................................................... 24 
9.4 
CORRELATIVE STUDIES ......................................................................................... 24 
10.0 
SAFETY MONITORING AND REPORTING ........................................................... 24 
10.1 
ADVERSE EVENTS ................................................................................................... 24 
10.1.1 
Definition and reporting ...................................................................................... 24 
10.2 
SERIOUS ADVERSE EVENTS .................................................................................. 25 
10.2.1 
Definition and reporting ...................................................................................... 25 
11.0 
CRITERIA FOR TREATMENT DISCONTINUATION .......................................... 25 
11.1 
FIRST-LINE THERAPY ............................................................................................. 25 
11.2 
SECOND-LINE THERAPY ........................................................................................ 26 
11.3 
POST-PROTOCOL THERAPY AND FOLLOW-UP ................................................. 26 
12.0 
STATISTICAL METHODS AND DATA ANALYSIS ............................................... 26 
12.1 
STATISTICAL DESIGN ............................................................................................. 26 
12.2 
RANDOMIZATION METHOD .................................................................................. 27 
12.3 
PRIMARY ENDPOINTS ............................................................................................ 27 
12.4 
SECONDARY ENDPOINTS ...................................................................................... 27 
13.0 
ETHICAL AND ADMINISTRATIVE PROCEDURES............................................. 27 
13.1 
REGULATORY AND ETHICAL COMPLIANCE .................................................... 27 
13.2 
RESPONSIBILTIES OF THE INVESTIGATOR AND IRB/IEC/REB ...................... 27 
13.3. 
INFORMED CONSENT PROCEDURES ................................................................... 28 
13.5 
PUBLICATION OF STUDY PROTOCOL AND RESULTS ...................................... 28 
13.6  
STUDY DOCUMENTATION, RECORD KEEPNG AND RETENTION ................. 28 
13.7 
CONFIDENTIALITY OF STUDY DOCUMENTS AND PATIENT RECORDS ...... 28 
13.8 
AUDITS AND INSPECTIONS ................................................................................... 28 
14.0 
CORRELATIVE STUDIES .......................................................................................... 28 
14.1 
BACKGROUND AND RATIONALE ........................................................................ 28 
14.2 
SAMPLE COLLECTION ............................................................................................ 29 
14.3 
SAMPLE PROCESSING AND ANALYSIS ............................................................... 29 
15.0  
APPENDICES ................................................................................................................ 30 
15.1  
APPENDIX A - ADVERSE EVENTS OF INTEREST ............................................... 30 
15.2 
APPENDIX B - RECIST 1.1 CRITERIA ..................................................................... 30 
15.2.1  
Criteria for Measurable Disease .......................................................................... 30 

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15.2.2  
Response Criteria for Target Lesions .................................................................. 30 
15.2.3 
 Response Criteria for Non-target Lesions .......................................................... 31 
15.3 
APPENDIX C - ECOG PERFORMANCE STATUS .................................................. 31 
15.4 
APPENDIX D – CREATININE CLEARANCE .......................................................... 31 
15.5 
APPENDIX E – MONTREAL COGNITIVE ASSESSMENT TOOL ......................... 32 
ADMINISTRATION AND SCORING INSTRUCTIONS ...................................................................... 32 
15.6 
APPENDIX F – PATIENT HEALTH QUESTIONNAIRE ......................................... 39 
15.7  
APPENDIX G – FACT-P QUESTIONNAIRE ............................................................ 41 
16.0 
REFERENCES ............................................................................................................... 44 
 
 
 

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1.0  
PROTOCOL SUMMARY 
Title 
A randomized phase II study of sequencing abiraterone acetate and enzalutamide in 
metastatic castration-resistant prostate cancer 
Background and 
rationale 
Abiraterone acetate and enzalutamide have emerged as standard therapies in 
metastatic castration-resistant prostate cancer (mCRPC). Both agents improve 
outcomes in patients previously treated with docetaxel and in those that are 
chemotherapy-naive1-4. Although their mechanisms of action differ, both abiraterone 
and enzalutamide target persistent androgen receptor (AR) signaling. Abiraterone 
inhibits CYP17 and testicular and extragonadal androgen production whereas 
enzalutamide directly antagonises the AR. Whether cross resistance occurs between 
these agents if used in sequence is unknown, but theoretically disparate mechanisms 
of resistance may allow for successful sequencing of these agents. Prior studies have 
reported PSA response rates of under 10% in patients treated with abiraterone after 
enzalutamide5,6 and 13%-29% in patients treated with enzalutamide after 
abiraterone7,8. Since these data were generated in small, retrospective series, a 
prospective clinical trial is warranted to evaluate effects of sequencing abiraterone 
and enzalutamide. A randomized phase II study is proposed in which patients with 
PSA progression on abiraterone or enzalutamide will be crossed over to the opposite 
agent. Although not a surrogate for clinical outcomes, PSA changes will be used to 
assess treatment efficacy since PSA expression is driven by AR activation.  
Apart from determining optimal sequencing of abiraterone and enzalutamide in 
mCRPC patients, a key issue associated with the use of these agents is identifying 
circulating biomarkers associated with treatment response and resistance. Our group 
has preliminary data showing that a high proportion of enzalutamide-resistant 
mCRPC patients and some abiraterone-resistant mCRPC patients possess focal AR 
amplification in cell-free tumour DNA extracted from plasma. In pre-clinical studies, 
other potential mechanisms of resistance to these agents include increased expression 
of AR splice variants (abiraterone and enzalutamide)9,10, increased expression of 
CYP17 (abiraterone)6,9, upregulation of the stress-activated chaperone protein 
clusterin (enzalutamide only)11 and a point mutation (F876L) in the ligand-binding 
domain of the AR (enzalutamide only)12,13. Non-coding RNAs (ncRNAs) are 
additional biomarkers of interest since they are implicated in tumorigenesis and are 
readily detectable in plasma of mCRPC patients14. Examination of these biomarkers 
in serum and plasma is planned, with the aim of identifying potentially novel factors 
associated with treatment efficacy and resistance in mCRPC patients receiving 
abiraterone and enzalutamide.  
The cognitive effects of abiraterone and enzalutamide are not well described. 
Enzalutamide is known to cross the blood-brain barrier and infrequently causes 
seizures, possibly related to effects on the γ-aminobutyric acid–gated chloride 
channel15. In the enzalutamide registration study, a small subset (< 5%) of patients 
also developed mental impairment disorders including amnesia, memory impairment, 
cognitive disorder and disturbance in attention16. Conversely, no central nervous 
system effects of abiraterone have been reported. Cognitive testing will therefore be 
undertaken in this study to evaluate potential differences between these agents. 
Hypothesis 
That the differing mechanisms through which abiraterone acetate and enzalutamide 
target AR signaling will permit effective sequencing of these agents. 
Primary 
Objectives 
1. To evaluate the PSA response rate (defined as a ≥ 30% decline in PSA from 
baseline confirmed on repeat measurement ≥ 28 days later) in mCRPC 

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patients with PSA progression on first-line therapy with abiraterone acetate 
or enzalutamide when crossed over to second-line therapy with the opposite 
agent. 
2. To evaluate the time to second PSA progression of combined first and 
second-line therapy (from start of first-line therapy to PSA progression on 
cross-over second-line therapy). 
Secondary 
Objectives 
1. To collect whole blood, serum and plasma to identify potential biomarkers 
that are associated with treatment efficacy and/or resistance in mCRPC 
patients receiving abiraterone acetate and enzalutamide. 
2. To evaluate the PSA response rate in mCRPC patients treated with first-line 
abiraterone acetate or enzalutamide.  
3. To evaluate time to PSA progression with first or second-line abiraterone 
acetate or enzalutamide.    
4. To evaluate duration of second-line therapy and time to clinical progression 
on second-line therapy.  
5. To evaluate cognitive, depressive, and functional effects of abiraterone 
acetate and enzalutamide 
6. To evaluate overall survival in patients treated with sequential abiraterone 
acetate and enzalutamide  
7. To evaluate safety and toxicity profiles of second-line abiraterone acetate or 
enzalutamide. 
Study Population 
Patients with metastatic castration-resistant prostate cancer  
Study Design 
Randomized phase II with 1:1 randomization to either Arm A or Arm B (see Figure 
1):  
Arm A:  Patients will receive abiraterone acetate 1000 mg PO OD with prednisone 5 
mg PO BID or 10 mg OD as per standard of care. At time of PSA progression (see 
Section 5.5), patients will receive enzalutamide 160 mg PO daily until clinical 
progression as per standard of care. 
Arm B: Patients will receive enzalutamide 160 mg PO OD as per standard of care. At 
time of PSA progression (see Section 5.5) patients will receive abiraterone acetate 
1000 mg PO OD with prednisone 5 mg PO BID or 10 mg OD until clinical 
progression as per standard of care. 
Inclusion Criteria 
Patients must meet ALL of the following criteria: 
1. Willing and able to provide informed consent 
2. Adult males ≥ 18 years age 
3. History of adenocarcinoma of the prostate diagnosed histologically without 
evidence of neuroendocrine or small cell differentiation, or if patient does not 
have pathology of adenocarcinoma of the prostate, patient has metastatic 
disease typical of prostate cancer (i.e., involving bone or pelvic lymph nodes 
or para-aortic lymph nodes) AND a serum concentration of PSA that is rising 
and >20ng/mL at the time of when the patient was clinically diagnosed with 
prostate cancer. 
4. Prior surgical orchiectomy or if on LHRH agonist/antagonist then 
testosterone < 1.7 nmol/L at screening visit (patients must maintain LHRH 
agonist/antagonist therapy for duration of study treatment if not surgically 
castrated) 

