Novel Hormonal Therapies (NHTs) for the Treatment of Metastatic Castration-sensitive Prostate Cancer (mCSPC) in the Medicare Population
Conditions: Prostatic Neoplasms
Sponsor: Pfizer

E nzal uta mi de
C 3 4 3 1 0 4 9 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C OL
A me n d me nt 3 , Versi o n 4 . 0, 0 4 N o ve m ber 2 0 2 4
P FI Z E R C O N FI D E N TI A L
C T 2 4- WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 
Pa ge 1 of 4 0
N O N- I N T E R V E N TI O N A L ( NI) S T U D Y P R O T O C O L
St u d y Inf or m ati o n
Title
N o vel h or m o nal t hera pies ( N H Ts) f or t he 
treat me nt of metastatic castrati o n-se nsiti ve 
pr ostate ca ncer ( m C S P C) i n t he Me dicare 
p o p ulati o n
Pr ot oc ol n u m ber
C 3 4 3 1 0 4 9
Pr ot oc ol versi o n i de ntifier
4 . 0
D ate
0 4 N o ve m ber 2 0 2 4
Acti ve s u bst a nce
A T C: L 0 2 B B 0 4, e nzal uta mi de
Me dici n al pr o d uct
Xta n di ®
(enzal uta mi de )
Rese arc h q uesti o n a n d o bjecti ves
Pri mar y
1.
Descri be treat me nt d urati o n a m o n g
patie nts i nitiati n g first-li ne treat me nt wit h 
N H T (a birater o ne, a pal uta mi de, or 
e nzal uta mi de) f or m C S P C 
E x pl orat or y
1.
 
 
 
 
 
2.
D escri be ti me t o ne xt t hera p y f or patie nts 
i nitiati n g first-li ne treat me nt wit h N H T 
f or m C S P C 
 
 
 
 
 
3.
Descri be a d here nce f or patie nts i nitiati n g 
0 9 0 1 7 7 e 1 a 2 4 0 b 6 3 e\ A p pr o v e d\ A p pr o v e d O n: 2 7- N o v- 2 0 2 4 1 6: 1 7 ( G M T)
C CI
C CI

E nzal uta mi de
C 3 4 3 1 0 4 9 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
A me n d me nt 3 , Versi o n 4 . 0, 0 4 N o ve m ber 2 0 2 4
P FI Z E R C O N FI D E N TI A L
C T 2 4- WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 
Pa ge 2 of 4 0
first-li ne treat me nt wit h N H T f or m C S P C 
 
 
 
 
 
4.
Descri be baseli ne c haracteristics
(i ncl u di n g de m o gra p hics, disease
c haracteristics, pr ostate ca ncer hist or y ,
c o m or bi dities, a n d res o urce use) o verall
f or patie nts i nitiati n g first-li ne treat ment
wit h N H T a n d c o m pare t he m acr oss
treat me nt c o h orts
5.
Descri be ne xt treat me nt recei ve d a m o n g
t he o verall c o h ort of patie nts i nitiati n g
first-li ne treat me nt wit h N H T f or m C S P C
a n d se paratel y f or patie nts wit h first -li ne
treat me nt wit h a birater o ne, a pal uta mide,
or e nzal uta mi de
A ut h or s
 M A
 – Xta n di
NI S Lea d
Pfizer I nc.
6 6 H u ds o n Bl v d E 
Ne w Y or k, N Y 1 0 0 0 1
0 9 0 1 7 7 e 1 a 2 4 0 b 6 3 e\ A p pr o v e d\ A p pr o v e d O n: 2 7- N o v- 2 0 2 4 1 6: 1 7 ( G M T)
C CI
P P D
C CI
P P D