Version 6.0 – July 16, 2018 
3
5. Evidence of metastatic disease on bone scan or CT scan 
6. Evidence of biochemical or imaging progression in the setting of surgical or 
medical castration. Progressive disease for study entry is defined by one of 
the following three criteria:  
a. PSA progression: minimum of two rising PSA values from a baseline 
measurement with an interval of ≥ 1 week between each 
measurement. Minimum PSA at screening visit is > 2.0 ug/L  
b. Soft tissue or visceral disease progression (see Appendix B for 
definition of measurable disease as per RECIST 1.1 criteria) 
c. Bone progression: ≥ 2 new lesions on bone scan 
7. ECOG performance status 0-2 (see Appendix C) 
8. Eligible for treatment with either abiraterone acetate or enzalutamide as per 
standard of care guidelines 
9. Adequate organ function defined as: 
a. Absolute neutrophil count ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L 
and hemoglobin ≥ 80 g/L  
b. Creatinine clearance ≥ 30 ml/min (calculated by Cockcroft-Gault 
formula, see Appendix D) 
c. Serum potassium > than lower limit of normal range 
d. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except for 
patients with known Gilbert’s syndrome (direct bilirubin ≤ 1.5 x 
ULN) 
e. Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤ 5 x ULN 
10. Able to swallow study drug and comply with study requirements including 
provision of peripheral blood samples at specified time points for correlative 
studies  
11. Recovery from all prior treatment-related toxicity to grade ≤ 2 (as per CTC 
AE 4.0) 
Exclusion 
Criteria 
Patients must NOT meet any of the following criteria: 
1. Severe concurrent illness or co-morbid disease that would make the subject 
unsuitable for enrolment 
2. Prior therapy with CYP17 inhibitors (including abiraterone acetate, TAK-
700, TOK-001 and ketoconazole), enzalutamide or other experimental anti-
androgens (e.g. ARN-509, TOK-001) 
3. Prior systemic chemotherapy for mCRPC  
4. Life expectancy < 6 months 
5. Active concurrent malignancy (with the exception of non-melanomatous skin 
cancer) 
6. Wide-field radiotherapy or radioisotopes such as Strontium-89 or Radium-
223 ≤ 28 days prior to starting study drug (limited-field palliative 
radiotherapy for 1-5 fractions is permitted) 
7. Brain metastases or active epidural disease (treated epidural disease is 
permitted)  
8. Use of herbal products that may lower PSA level (e.g. saw palmetto) 
9. Contraindication to prednisone therapy including poorly controlled diabetes 
mellitus 
10. History of seizure or seizure disorder, or history of any cerebrovascular event 

Version 6.0 – July 16, 2018 
4
within 6 months of study entry.  
11. Gastrointestinal disorder affecting absorption 
12. Major surgery within 4 weeks of starting study treatment 
Laboratory and 
imaging 
assessments (see 
Table 1) 
1. Screening visit: CBC, electrolytes, creatinine, random glucose, AST, ALT, 
alkaline phosphatase (ALP), lactate dehydrogenase (LDH), bilirubin, 
gamma-glutamyl transpeptidase (GGT), PSA, testosterone, albumin, bone 
scan, CT chest (or X-Ray chest), CT abdomen and pelvis (CT C/A/P; or CXR 
and CT A/P) 
2. Start of first-line therapy: CBC, electrolytes, creatinine, AST, ALT, ALP, 
LDH, bilirubin, random glucose, GGT, PSA & albumin, correlative studies 
3. On Study: PSA every 28 days, other labs for safety will be performed as per 
standard of care, bone scan and CT A/P + Chest imaging (CT or Chest X-ray 
as was done at baseline) every 12 weeks from cycle 1 (or more frequently as 
clinically indicated), patients on Abiraterone arm are required to have safety 
labs from cycles 1-3 (inclusive) 
4. Start of second-line therapy: CBC, electrolytes, creatinine, random glucose, 
AST, ALT, ALP, LDH, bilirubin, GGT, PSA, albumin, correlative studies, 
bone and CT scans required +/- 4 weeks from cross-over  
5. End of second-line therapy or End of first-line therapy if subject will not 
cross-over to second-line therapy:  CBC, electrolytes, creatinine, AST, ALT, 
ALP, LDH, bilirubin, GGT, PSA, albumin, correlative studies 
Correlative 
studies (see 
Table 1) 
Participation in correlative studies is mandatory for study enrolment. In addition 
to routine laboratory tests, peripheral blood samples will be collected at start of first-
line therapy, start of second-line therapy and end of study treatment (i.e. 
maximum 3 draws per patient). A total of 4 EDTA tubes (6 ml per tube), 1 SST tube 
(5 ml), and 1 PAXgene (2.5mL) will be collected per patient at each time point. If 
subject will not cross-over to second-line therapy, correlative studies are required at 
the end of first-line therapy.  
Primary End 
Points 
1. PSA response rate in subjects with PSA progression on first-line abiraterone 
acetate or enzalutamide when crossed over to second-line therapy with the 
opposite agent. PSA response is defined as ≥ 30% decline in PSA value from 
commencement of second-line therapy confirmed on repeat measurement ≥ 
28 days later.  
Secondary End 
Points 
1. Correlation of serum and plasma biomarker expression with PSA response to 
first-line and second-line abiraterone acetate or enzalutamide 
2. PSA response rates to first-line abiraterone acetate or enzalutamide  
3. Time to PSA progression on first-line and second-line abiraterone acetate or 
enzalutamide 
4. Time on study treatment and time to clinical progression on second-line 
abiraterone acetate or enzalutamide 
5. Overall survival in patients treated with sequential abiraterone acetate and 
enzalutamide 
6. Safety of second-line treatment with abiraterone acetate or enzalutamide 
Duration of 
therapy 
First-line therapy 
Study treatment will continue until ANY of the following occur: 
1. Development of PSA progression, which is defined as:  
a. In patients without a PSA decline: A PSA that is ≥ 25% and ≥ 2 
ug/L above baseline after ≥ 12 weeks of study treatment. 
b. In patients with a PSA decline at any time on first-line therapy: 

Version 6.0 – July 16, 2018 
5
A PSA increase of ≥ 25% and ≥ 2 ug/L above nadir, confirmed by a 
repeat measurement ≥ 28 days later (confirmed rising trend). 
2. Treatment of symptomatic bone metastases with wide-field radiation, as this 
would indicate treatment failure  
3. Unacceptable treatment-related toxicity.  
4. Withdrawal of consent. 
Second-line therapy 
Treatment will continue until ANY of the following occur: 
1. Symptomatic or clinical progression that, in the opinion of the Investigator, 
signifies the subject is no longer benefiting from study treatment. NB: PSA 
progression on second-line therapy will be documented but does not 
mandate cessation of study treatment. 
2. Unacceptable treatment-related toxicity.  
3. Withdrawal of consent. 
Statistical design 
The primary clinical endpoint is the proportion of patients with a PSA response 
defined as a PSA decline ≥ 30% from baseline with second-line therapy. A “pick the 
winner” randomized phase 2, Simon’s Optimal two-stage design will be employed. A 
PSA response rate in either arm of 10% or less would not be of interest for further 
study (null hypothesis). If the PSA response rate for either arm were 30% or greater, 
then this would be considered of interest to further evaluate in larger trials. Using an 
alpha error of 0.1 and a beta error of 0.1, 12 patients per arm will be initially accrued. 
If 2 or more patients respond in either arm, both arms will be expanded to 35 
evaluable patients. Accounting for a 10% drop-out/non-evaluable rate, approximately 
78 evaluable patients (39 per arm) will be required to meet the statistical end points to 
address this objective.   
 
The other primary endpoint of this study is time to second PSA progression, 
calculated from time of start of first-line therapy to time of PSA progression on cross-
over second-line therapy. Accrual will continue to a total of 200 patients (100 per 
arm). The probability is 70 percent that the study will detect a treatment sequence 
difference at a two sided 0.05 significance level, if the true hazard ratio is 1.519. This 
is based on the assumption that the accrual period will be 18 months, the follow up 
period will be 18 months and a median time to PSA progression of 12 months (null 
hypothesis). The total number of events will be 140. 

Version 6.0 – July 16, 2018 
6
 
 
 
FIGURE 1: STUDY DESIGN 
 
 
R 
A 
N 
D 
O 
M 
I S 
E   
A BIRA T E RO N E +  
P RE D N IS O N E   
E N Z A L U T A M ID E    
P S 
A   
P 
R 
O 
G 
R 
E 
S S 
I O 
N   
n =  100 
n =  100 
ARM  A   
A R M B  
CRO S S -O V E R  T O   
E N Z A L U T A M ID E    
CRO S S -O V E R  T O   
A BIRA T E RO N E +  
P RE D N IS O N E   
A R M B  
ARM  A   
CO N T IN U E U N T IL   
CL IN ICA L   
P RO G RE S S IO N   
CO N T IN U E U N T IL   
CL IN ICA L   
P RO G RE S S IO N   
MANDA T OR Y   
C O R R ELA TI V E  
S TU D I ES   
1 ST  L IN E   T H E RA P Y   
2 ND  L IN E   T H E RA P Y   

Version 6.0 – July 16, 2018 
7
TABLE 1: STUDY ASSESSMENTS 
 
 
 
FIRST-LINE THERAPY 
SECOND-LINE THERAPY 
 
 
 
Study Day 
Screening 
Visit 
 
C1 
C2 - C4a 
Subseque
nt Cycles 
q 
 
C1b  
C2 - 4a   
Subsequent 
Cycles 
End of 
second-line 
therapyp 
Follow-
Up  
 
Timeline 
Day -28 to 
Day -1r 
Day 1 
(Baseline) 
Day 1 of every 
cycle 
Day 1 of 
cycle 
Day 1 
(Baseline) 
Day 1 of every 
cycle 
Day 1 of 
cycle 
Last dose 
 
Window (days) 
 
 
± 5 days 
± 5 days 
- 5 dayss 
± 5 days 
± 5 days 
± 5 days 
 
Protocol Section 
8.1 
8.2.1 
8.2.2 
8.2.3 
8.3.1 
8.3.2 
8.3.3 
8.4 
 
Informed consent 
× 
 
 
 
 
 
 
 
 
Medical history & 
demographics 
× 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
× 
×c 
 
 
 
 
 
 
 
Randomisation  
 
× 
 
 
 
 
 
 
 
Vital signs 
× 
×c 
× 
 
× 
× 
 
× 
 
Physical examination 
× 
×c 
× 
 
× 
× 
 
× 
 
PHQ-9 Questionnairem 
× 
× c 
× 
x 
× 
× 
x 
× 
 
FACT-P Questionnairen 
× 
× c 
x 
x 
× 
× 
x 
× 
 
Montreal Cognitive 
Assessmentou 
× 
 
Cycle 4 visit 
only 
 
×l 
Cycle 4 visit 
only 
 
×u 
 
ECOG 
× 
×c 
× 
 
× 
× 
 
× 
 
AEs (of interest & Grade 
≥ 3 only)d 
 
× 
× 
x 
× 
× 
x 
× 
 
Concomitant medications 
× 
× 
× 
x 
× 
× 
x 
× 
 
Clinical labse 
× 
×ch 
×  
Safety labs for 
subjects on 
Abirateroneh 
 
×h 
× 
Safety labs for 
subjects on 
Abirateroneh 
 
× 
 
PSAf 
× 
×c 
x 
x 
× 
× 
x 
× 
 
Correlative studiesg 
 
× 
 
 
× 
 
 
 
× 
 
CT chest (or X-Ray chest) 
and CT abdomen/pelvis 
×i 
 
Every 12 (+/- 1) 
weeksj 
Every 12 
(+/- 1) 
weeksj 
×t 
Every 12 (+/- 
1) weeksj 
Every 12 (+/- 
1) weeksj 
 
 
Whole body bone scan 
×i 
 
Every 12 (+/- 1) 
weeksj 
Every 12 
(+/- 1) 
weeksj 
×t 
Every 12 (+/- 
1) weeksj 
Every 12 (+/- 
1) weeksj 
 
 
Study drug treatment 
 
× 
× 
x 
× 
× 
x 
 
 
Overall survivalk 
 
 
 
 
 
 
 
 
× 

Version 6.0 – July 16, 2018 
8
 
aStudy visits for cycles 2-4 (inclusive) on first-line therapy will be every 4 weeks  from commencement of study medication.   
bCross-over from first-line therapy to second-line therapy is mandatory when PSA progression occurs. Patients who cease first-
line therapy due to PSA progression will immediately commence second-line therapy. Please refer to Section 11.1 for instructions on 
initiation of second-line therapy in patients who cease first-line therapy in the absence of PSA progression.  
cIf cycle 1, day 1 occurs within 7 days of screening visit, the following assessments can be omitted: Inclusion/exclusion criteria, vital 
signs, physical examination, ECOG, clinical labs, PSA, questionnaires. However, correlative studies must be performed at 
commencement of first-line therapy.  
dSee Appendix A for AEs of interest  
eSee Section 8.1 to 8.4 Bilirubin, AST and ALT can be performed as per standard of care. 
fPSA must be performed every 4 weeks while subjects are on study (even if on treatment break due to toxicity or recovery 
from radiation). Wherever possible, PSA testing should be performed at the same laboratory throughout the study.  
gMandatory correlative studies at start of first-line therapy, start of second-line therapy and end of second-line therapy. 
Mandatory correlative studies are required at the end of first-line therapy if subject will not cross-over to second-line therapy.  
hElectrolytes, Bilirubin, AST and ALT as per standard of care on D15 of cycles 1, 2, and 3 for patients on abiraterone acetate + 
prednisone  
iStandard of care CT and bone scans performed within 6 weeks of commencing first-line therapy can be used even if done prior to 
consent being signed  
jCT and bone scan are required at a minimum of every 12 weeks from cycle 1 (+/- 1 week) or more frequently at Investigator 
discretion. Patients without pulmonary or mediastinal metastatic disease on screening CT or Chest X-ray are permitted to have CT 
abdomen/pelvis only on follow-up scans.  
kAfter discontinuation of second-line therapy or first-line therapy if subject does not cross over to second-line therapy, survival data 
will be collected every 12 weeks.  
l A baseline cognitive assessment will be undertaken prior to initiation of second line therapy. 
m PHQ-9 depression assessments will be completed at screening, at the beginning of cycles 1- 4 and subsequent cycles, and at the end 
of second-line therapy or end of first-line therapy if subject will not be crossing over to second-line therapy. Not required after July 1, 
2018 
nFACT-P questionnaire will be completed at screening, at the beginning of cycles 1 – 4 and subsequent cycles, and at the end of the 
second-line therapy or end of first-line therapy if subject will not be crossing over to second-line therapy. Not required after July 1, 
2018.  
o Use alternate versions of assessment if done within 3 months or less from previous one.  Not required after July 1, 2018 
p Complete End of second-line therapy visit if subject will not be crossing over to second-line therapy.  
q All subsequent cycle visits will be as per standard of care (however, PSA must be performed every 4 weeks).  
r First-line therapy, Cycle 1/ Day 1 (Baseline) visit may be completed on the same day as Screening visit if feasible however, subject’s 
eligibility will need to be confirmed prior to correlatives sample collection, randomization, and study drug treatment.  
s Second –line therapy Cycle 1 assessments can be completed up to 5 days prior to commencing second-line therapy.  
t CT and bone scans are required +/- 4 weeks from cross-over. 

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u MoCA is required to be completed at end of therapy only if it is before the Cycle 4 visit (i.e. patient discontinues therapy before 
Cycle 4). Not required after July 1, 2018 

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10
2.0  
BACKGROUND AND RATIONALE 
2.1  
PROSTATE CANCER 
Prostate cancer is the most common cancer among men and the third most common cause of 
cancer deaths in males in the developed world17. Although the majority of men with metastatic 
prostate cancer initially respond to androgen deprivation therapy, development of castration-
resistant disease is inevitable. Until recently, docetaxel remained the only available systemic 
agent proven to prolong overall survival in mCRPC18. In the past three years however, five novel 
agents including abiraterone acetate1, enzalutamide3, cabazitaxel19, radium-223 dichloride20 and 
sipuleucel-T21 have demonstrated a significant overall survival benefit in phase III trials in 
mCRPC. Although the development of these agents has greatly expanded the therapeutic 
armamentarium for mCRPC, it has also led to questions about optimal sequencing of systemic 
therapy.  
2.2  
ABIRATERONE ACETATE AND ENZALUTAMIDE 
It is now well established that the androgen receptor (AR) pathway remains active in CRPC22 
and this knowledge has provided a rationale for developing novel hormonal compounds such as 
abiraterone acetate and enzalutamide. Abiraterone is a potent, selective and irreversible inhibitor 
of CYP17, a cytochrome P450 (CYP) enzyme centrally involved in extra-gonadal androgen 
biosynthesis23. Enzalutamide is a potent AR antagonist that remains active in the setting of 
increased AR expression and has been shown to inhibit nuclear translocation and peptide co-
activator recruitment of the ligand-receptor complex24. Importantly, both agents have 
demonstrated efficacy in mCRPC irrespective of prior chemotherapy use (see Section 3.2). In 
post-docetaxel mCRPC patients, abiraterone plus prednisone significantly improved median 
overall survival by 4.6 months over prednisone monotherapy (COU-AA-301 trial)1 while 
enzalutamide significantly increased median overall survival by 4.8 months compared to placebo 
(AFFIRM trial)3. In chemotherapy-naïve mCRPC patients, abiraterone plus prednisone was 
shown to significantly improve radiological progression-free survival (PFS) compared with 
prednisone in the COU-AA-302 trial2. As radiological PFS was a co-primary endpoint of the 
COU-AA-302 trial, this study was terminated prior to statistical significance being met for a 
difference in overall survival. Nevertheless, treatment with abiraterone plus prednisone resulted 
in longer median overall in comparison to prednisone alone (HR 0.75). Enzalutamide also has 
activity in chemotherapy-naïve mCRPC, with recent results released from the PREVAIL study 
demonstrating a significant increase in median overall survival for enzalutamide over placebo 
(HR 0.70)4.  
 
Thus, both abiraterone acetate and enzalutamide have proven and comparable activity in 
mCRPC. Despite their efficacy however, an unresolved question regarding the use of abiraterone 
acetate and enzalutamide is the best sequence in which these agents should be used. While both 
agents target androgen-AR signaling, their mechanisms of action differ and theoretically 
disparate mechanisms of resistance may allow for successful sequencing of these agents. Prior 
studies have reported PSA response rates (PSA decline ≥ 50% from baseline) of under 10% in 
patients treated with abiraterone after enzalutamide5,6 and 13%-29% in patients treated with 
enzalutamide after abiraterone7,8. These data were generated in small, retrospective series, 
highlighting the need for a randomized clinical trial to examine the activity of second-line 
abiraterone and enzalutamide after treatment with the opposite agent. 

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11
2.3 
RESISTANCE MECHANISMS TO ABIRATERONE ACETATE AND 
ENZALUTAMIDE  
Despite their proven activity in mCRPC, resistance to abiraterone acetate and enzalutamide 
ultimately occurs in all patients. Various mechanisms have been identified as being associated 
with resistance to these agents, mainly from pre-clinical studies. Among these mechanisms is 
induction of AR splice variants, increased expression of CYP17, a novel mutation (F876L) of the 
ligand-binding domain (LBD) of the AR and increased expression of a stress-activated 
chaperone protein (clusterin).  
 
AR splice variants are truncated AR isoforms which, despite lacking a C-terminal LBD, enhance 
the transcription of AR-regulated genes in a ligand-independent manner25. The transcriptional 
activity of splice variants results from the fact that the N-terminal domain contains AF1, the 
principal transactivation domain of the AR26. Pre-clinical studies indicate that induction of AR 
splice variants accompanies resistance to both abiraterone9,27 and enzalutamide9,10,28. Resistance 
to abiraterone has also been linked to increased expression of its primary target, CYP17, in pre-
clinical models27,29 and a solitary clinical study29. Resistance to enzalutamide in prostate cancer 
cells has been associated with a novel point mutation in the AR LBD (F876L), which produces a 
conformational change that leads to enzalutamide aberrantly behaving as an AR agonist rather 
than as an antagonist13,30. Lastly, a recent pre-clinical report identified upregulation of the PI3K 
and MAPK signaling pathways by the stress-activated chaperone protein clusterin as a novel 
resistance mechanism to enzalutamide11. Collectively, these predominantly pre-clinical data 
indicate that multiple mechanisms may contribute to resistance of mCRPC to abiraterone and 
enzalutamide. This in turn highlights the importance of further examining resistance to 
abiraterone and enzalutamide in patient-derived clinical samples.  
2.4  
CIRCULATING CELL-FREE TUMOUR DNA  
A major obstacle to examining molecular markers in mCRPC is the ability to readily access 
metastatic tumour tissue from bone or intra-abdominal lymph nodes. As a consequence, 
capturing circulating cell-free tumor DNA from plasma represents a highly attractive approach 
for molecular characterisation of mCRPC. Importantly, it has previously been shown that cell-
free tumour DNA is present in plasma from patients with mCRPC and its amount and copy 
number profile can be modulated by therapeutic interventions31,32. Our group has preliminary 
data suggesting that most enzalutamide-resistant mCRPC patients and some abiraterone-resistant 
mCRPC patients possess focal AR amplification in cell-free tumour DNA extracted from 
plasma. Further evaluation of biomarkers in cell-free tumour DNA and correlation of treatment 
outcome with abiraterone acetate and enzalutamide may uncover novel molecular factors 
associated with treatment efficacy and resistance.    
 
2.5  
COGNITIVE EFFECTS OF ABIRATERONE ACETATE AND ENZALUTAMIDE  
The cognitive effects of abiraterone and enzalutamide are not well described. Enzalutamide is 
known to cross the blood-brain barrier and infrequently causes seizures, possibly related to 
effects on the γ-aminobutyric acid–gated chloride channel15. In the enzalutamide registration 
study, a small subset (< 5%) of patients also developed mental impairment disorders including 
amnesia, memory impairment, cognitive disorder and disturbance in attention16. Conversely, no 

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12
central nervous system effects of abiraterone have been reported. Cognitive testing will therefore 
be undertaken in this study to evaluate potential differences between these agents. 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION 
Abiraterone acetate and enzalutamide will be purchased from commercial supply and provided 
though the BC Cancer Agency. Abiraterone acetate and enzalutamide are both approved by 
Health Canada for treatment of mCRPC. Please refer to product monograph for full details. The 
following information is for summary purposes only.   
3.1 
PHARMACOLOGY 
Abiraterone acetate is converted in vivo to abiraterone, which is an irreversible inhibitor of the 
enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This enzyme is upregulated in CRPC tissue 
and is required for extra-gonadal androgen biosynthesis in the adrenal gland and within prostate 
cancer tissue. CYP17 catalyses the conversion of pregnenolone and progesterone into the 
testosterone precursors, DHEA and androstenedione, respectively.  
Enzalutamide is an AR antagonist that has more than 10 times the affinity for the AR when 
compared to bicalutamide. Unlike bicalutamide it also inhibits nuclear co-localisation of the AR 
and peptide co-activator recruitment. 

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13
 
3.2 
CLINICAL EFFICACY DATA 
 
TABLE 2: EFFICACY OF ABIRATERONE ACETATE (AA) AND ENZALUTAMIDE IN RANDOMIZED PHASE III 
STUDIES IN mCRPC PATIENTS 
 
Study 
Population 
Treatment 
PSA RRa 
Time to PSA 
progression 
(median, months) 
Radiological PFSb 
(median, months) 
Overall survival 
(median, months) 
COU-AA-
30133 
Post-
docetaxel 
AA + prednisone (n=797) 
vs. prednisone (n=398) 
30% vs. 6% 
p<0·0001 
8.5 vs. 6.6 
HR 0.63, p<0·0001 
5.6 vs. 3.6 
HR 0.66, p<0·0001 
15.8 vs. 11.2 
HR 0.74, p<0·0001 
COU-AA-
3022 
Docetaxel-
naïve 
AA + prednisone (n=546) 
vs. prednisone (n=542) 
62% vs. 24% 
p<0.001 
11.1 vs. 5.6 
HR 0.49, p<0·001 
16.5 vs. 8.3 
HR 0.53, p<0·001 
NR vs. 27.2 
HR 0.75, p=0.01c 
AFFIRM3 
Post-
docetaxel 
Enzalutamide (n=800) vs. 
placebo (n=399) 
54% vs. 2% 
p<0.001 
8.3 vs. 3.0 
HR 0.25, p<0·001 
8.3 vs. 2.9 
HR 0.40, p<0·001 
18.4 vs. 13.6 
HR 0.63, p<0·001 
PREVAILd 
Docetaxel-
naive 
Enzalutamide vs. placebo 
NR 
NR 
NR vs. 3.9 
HR 0.19, p<0.0001 
32.4 vs. 30.2 
HR 0.70, p<0.0001 
 
a PSA RR (response rate): PSA decline ≥ 50% 
b PFS: Progression-free survival  
c Not significant 
d Unpublished data 
NR: Not reported 

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14
3.3 
CLINICIAL TOXICITY DATA 
3.3.1 Abiraterone acetate + prednisone  
ORGAN SITE 
SIDE EFFECTS 
Cardiovascular 
Hypertension (9%, severe < 1%) 
Atrial fibrillation (4%, severe 1%) 
Cardiac failure (2%, severe < 1%) 
Angina (1%, severe < 1%) 
Gastrointestinal 
Diarrhoea (18%, severe < 1%) 
Dyspepsia (6%) 
General 
Fatigue (39%) 
Peripheral oedema (28%, severe < 1%) 
Hot flashes (19%) 
Fracture (6%, severe 1%) 
Laboratory 
ALT, increased (12%, severe 5%) 
AST, increased (11%, severe 3%) 
Hypokalaemia (17%, severe 2%) 
Musculoskeletal Bone pain (20%) 
Renal 
Urinary symptoms (7%) 
 
 
3.3.2 Enzalutamide 
ORGAN SITE 
SIDE EFFECTS 
Cardiovascular 
Hypertension (6%, severe 2%) 
Myocardial infarction (2%, severe < 1%) 
Gastrointestinal 
Diarrhoea (21%, severe 1%) 
General 
Fatigue (34-51%, severe 6%) 
Hot flashes (20%) 
Peripheral oedema (15%) 
Headache (12%, severe 1%) 
Fracture (4%) 
Laboratory 
ALT increased (10%, severe < 1%) 
AST increased (23%, severe < 1%) 
Musculoskeletal Musculoskeletal pain (14%, severe 1%) 
Neurological 
Seizure (< 1%) 
Renal 
Urinary symptoms (7%) 
 
Clinically significant side effects of interest are in bold.  
 

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15
4.0  
STUDY OBJECTIVES 
4.1 
PRIMARY OBJECTIVES 
i. 
To evaluate the PSA response rate (defined as a ≥ 30% decline in PSA from baseline 
confirmed on repeat measurement ≥ 28 days later) in mCRPC patients with PSA 
progression on first-line therapy with abiraterone acetate or enzalutamide when crossed 
over to second-line therapy with the opposite agent. 
ii. 
To evaluate the time to second PSA progression of combined first and second-line therapy (from 
start of first-line therapy to PSA progression on cross-over second-line therapy). 
4.2 
SECONDARY OBJECTIVES 
i. 
To collect whole blood, serum and plasma to potentially identify biomarkers that are 
associated with treatment efficacy and/or resistance in mCRPC patients receiving 
abiraterone acetate and enzalutamide. 
ii. 
To evaluate the PSA response rate in mCRPC patients treated with first-line abiraterone 
acetate or enzalutamide.  
iii. 
To evaluate time to PSA progression with first or second-line abiraterone acetate or 
enzalutamide.    
iv. 
To evaluate duration of second-line therapy and time to clinical progression on second-
line therapy.  
v. 
To evaluate cognitive, depressive, and functional effects of abiraterone acetate and 
enzalutamide 
vi. 
To evaluate overall survival in patients treated with sequential abiraterone acetate and 
enzalutamide.  
vii. 
To evaluate safety and toxicity profiles of second-line abiraterone acetate or 
enzalutamide. 
 
5.0 
STUDY DESIGN AND ENDPOINTS 
5.1 
DESCRIPTION OF STUDY DESIGN 
This is a multi-centre, randomized phase II study of sequencing abiraterone acetate and 
enzalutamide in patients with mCRPC. Subjects will be allocated to either Arm A (first-line 
abiraterone acetate plus prednisone followed by second-line enzalutamide) or Arm B (first-line 
enzalutamide followed by second-line abiraterone acetate plus prednisone). Total accrual of 200 
subject is planned, 100 per arm.   
5.2 
SCREENING PHASE  
Patients must sign an Informed Consent Form before any study-related procedures can 
commence. Eligibility for enrollment will be determined on the basis of Inclusion and Exclusion 
Criteria as outlined in Sections 6.2 and 6.3 respectively. A list of procedures to be undertaken at 
screening is summarized in Table 1 and Section 8.1.  

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16
5.3 
RANDOMIZATION AND TREATMENT ALLOCATION 
After completing screening procedures and determining eligibility for trial enrollment, subjects 
will be randomized 1:1 to either Arm A or Arm B as outlined in Section 12.2. 
5.4 
FIRST-LINE THERAPY 
5.4.1 Cycle 1  
Subjects will commence cycle 1 on first-line therapy within 5 days of randomization. A list of 
study-related procedures (including mandatory correlative studies) required at commencement 
of cycle 1 on first-line therapy is summarized in Table 1 and outlined in Section 8.2.1. Subjects 
randomized to Arm A will receive abiraterone acetate 1000 mg PO daily plus prednisone 5 mg 
PO BID or 10 mg OD as per standard of care. Subjects randomized to Arm B will receive 
enzalutamide 160 mg PO OD as per standard of care. 
5.4.2 Cycle 2 and subsequent cycles 
Treatment will be organized into 28-day cycles. A list of study-related procedures required for 
cycle 2 and subsequent cycles on first-line therapy is summarized in Table 1 and outlined in 
Sections 8.2.2 and 8.2.3.  
5.5 
CROSS-OVER FROM FIRST-LINE TO SECOND-LINE THERAPY 
Cross-over from first-line to second-line therapy is mandated when subjects develop PSA 
progression. Other reasons for discontinuation of first-line therapy are outlined in Section 11.1. 
For the purposes of determining time of cross-over to second-line therapy, PSA progression is 
defined as: 
i. 
In patients without a PSA decline: A PSA that is ≥ 25% and ≥ 2 ug/L above baseline 
after ≥ 12 weeks of study treatment. 
ii. 
In patients with a PSA decline at any time on first-line therapy: A PSA increase of ≥ 
25% and ≥ 2 ug/L above nadir, confirmed by a repeat measurement ≥ 28 days later 
(confirmed rising trend). 
Patients who cease first-line therapy due to PSA progression will immediately commence 
second-line therapy. Please refer to Section 11.1 for instructions on initiation of second-line 
therapy in patients who cease first-line therapy in the absence of PSA progression. If subject will 
not be crossing over to second-line therapy, subject will still be required to complete end of 
second-line therapy visit.  
5.6 
SECOND-LINE THERAPY 
5.6.1 Cycle 1 
Patients randomized to Arm A will cease abiraterone acetate and commence enzalutamide 160 
mg PO OD. It is recommended that subjects be weaned off prednisone when ceasing abiraterone 
acetate although Investigators have the option of continuing prednisone. A suggested weaning 
programme would be to administer prednisone 5mg PO daily for 2 weeks, reduce to 2.5 mg PO 
daily for 2 weeks and then to cease. Patients randomized to Arm B will cease enzalutamide and 
commence abiraterone acetate 1000 mg PO OD plus prednisone 5 mg PO BID or 10 mg PO OD. 

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17
A list of study-related procedures (including mandatory correlative studies) at commencement 
of cycle 1 on second-line therapy is summarized in Table 1 and outlined in Section 8.3.1. 
5.6.2 Cycle 2 and subsequent cycles 
Treatment will be organized into cycles of 28 days. A list of study-related procedures required 
for cycle 2 and subsequent cycles on second-line therapy is summarized in Table 1 and outlined 
in Sections 8.3.2 and 8.3.3. 
5.7 
END OF SECOND-LINE THERAPY  
Second-line therapy will be continued until the Investigator deems a subject is no longer 
benefitting from treatment. NB: PSA progression on second-line therapy will be documented 
but does not mandate cessation of study treatment. Other reasons for discontinuing second-
line therapy are outlined in Section 11.2. A list of study-related procedures (including 
mandatory correlative studies) is summarized in Table 1 and outlined in Section 8.4.   
 
6.0 
STUDY POPULATION 
6.1 
PATIENT POPULATION 
Patients with metastatic castration-resistant prostate cancer.  
6.2 
INCLUSION CRITERIA 
Patients must meet ALL of the following criteria: 
1. 
Willing and able to provide informed consent 
2. 
Adult males ≥ 18 years age 
3. 
History of adenocarcinoma of the prostate diagnosed histologically without evidence of 
neuroendocrine or small cell differentiation, or if patient does not have pathology of 
adenocarcinoma of the prostate, patient has metastatic disease typical of prostate cancer 
(i.e., involving bone or pelvic lymph nodes or para-aortic lymph nodes) AND a serum 
concentration of PSA that is rising and >20ng/mL at the time of when the patient was 
clinically diagnosed with prostate cancer 
4. 
Prior surgical orchiectomy or if on LHRH agonist/antagonist then testosterone < 1.7 
nmol/L at screening visit (patients must maintain LHRH agonist/antagonist therapy for 
duration of study treatment if not surgically castrated) 
5. 
Evidence of metastatic disease by bone scan or CT scan 
6. 
Evidence of biochemical or imaging progression in the setting of surgical or medical 
castration. Progressive disease for study entry is defined by one of the following three 
criteria:  
a. PSA progression: minimum of two rising PSA values from a baseline 
measurement with an interval of ≥ 1 week between each measurement. Minimum 
PSA at screening visit is > 2.0 ug/L  
b. Soft tissue or visceral disease progression: (see Appendix B for definition of 
measurable disease as per RECIST 1.1 criteria) 

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18
c. Bone progression: ≥ 2 new lesions on bone scan  
7. 
ECOG performance status 0-2 (see Appendix C) 
8. 
Eligible for treatment with either abiraterone acetate or enzalutamide as per standard of 
care guidelines 
9. 
Adequate organ function defined as: 
a. Absolute neutrophil count ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L and 
hemoglobin ≥ 80 g/L  
b. Creatinine clearance ≥ 30 ml/min (calculated by Cockcroft-Gault formula, see 
Appendix D) 
c. Serum potassium > than lower limit of normal range  
d. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients with 
known Gilbert’s syndrome (direct bilirubin ≤ 1.5 x ULN) 
e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x 
ULN 
10. 
Able to swallow study drug and comply with study requirements including provision of 
peripheral blood samples at specified time points for correlative studies  
11. 
Recovery from all prior treatment-related toxicity to grade ≤ 2 (as per CTC AE 4.0) 
6.3 
EXCLUSION CRITERIA 
Patients must NOT meet any of the following criteria: 
1. 
Severe concurrent illness or co-morbid disease that would make the subject unsuitable for 
enrolment 
2. 
Prior therapy with CYP17 inhibitors (including abiraterone acetate, TAK-700, TOK-001 
and ketoconazole), enzalutamide or other experimental anti-androgens (e.g. ARN-509, 
TOK-001) 
3. 
Prior systemic chemotherapy for mCRPC  
4. 
Life expectancy < 6 months 
5. 
Active concurrent malignancy (with the exception of non-melanomatous skin cancer) 
6. 
Wide-field radiotherapy or radioisotopes such as Strontium-89 or Radium-223 ≤ 28 days 
prior to starting study drug (limited-field palliative radiotherapy for 1-5 fractions is 
permitted) 
7. 
Brain metastases or active epidural disease (treated epidural disease is permitted)  
8. 
Use of herbal products that may lower PSA level (e.g. saw palmetto)  
9. 
Contraindication to prednisone therapy including poorly controlled diabetes mellitus 
10. 
History of seizure or seizure disorder, or history of any cerebrovascular event within 6 
months of study entry.  
11. 
Gastrointestinal disorder affecting absorption 
12. 
Major surgery within 4 weeks of starting study treatment 
 

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7.0 
TREATMENT 
7.1 
STUDY TREATMENT  
7.1.1 Dosing 
Arm A:  Patients will receive abiraterone acetate 1000 mg PO OD with prednisone 5 mg PO 
BID or 10 mg OD as per standard of care. At time of PSA progression (see Section 5.5), patients 
will receive enzalutamide 160 mg PO daily until symptomatic or clinical progression that, in the 
opinion of the Investigator, signifies the subject is no longer benefiting from study treatment. 
Arm B: Patients will receive enzalutamide 160 mg PO OD as per standard of care. At time of 
PSA progression (see Section 5.5), patients will receive abiraterone acetate 1000 mg PO OD 
with prednisone 5 mg PO BID or 10 mg OD until symptomatic or clinical progression that, in the 
opinion of the Investigator, signifies the subject is no longer benefiting from study treatment. 
7.1.2 Dose modification 
Dose modification for treatment-related toxicity will be at Investigator discretion as per standard 
of care.   
7.1.3 Compliance 
Formal monitoring of compliance with study treatment will not be performed. Investigators are 
encouraged to reinforce the importance of medication compliance to subjects.  
7.1.4 Treatment duration 
First-line and second-line therapy will be administered until discontinuation as outlined in 
Sections 11.1 and 11.2 respectively. 
7.2 
PRIOR TREATMENT 
Prior therapy with CYP17 inhibitors (including abiraterone acetate, TAK-700, TOK-001 and 
ketoconazole), enzalutamide or other experimental anti-androgens (e.g. ARN-509, TOK-001) is 
not permitted. Patients previously treated with chemotherapy for mCRPC (including but not 
limited to docetaxel, cabazitaxel and mitoxantrone) will not be recruited to this study. 
7.3 
PROHIBITED CONCOMITANT TREATMENT 
The following treatments are not permitted at any time while on study drugs: 
• Anti-androgens (bicalutamide, flutamide, nilutamide) 
• 5-α reductase inhibitors (finasteride, dutasteride) 
• Estrogens 
• Chemotherapy 
• Androgens (testosterone, DHEA) 
• Radioisotopes (including but not limited to Strontium-89 and Radium-223) 
• Herbal products that may lower PSA (e.g. saw palmetto) 
• Treatment of symptomatic metastases with radiation is allowed (NB: except for 
wide-field (i.e. hemibody)).  

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20
7.4 
PERMITTED CONCOMITANT MEDICATIONS AND TREATMENT 
• Bisphosphonates or RANKL inhibitors 
• Topical, inhaled or local corticosteroid preparations 
• Supportive care medications including anti-emetics, laxatives, analgesics 
• Radiation to symptomatic bone metastases (except wide-field (i.e. hemibody) is allowed 
at first and second line therapies.  No washout required prior to starting second-line 
therapy).  
8.0 
VISIT SCHEDULE  
8.1 
SCREENING 
After signing the informed consent form, subjects will undergo screening assessments as 
outlined in Table 1 ≤ 28 days prior to commencing study treatment. As part of screening, the 
following assessments will be performed: 
• Medical history including prior anti-neoplastic therapies (surgery, radiation, 
chemotherapy, biological, immunological and other investigational), co-morbid medical 
conditions and concomitant medications (from time of screening visit), and demographics 
(race and ethnicity). 
• Physical examination including vital signs (blood pressure, heart rate, weight, height) 
• Cognitive, depression, and functional assessments 
• ECOG performance status 
• Laboratory tests including CBC, electrolytes, creatinine, random glucose, AST, ALT, 
ALP, LDH, bilirubin, GGT, PSA, testosterone, and albumin  
• Bone scan and CT chest (or X-ray chest) and CT abdomen/pelvis 
8.2 
FIRST-LINE THERAPY 
8.2.1  Cycle 1 (Day 1 – Baseline) 
As outlined in Table 1, the following assessments will be performed at commencement of first-
line therapy: 
• Concomitant medications 
• Physical examination including vital signs (blood pressure, heart rate, weight) 
• ECOG performance status 
• Depression and functional assessments (not required after July 1, 2018) 
• Adverse events (those of interest (see Appendix A) and Grade ≥ 3 only) 
• Laboratory tests including CBC, electrolytes, creatinine, AST, ALT, ALP, LDH, 
bilirubin, random glucose, GGT, PSA, and albumin  
• Correlative studies including processing and shipping (see Section 14.2 & 14.3) 
• Electrolytes, bilirubin, AST and ALT on Day 15 for subjects on abiraterone acetate + 
prednisone. 

Version 6.0 – July 16, 2018 
21
8.2.2  Cycles 2 - 4 
Study visits will be scheduled for every 4 weeks from commencement of study medication.  As 
outlined in Table 1, the following assessments will be performed: 
• Concomitant medications 
• Physical examination including vital signs (blood pressure, heart rate) 
• ECOG performance status 
• Cognitive testing at cycle 4 visit only (not required after July 1, 2018) 
• Depression and functional assessments at the beginning of every cycle (not required after 
July 1, 2018) 
• Adverse events (those of interest (see Appendix A) and Grade ≥ 3 only) (reporting not 
required after July 1, 2018) 
• PSA every 4 weeks; other labs for safety will also be performed as per standard of care 
• Electrolytes, bilirubin, AST and ALT on Day 15 of cycles 2 and 3 for patients on 
abiraterone acetate + prednisone. 
• Bone scan and CT abdomen/pelvis + chest imaging (CT or Chest X-ray as was done at 
baseline). Imaging is required every 12 weeks from Cycle 1.  
 
8.2.3 Subsequent Cycles  
Study visits following Cycle 4 will be as per standard of care.  As outlined in Table 1, the 
following will be measured: 
• Depression and functional assessment at the beginning of each subsequent cycle’s visit  
(not required after July 1, 2018) 
• Adverse events (those of interest (see Appendix A) and Grade ≥ 3 only) (reporting not 
required after July 1, 2018) 
• Concomitant medications 
• PSA every 4 weeks must be performed; other labs for safety will be performed as per 
standard of care. 
• Bone scan and CT abdomen/pelvis + chest imaging (CT or Chest X-ray as was done at 
baseline). Imaging is required every 12 weeks from Cycle 1. 
 
8.3 
SECOND-LINE THERAPY 
8.3.1 Cycle 1 (Day 1 – Baseline) 
Treatment with first-line therapy will be continued until any of the criteria outlined in Section 
11.1 are met. Patients on Arm A (abiraterone plus prednisone) will be weaned off prednisone at 
discretion of Investigator (please see Section 5.6.1).  

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22
Patients who cease first-line therapy due to PSA progression will immediately commence 
second-line therapy. Please refer to Section 11.1 for instructions on initiation of second-line 
therapy in patients who cease first-line therapy in the absence of PSA progression.  
At commencement of second-line therapy, subjects will undergo the following assessments (see 
Table 1): 
• Concomitant medications 
• Physical examination including vital signs (blood pressure, heart rate, weight) 
• Cognitive, functional, and depression assessments (not required after July 1, 2018) 
• ECOG performance status 
• Adverse events (those of interest (see Appendix A) and Grade ≥ 3 only) (reporting not 
required after July 1, 2018) 
• Laboratory tests including CBC, electrolytes, creatinine, random glucose, AST, ALT, 
ALP, LDH, bilirubin, GGT, PSA & albumin . 
• Correlative studies including processing and shipping (see Section 14.2 & 14.3) 
• Electrolytes, bilirubin, AST and ALT on D15 for subjects on abiraterone acetate + 
prednisone. 
• CT and bone scans required +/- 4 weeks from cross-over. 
8.3.2 Cycle 2 - 4  
Study visits will be scheduled for every 4 weeks from commencement of second-line study 
medication.  Study visits will be scheduled every 4 weeks. As outlined in Table 1, the following 
assessments will be performed: 
• Concomitant medications 
• Physical examination including vital signs (blood pressure, heart rate) 
• ECOG performance status 
• Cognitive testing at cycle 4 visit only (not required after July 1, 2018) 
• Depression and functional assessments at the beginning of every cycle (not required after 
July 1, 2018) 
• Adverse events (those of interest (see Appendix A) and Grade ≥ 3 only) (reporting not 
required after July 1, 2018) 
• PSA every 4 weeks; other labs for safety will also be performed as per standard of care  
• Electrolytes, bilirubin, AST and ALT on Day 15 of cycles 2 and 3 for patients on 
abiraterone acetate + prednisone. 
• Bone scan and CT abdomen/pelvis + chest imaging ((CT or Chest X-ray as was done at 
baseline). Imaging is required every 12 weeks from Cycle 1. 
 
8.3.3 Subsequent Cycles  
Study visits following Cycle 4 will be at the beginning of every cycle.  As outlined in as outlined 
in Table 1, the following will be measured: 

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• Depression and functional assessments at the beginning of every cycle (not required after 
July 1, 2018) 
• Adverse events (those of interest (see Appendix A) and Grade ≥ 3 only) (reporting not 
required after July 1, 2018) 
• Concomitant medications 
• PSA every 4 weeks; other labs for safety will be performed as per standard of care  
• Bone scan and CT abdomen/pelvis +chest imaging (CT or Chest X-ray as was done at 
baseline). Imaging is required every 12 weeks from Cycle 1. 
8.4 
END OF SECOND-LINE THERAPY 
Treatment with second-line therapy will be continued until any of the criteria outlined in Section 
11.2 are met. Subjects who will not cross-over to second-line therapy from first-line therapy, is 
also required to complete this study visit and the following assessments will be performed (see 
Table 1): 
• Concomitant medications 
• Physical examination including vital signs (blood pressure, heart rate, weight) 
• ECOG performance status 
• Depression and functional assessments (not required after July 1, 2018) 
• Cognitive assessment is required only if end of therapy visit is before Cycle 4 visit (i.e. 
patient discontinues therapy before Cycle 4).  Otherwise not required at the end of 
therapy visit. Not required after July 1, 2018. 
• Adverse events (those of interest (see Appendix A) and Grade ≥ 3 only) (reporting not 
required after July 1, 2018) 
• Laboratory tests including CBC, electrolytes, creatinine, AST, ALT, ALP, LDH, 
bilirubin, GGT, PSA & albumin. 
• Correlative studies including processing and shipping (see Section 14.2 & 14.3) 
9.0 
ASSESSMENTS 
9.1 
EFFICACY 
PSA measurements will be performed as outlined in Table 1 and Section 8.1-8.4. The following 
definitions will be employed: 
9.1.1 PSA response 
A ≥ 30% decline in PSA from baseline confirmed on repeat measurement ≥ 28 days later. 
9.1.2 PSA progression 
Patients without a PSA decline: A PSA that is ≥ 25% and ≥ 2 ug/L above baseline after ≥ 12 
weeks of study treatment. 
Patients with a PSA decline: A PSA increase of ≥ 25% and ≥ 2 ug/L above nadir, confirmed by 
a repeat measurement ≥ 28 days later (confirmed rising trend). 

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9.1.3 Radiological Tumour Assessments 
Visceral/soft tissue disease: Tumour assessments in patients with measurable disease will be 
based on RECIST criteria version 1.1 (see Appendix B). 
Bone disease: Progression on bone scan will be defined as the appearance of ≥ 2 new lesions 
with a confirmatory scan performed 6 or more weeks later that shows a minimum of 2 or more 
additional new lesions. 
9.2 
COGNITIVE, DEPRESSION, AND FUNCTIONAL TESTING 
Cognitive testing will be conducted via the Montreal Cognitive Assessment (MoCA), a validated 
screening tool for cognitive impairment (see Appendix E)34.  This test will be administered by 
study staff at screening, at cycle 4 on first-line treatment, prior to initiation of second line 
treatment and at cycle 4 on second-line treatment. If patient’s end of therapy visit is before the 
Cycle 4 visit, then MoCA is required to be completed. Alternate versions of assessment should 
be used if done within 3 months or less from previous assessment.   
 
The Patient Health Questionnaire-9 (PHQ-9) is a validated, self-administered depression-rating 
tool35 (see Appendix F).  It will be administered to patients at as outlined on Table 1. 
 
Functional Assessment of Chronic Illness Therapy is a validated tool to evaluate quality of life of 
patients with prostate cancer36 (see Appendix G).  This assessment will be self-administered at as 
outlined on Table 1.  
 
All questionnaires and assessments will only record subject’s unique study code and initials in 
place of the fields for personal identifying information. 
 
After July 1, 2018, subjects will not be required to perform the MoCA, PHQ-9 and FACT-P. 
9.3 
SAFETY AND TOLERABILITY  
Safety will be monitored by assessing physical examination, vital signs, ECOG performance 
status (see Appendix C), laboratory evaluations and adverse events (refer to Sections 10.1 & 
10.2). 
9.4 
CORRELATIVE STUDIES 
Please refer to Sections 14.2 & 14.3. 
 
10.0 SAFETY MONITORING AND REPORTING 
10.1 
ADVERSE EVENTS 
10.1.1 Definition and reporting 
Adverse events will use the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE). This study will utilize the CTCAE Version 
4.0 for adverse event reporting. All appropriate treatment areas should have access to a copy of 
the CTCAE Version 4.0. As the adverse event profiles for abiraterone acetate and enzalutamide 
are well characterized and these are approved medications, only adverse events of interest (see 

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Appendix A) and Grade ≥ 3 adverse events will be collected for this study on case report 
forms. Adverse events will no longer be required for case report forms after July 1, 2018.  
10.2 
SERIOUS ADVERSE EVENTS 
10.2.1 Definition and reporting 
Serious adverse events (SAE) will be captured following commencement of therapy.  A serious 
adverse event is any adverse event that at any dose: 
• results in death 
• is life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care) 
• results in persistent or significant disability or incapacity is a congenital anomaly/birth 
defect 
All serious adverse events must be reported as follows: 
Within 24 hours: 
Report event by email to:  
 
safetyreporting@bccancer.bc.ca  
 
Within 7 days: 
Email completed Serious Adverse Event Form to: 
 
safetyreporting@bccancer.bc.ca 
(signed by the investigator and updated as much as possible) 
 
All Serious Adverse Event Forms will be reviewed by Dr. Chi.   
 
11.0 CRITERIA FOR TREATMENT DISCONTINUATION 
11.1 
FIRST-LINE THERAPY 
Study treatment will continue until ANY of the following occur: 
i. 
Development of PSA progression, which is defined as:  
a. In patients without a PSA decline: A PSA that is ≥ 25% and ≥ 2 ug/L above 
baseline after ≥ 12 weeks of study treatment. 
b. In patients with a PSA decline at any time on first-line therapy: A PSA 
increase of ≥ 25% and ≥ 2 ug/L above nadir, confirmed by a repeat measurement 
≥ 28 days later (confirmed rising trend). 
ii. 
Treatment of symptomatic bone metastases with wide-field radiation, as this would 
indicate treatment failure. Cross-over to second-line therapy will be permitted once ≥ 14 
days have elapsed from completion of radiation and treatment-related toxicity has 
recovered to grade ≤ 2. 

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iii. 
Unacceptable treatment-related toxicity. These patients will be eligible to commence 
second-line therapy once toxicity has recovered to grade ≤ 2. 
iv. 
Withdrawal of consent. 
11.2 
SECOND-LINE THERAPY 
Treatment will continue until ANY of the following occur: 
i. 
Symptomatic or clinical progression that, in the opinion of the Investigator, signifies the 
subject is no longer benefiting from study treatment. NB: PSA progression on second-
line therapy will be documented but does not mandate cessation of study treatment. 
ii. 
Unacceptable treatment-related toxicity. These patients will cease study treatment. 
iii. 
Withdrawal of consent. 
11.3 
POST-PROTOCOL THERAPY AND FOLLOW-UP 
Further treatment, if any, is at the discretion of the Investigator. Follow-up data on overall 
survival will be collected.  
 
 
12.0 STATISTICAL METHODS AND DATA ANALYSIS 
12.1 
STATISTICAL DESIGN 
The primary clinical endpoint is the proportion of patients with a PSA response defined as a PSA 
decline ≥ 30% from baseline with second-line therapy. A “pick the winner” randomized phase 2, 
Simon’s Optimal two-stage design will be employed. A PSA response rate in either arm of 10% 
or less would not be of interest for further study (null hypothesis). If the PSA response rate for 
either arm were 30% or greater, then this would be considered of interest to further evaluate in 
larger trials. Using an alpha error of 0.1 and a beta error of 0.1, 12 patients per arm will be 
initially accrued. If 2 or more patients respond in either arm, both arms will be expanded to 35 
evaluable patients. Accounting for a 10% drop-out/non-evaluable rate, approximately 78 
evaluable patients (39 per arm) will be required to meet the statistical end points of this 
objective.  
 
The other primary endpoint of this study is time to second PSA progression, calculated from time 
of start of first-line therapy to time of PSA progression on cross-over second-line therapy. 
Accrual will continue to a total of 200 patients (100 per arm). The probability is 70 percent that 
the study will detect a treatment difference at a two sided 0.05 significance level, if the true 
hazard ratio is 1.519. This is based on the assumption that the accrual period will be 18 months, 
the follow up period will be 18 months and the median survival is 12 months (null hypothesis). 
The total number of events will be 140. The design is based on the null hypothesis assumption is 
that sequential therapy is of no benefit (median PSA progression-free survival in chemotherapy-
naïve patients approximately 12 months based on the COU-302 trial2), and that a 6-month 
improvement in median time to PSA progression of one treatment sequence over another would 
be a clinically significant benefit. Patients that do not cross over to second-line protocol therapy 
will not be censored and the date of first-line PSA progression used as the date of progression for 
the purposes of this analysis which seeks to evaluate the overall efficacy of planned sequential 
therapy. 

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12.2 
RANDOMIZATION METHOD 
Subjects will be centrally randomized using a random number generator. Patients will be 
assigned at random to Arm A and Arm B in 1:1 ratio, respectively. First-line study treatment 
must begin within 5 working days of randomization.    
12.3 
PRIMARY ENDPOINTS 
The primary end points are: 
i. 
PSA response rate in subjects with PSA progression on first-line abiraterone acetate or 
enzalutamide when crossed over to second-line therapy with the opposite agent. PSA 
response is defined as ≥ 30% decline in PSA value from commencement of second-line 
therapy confirmed on repeat measurement ≥ 28 days later.  
ii. 
To evaluate the time to second PSA progression of combined first and second-line therapy (from 
start of first-line therapy to PSA progression on cross-over second-line therapy). 
12.4 
SECONDARY ENDPOINTS 
The secondary end points are: 
i. 
Correlation of serum and plasma biomarker expression with PSA response to first-line 
and second-line abiraterone acetate or enzalutamide  
ii. 
PSA response rates to first-line abiraterone acetate or enzalutamide  
iii. 
Time to PSA progression on first-line and second-line abiraterone acetate or 
enzalutamide 
iv. 
Time on study treatment and time to clinical progression on second-line abiraterone 
acetate or enzalutamide 
v. 
Change in Montreal Cognitive Assessment score on first-line and second-line abiraterone 
acetate and enzalutamide 
vi. 
Overall survival in patients treated with sequential abiraterone acetate and enzalutamide 
vii. 
Safety of second-line abiraterone acetate or enzalutamide. 
13.0 ETHICAL AND ADMINISTRATIVE PROCEDURES 
13.1 
REGULATORY AND ETHICAL COMPLIANCE 
This study will be conducted in accordance with ICH Harmonized Tripartite Guidelines for 
Good Clinical Practice and with the ethical principles laid down in the Declaration of Helsinki. 
13.2 
RESPONSIBILTIES OF THE INVESTIGATOR AND IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the protocol 
and informed consent have been approved by the IRB/IEC/REB must be given to the sponsor 
before study initiation. Prior to study start, the investigator is required to sign a protocol 
signature page confirming his/her agreement to conduct the study in accordance with these 

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documents and all of the instructions and procedures found in this protocol and to give access to 
all relevant data and records to the sponsor, IRBs/IECs/REBs and regulatory authorities as 
required. 
13.3. INFORMED CONSENT PROCEDURES 
Eligible subjects will only be enrolled on this study after a signed informed consent form has 
been obtained. This information should be recorded in the patient source documents. No 
additional consent form will be provided for correlative studies.  
13.5 
PUBLICATION OF STUDY PROTOCOL AND RESULTS 
The sponsor will post a summary of this study on a publicly accessible database such as 
clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this study will be either submitted for publication and/or posted in a publicly accessible 
database. 
13.6  STUDY DOCUMENTATION, RECORD KEEPNG AND RETENTION  
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. Investigators must retain on file all patient 
records and study files, including but not limited to Case Report Forms, SAE reporting forms, 
patient files, patient exclusion logs, informed consent forms, informed consent log, and all 
correspondence and other documents pertaining to the conduct of the study for a minimum of 2 
years after the trial is discontinued. 
13.7 
CONFIDENTIALITY OF STUDY DOCUMENTS AND PATIENT RECORDS 
All patient data must be kept anonymous with no identifying information being recorded in 
documents submitted to the sponsor. Signed informed consent forms and patient enrollment log 
must be kept strictly confidential to enable patient identification at each participating centre. All 
questionnaires will only record subject’s unique study code and initials in place of the fields for 
personal identifying information. 
 
13.8 
AUDITS AND INSPECTIONS 
In addition to the routine review of case report forms and supporting documents sent to the 
sponsor, site monitoring will be conducted at participating centres in the course of the study as 
part of the overall quality assurance programme. The monitors/auditors will require access to 
patient medical records to verify the data, as well as essential document binders and standard 
operating procedures (including electronic information). 
 
14.0 CORRELATIVE STUDIES 
14.1 
BACKGROUND AND RATIONALE 
Apart from determining optimal sequencing of abiraterone and enzalutamide in mCRPC patients, 
a key issue associated with the use of these agents is identifying circulating biomarkers 
associated with treatment response and resistance. Our group has preliminary data showing that a 

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high proportion of enzalutamide-resistant mCRPC patients and some abiraterone-resistant 
mCRPC patients possess focal AR amplification in cell-free tumour DNA extracted from 
plasma. In pre-clinical studies, other potential mechanisms of resistance to these agents include 
increased expression of AR splice variants (abiraterone and enzalutamide)9,10, increased 
expression of CYP17 (abiraterone)6,9, upregulation of the stress-activated chaperone protein 
clusterin (enzalutamide only)11 and a point mutation (F876L) in the ligand-binding domain of the 
AR (enzalutamide only)12,13. Recently, the presence of AR splice variants was linked to primary 
resistance to abiraterone and enzalutamide in mCRPC patients35 supporting further assessment of 
the link between splice variants and treatment outcome with novel hormonal agents. Non-coding 
RNAs (ncRNAs) are additional biomarkers of interest since they are implicated in tumorigenesis 
and are readily detectable in plasma of mCRPC patients14. Examination of these biomarkers in 
serum and plasma is planned, with the aim of identifying novel biomarkers associated with 
treatment efficacy and resistance in mCRPC patients receiving abiraterone and enzalutamide. 
14.2 
SAMPLE COLLECTION 
Peripheral blood samples will be collected at start of first-line therapy, start of second-line 
therapy and end of study treatment (i.e. maximum 3 draws per patient).  Mandatory 
correlative samples are required at the end of first-line therapy if subject will not be crossing 
over to second-line therapy.  A total of 2 Streck tubes (10 ml per tube) for cell-free DNA 
(ctDNA), 1 SST tube (5 ml) for non-coding RNA (ncRNA), and 1 PAXgene  tube (2.5 ml) for 
assessing AR splice variants and other cancer associated mRNA transcripts will be collected per 
patient at each time point. Please refer to laboratory manual for full details of sample processing 
and collection. 
14.3 
SAMPLE PROCESSING AND ANALYSIS 
Please refer to Laboratory Manual.

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15.0  APPENDICES 
15.1  APPENDIX A - ADVERSE EVENTS OF INTEREST 
In addition to grade ≥ 3 adverse events, the following adverse events are considered of interest 
and will be recorded irrespective of grading: 
i. 
Hypertension 
ii. 
Fatigue 
iii. 
Hypokalaemia 
iv. 
Peripheral edema 
v. 
Elevated liver enzyme tests 
vi. 
Seizure 
Any adverse event irrespective of grading leading to treatment interruption, delay, 
discontinuation or dose adjustment must also be documented and reported.  
15.2 
APPENDIX B - RECIST 1.1 CRITERIA  
15.2.1  Criteria for Measurable Disease 
Tumour lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of 10 mm by CT scan. 
Malignant lymph nodes: Must be ≥ 15 mm in short axis when assessed by CT scan. Only the 
short axis will be measured at baseline and followed. 
All other lesions are considered non-target for the purposes of RECIST response.  
15.2.2  Response Criteria for Target Lesions 
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all non-nodal target lesions. In addition, any 
pathological lymph nodes assigned as target lesions must have 
a reduction in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameter of all target 
lesions, taking as reference the baseline sum of diameters. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameter of all measured 
target lesions, taking as reference the smallest sum of diameter 
of all target lesions recorded at or after baseline. In addition to 
the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR or CR nor an 
increase in lesions which would qualify for PD. 
Unknown (UNK) 
Progression has not been documented and one or more target 
lesions have not been assessed or have been assessed using a 
different method than baseline 

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15.2.3  Response Criteria for Non-target Lesions 
Response Criteria 
Evaluation of Non-target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. In addition, all lymph 
nodes assigned as non-target lesions must be non-pathological 
in size (< 10 mm short axis) 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions. 
Stable Disease (SD) 
Neither CR nor PD. 
Unknown (UNK) 
Progression has not been documented and one or more non-
target lesions have not been assessed or have been assessed 
using a different method than baseline. 
 
15.3 
APPENDIX C - ECOG PERFORMANCE STATUS  
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
 
15.4 
APPENDIX D – CREATININE CLEARANCE 
Calculated creatinine clearance (Cockcroft-Gault formula): 
 
 
N x (140-Age) x weight in kg ÷ Serum Creatinine in µmol/L 
 
* For males N=1.23; for females N=1.04 
 
 
 
 
 
 
 
 
 
 

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15.5 
APPENDIX E – MONTREAL COGNITIVE ASSESSMENT TOOL 
 
 Montreal Cognitive Assessment  
(MoCA)  
Administration and Scoring Instructions  
The Montreal Cognitive Assessment (MoCA) was designed as a rapid screening instrument for mild 
cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive 
functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and 
orientation. Time to administer the MoCA is approximately 10 minutes. The total possible score is 30 
points; a score of 26 or above is considered normal.  
 
1. Alternating Trail Making:  
Administration: The examiner instructs the subject: "Please draw a line, going from a 
number to a letter in ascending order. Begin here [point to (1)] and draw a line from 1 then to A 
then to 2 and so on. End here [point to (E)]."  
 
Scoring: Allocate one point if the subject successfully draws the following pattern:  
1 −A- 2- B- 3- C- 4- D- 5- E, without drawing any lines that cross. Any error that is not 
immediately self-corrected earns a score of 0.  
 
2. Visuoconstructional Skills (Cube):  
Administration: The examiner gives the following instructions, pointing to the cube: 
“Copy this drawing as accurately as you can, in the space below”.  
 
Scoring: One point is allocated for a correctly executed drawing.  
• Drawing must be three-dimensional  
• All lines are drawn  
• No line is added  
• Lines are relatively parallel and their length is similar (rectangular prisms 
are accepted)  
A point is not assigned if any of the above-criteria are not met.  
 
3. Visuoconstructional Skills (Clock):  
Administration: Indicate the right third of the space and give the following instructions: 
“Draw a clock. Put in all the numbers and set the time to 10 after 11”.  
 
Scoring: One point is allocated for each of the following three criteria:  
 Contour (1 pt.): the clock face must be a circle with only minor distortion 
acceptable (e.g., slight imperfection on closing the circle);  
 Numbers (1 pt.): all clock numbers must be present with no additional numbers; 
numbers must be in the correct order and placed in the approximate quadrants on 
the clock face; Roman numerals are acceptable; numbers can be placed outside 
the circle contour;  
 Hands (1 pt.): there must be two hands jointly indicating the correct time; the 
hour hand must be clearly shorter than the minute hand; hands must be centred 
within the clock face with their junction close to the clock centre.  
 
A point is not assigned for a given element if any of the above-criteria are not met.  

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4. Naming:  
Administration: Beginning on the left, point to each figure and say: “Tell me the name of 
this animal”.  
 
Scoring: One point each is given for the following responses: (1) camel or dromedary, (2) 
lion, (3) rhinoceros or rhino.  
 
5. Memory:  
Administration: The examiner reads a list of 5 words at a rate of one per second, giving 
the following instructions: “This is a memory test. I am going to read a list of words that you 
will have to remember now and later on. Listen carefully. When I am through, tell me as 
many words as you can remember. It doesn’t matter in what order you say them”. Mark a 
check in the allocated space for each word the subject produces on this first trial. When the 
subject indicates that (s)he has finished (has recalled all words), or can recall no more words, read 
the list a second time with the following instructions: “I am going to read the same list for a 
second time. Try to remember and tell me as many words as you can, including words you said 
the first time.” Put a check in the allocated space for each word the subject recalls after the 
second trial.  
At the end of the second trial, inform the subject that (s)he will be asked to recall these words 
again by saying, “I will ask you to recall those words again at the end of the test.”  
 
Scoring: No points are given for Trials One and Two.  
 
6. Attention:  
Forward Digit Span: Administration: Give the following instruction: “I am going to say 
some numbers and when I am through, repeat them to me exactly as I said them”. Read the five 
number sequence at a rate of one digit per second.  
Backward Digit Span: Administration: Give the following instruction: “Now I am going 
to say some more numbers, but when I am through you must repeat them to me in the backwards 
order.” Read the three number sequence at a rate of one digit per second.  
 
Scoring: Allocate one point for each sequence correctly repeated, (N.B.: the correct 
response for the backwards trial is 2-4-7).  
 
Vigilance: Administration: The examiner reads the list of letters at a rate of one per 
second, after giving the following instruction: “I am going to read a sequence of letters. Every 
time I say the letter A, tap your hand once. If I say a different letter, do not tap your hand”.  
 
Scoring: Give one point if there is zero to one errors (an error is a tap on a wrong letter or 
a failure to tap on letter A).  

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Serial 7s: Administration: The examiner gives the following instruction: “Now, I will ask 
you to count by subtracting seven from 100, and then, keep subtracting seven from your answer 
until I tell you to stop.” Give this instruction twice if necessary.  
 
Scoring: This item is scored out of 3 points. Give no (0) points for no correct 
subtractions, 1 point for one correction subtraction, 2 points for two-to-three correct subtractions, 
and 3 points if the participant successfully makes four or five correct subtractions. Count each 
correct subtraction of 7 beginning at 100. Each subtraction is evaluated independently; that is, if 
the participant responds with an incorrect number but continues to correctly subtract 7 from it, 
give a point for each correct subtraction. For example, a participant may respond “92 – 85 – 78 – 
71 – 64” where the “92” is incorrect, but all subsequent numbers are subtracted correctly. This is 
one error and the item would be given a score of 3.  
 
7. Sentence repetition:  
Administration: The examiner gives the following instructions: “I am going to read you a 
sentence. Repeat it after me, exactly as I say it [pause]: I only know that John is the one to help 
today.” Following the response, say: “Now I am going to read you another sentence. Repeat it 
after me, exactly as I say it [pause]: The cat always hid under the couch when dogs were in the 
room.”  
 
Scoring: Allocate 1 point for each sentence correctly repeated. Repetition must be exact. 
Be alert for errors that are omissions (e.g., omitting "only", "always") and substitutions/additions 
(e.g., "John is the one who helped today;" substituting "hides" for "hid", altering plurals, etc.).  
 
8. Verbal fluency:  
Administration: The examiner gives the following instruction: “Tell me as many words as 
you can think of that begin with a certain letter of the alphabet that I will tell you in a moment. 
You can say any kind of word you want, except for proper nouns (like Bob or Boston), numbers, 
or words that begin with the same sound but have a different suffix, for example, love, lover, 
loving. I will tell you to stop after one minute. Are you ready? [Pause] Now, tell me as many 
words as you can think of that begin with the letter F. [time for 60 sec]. Stop.”  
 
Scoring: Allocate one point if the subject generates 11 words or more in 60 sec. Record 
the subject’s response in the bottom or side margins.  
 
9. Abstraction:  
Administration: The examiner asks the subject to explain what each pair of words has in 
common, starting with the example: “Tell me how an orange and a banana are alike”. If the 
subject answers in a concrete manner, then say only one additional time: “Tell me another way in 
which those items are alike”. If the subject does not give the appropriate response (fruit), say, 
“Yes, and they are also both fruit.” Do not give any additional instructions or clarification.  
After the practice trial, say: “Now, tell me how a train and a bicycle are alike”. Following 
the response, administer the second trial, saying: “Now tell me how a ruler and a watch are alike”. 
Do not give any additional instructions or prompts.  

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Scoring: Only the last two item pairs are scored. Give 1 point to each item pair correctly 
answered. The following responses are acceptable:  
Train-bicycle = means of transportation, means of travelling, you take trips in both;  
Ruler-watch = measuring instruments, used to measure.  
The following responses are not acceptable: Train-bicycle = they have wheels; Ruler-watch = 
they have numbers.  
 
10. Delayed recall:  
Administration: The examiner gives the following instruction: “I read some words to you 
earlier, which I asked you to remember. Tell me as many of those words as you can remember. 
Make a check mark () for each of the words correctly recalled spontaneously without any cues, 
in the allocated space.  
 
Scoring: Allocate 1 point for each word recalled freely without any cues.  
 
Optional:  
Following the delayed free recall trial, prompt the subject with the semantic category cue 
provided below for any word not recalled. Make a check mark () in the allocated space if the 
subject remembered the word with the help of a category or multiple-choice cue. Prompt all non-
recalled words in this manner. If the subject does not recall the word after the category cue, give 
him/her a multiple choice trial, using the following example instruction, “Which of the following 
words do you think it was, NOSE, FACE, or HAND?”  
Use the following category and/or multiple-choice cues for each word, when appropriate:  
FACE: category cue: part of the body multiple choice: nose, face, hand  
VELVET: category cue: type of fabric multiple choice: denim, cotton, velvet  
CHURCH: category cue: type of building multiple choice: church, school, hospital  
DAISY: category cue: type of flower multiple choice: rose, daisy, tulip  
RED: category cue: a colour multiple choice: red, blue, green  
Scoring: No points are allocated for words recalled with a cue. A cue is used for clinical 
information purposes only and can give the test interpreter additional information about the type 
of memory disorder. For memory deficits due to retrieval failures, performance can be improved 
with a cue. For memory deficits due to encoding failures, performance does not improve with a 
cue.  
 
11. Orientation:  
Administration: The examiner gives the following instructions: “Tell me the date today”. 
If the subject does not give a complete answer, then prompt accordingly by saying: “Tell me the 
[year, month, exact date, and day of the week].” Then say: “Now, tell me the name of this place, 
and which city it is in.”  
 
Scoring: Give one point for each item correctly answered. The subject must tell the exact 
date and the exact place (name of hospital, clinic, office). No points are allocated if subject makes 
an error of one day for the day and date.  
 
 
TOTAL SCORE: Sum all subscores listed on the right-hand side. Add one point for an individual who 
has 12 years or fewer of formal education, for a possible maximum of 30 points. A final total score of 26 
and above is considered normal. 
 
MoCA Version November 12, 2004 © Z. Nasreddine MD 
www.mocatest.org  

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15.6  APPENDIX F – PATIENT HEALTH QUESTIONNAIRE  
 
PHQ-9 Patient Depression Questionnaire 
 
For initial diagnosis: 
1. Patient completes PHQ-9 Quick Depression Assessment. 
2. If there are at least 4 s in the shaded section (including Questions #1 and #2), consider a depressive 
disorder. Add score to determine severity. 
 
Consider Major Depressive Disorder 
- if there are at least 5 s in the shaded section (one of which corresponds to Question #1 or #2) 
 
Consider Other Depressive Disorder 
- if there are 2-4 s in the shaded section (one of which corresponds to Question #1 or #2) 
 
Note: Since the questionnaire relies on patient self-report, all responses should be verified by the clinician, and a 
definitive diagnosis is made on clinical grounds taking into account how well the patient understood the 
questionnaire, as well as other relevant information from the patient. 
Diagnoses of Major Depressive Disorder or Other Depressive Disorder also require impairment of social, 
occupational, or other important areas of functioning (Question #10) and ruling out normal bereavement, a history of 
a Manic Episode (Bipolar Disorder), and a physical disorder, medication, or other drug as the biological cause of the 
depressive symptoms. 
 
To monitor severity over time for newly diagnosed patients or patients in current treatment for 
depression: 
 
1. Patients may complete questionnaires at baseline and at regular intervals (eg, every 2 weeks) at home and bring 
them in at their next appointment for scoring or they may complete the questionnaire during each scheduled 
appointment. 
2. Add up √s by column. For every √: Several days = 1 More than half the days = 2 Nearly every day = 3 
3. Add together column scores to get a TOTAL score. 
4. Refer to the accompanying PHQ-9 Scoring Box to interpret the TOTAL score. 
5. Results may be included in patient files to assist you in setting up a treatment goal, determining degree of 
response, as well as guiding treatment intervention. 
 
Scoring: add up all checked boxes on PHQ-9 
 
For every √ Not at all = 0; Several days = 1; 
More than half the days = 2; Nearly every day = 3 
 
Interpretation of Total Score 
 
Total Score 
Depression Severity 
1-4 
Minimal depression 
5-9 
Mild depression 
10-14 
Moderate depression 
15-19 
Moderately severe depression 
20-27 
Severe depression 
 
PHQ9 Copyright © Pfizer Inc. All rights reserved. Reproduced with permission. PRIME-MD ® is a 
trademark of Pfizer Inc. 
A2662B 10-04-2005 
 

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15.7  APPENDIX G – FACT-P QUESTIONNAIRE 
 

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