Enzalutamide
C3431049 NON-INTERVENTIONAL STUDY PROTOCOL
Amendment 3, Version 4.0, 04 November 2024
PFIZER CONFIDENTIAL
CT24-WI-GL02-RF02 5.0 Non-Interventional Study Protocol Template For Secondary Data Collection Study 
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This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the event of 
any actual or suspected breach of this obligation, Pfizer must be promptly notified.
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Enzalutamide
C3431049 NON-INTERVENTIONAL STUDY PROTOCOL
Amendment 3, Version 4.0, 04 November 2024
PFIZER CONFIDENTIAL
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Page 4 of 40
1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................4
2. LIST OF ABBREVIATIONS................................................................................................6
3. RESPONSIBLE PARTIES....................................................................................................8
4. AMENDMENTS AND UPDATES.......................................................................................9
5. MILESTONES.....................................................................................................................12
6. RATIONALE AND BACKGROUND................................................................................12
7. RESEARCH QUESTION AND OBJECTIVES .................................................................13
8. RESEARCH METHODS ....................................................................................................14
8.1. Study Design ...........................................................................................................14
8.2. Setting......................................................................................................................15
8.2.1. Inclusion Criteria ........................................................................................15
8.2.2. Exclusion Criteria.......................................................................................16
8.2.3. Inclusion/Exclusion Criteria Detailed Definitions......................................17
8.3. Variables..................................................................................................................22
8.4. Data Sources............................................................................................................24
8.5. Study Size................................................................................................................25
8.6. Data Management ...................................................................................................25
8.7. Data Analysis ..........................................................................................................25
8.8. Quality Control........................................................................................................33
8.9. Limitations of the Research Methods......................................................................33
8.10. Other Aspects ........................................................................................................34
9. PROTECTION OF HUMAN PARTICIPANTS .................................................................35
9.1. Patient Information..................................................................................................35
9.2. Patient Consent........................................................................................................35
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............35
9.4. Ethical Conduct of the Study ..................................................................................35
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................36
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........36
12. REFERENCES ..................................................................................................................37
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Amendment 3, Version 4.0, 04 November 2024
PFIZER CONFIDENTIAL
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13. LIST OF TABLES.............................................................................................................40
14. LIST OF FIGURES ...........................................................................................................40
ANNEX 1.
LIST OF STAND ALONE DOCUMENTS ....................................................40
ANNEX 2.
ADDITIONAL INFORMATION....................................................................40
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Amendment 3, Version 4.0, 04 November 2024
PFIZER CONFIDENTIAL
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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
ADT
Androgen deprivation therapy
AE
Adverse event
ANOVA
Analysis of Variance
CI
Confidence Interval
CMS
Center for Medicare and Medicaid Services
CPT
Current Procedural Terminology 
FDA
Food and Drug Administration
HCPCS 
Healthcare Common Procedure Coding System
HIPAA
Health Insurance Portability and Accountability Act
ICD-10-CM
International Classification of Diseases, Tenth 
Revision, Clinical Modification
ICD-10-PCS
International Classification of Diseases, Tenth 
Revision, Procedure Coding System 
IEC
Independent ethics committee
IRB
Institutional review board
mCSPC
Metastatic castration-sensitive prostate cancer
NDC
National Drug Code
NHT
Novel hormonal therapy
PARP
Poly adenosine diphosphate-ribose polymerase
PDC
Proportion of days covered
PH
Proportional hazard
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C3431049 NON-INTERVENTIONAL STUDY PROTOCOL
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PFIZER CONFIDENTIAL
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Abbreviation
Definition
US
United States
VRDC
Virtual Research Data Center
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C3431049 NON-INTERVENTIONAL STUDY PROTOCOL
Amendment 3, Version 4.0, 04 November 2024
PFIZER CONFIDENTIAL
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3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, Degree(s)
Job Title
Affiliation
Address
Jasmina Ivanova, MA
Senior Director, Value 
& Evidence – Xtandi
NIS Lead
Pfizer, Inc.
66 Hudson Blvd E, New 
York, NY 10001
Matthew Davis, MA
Principal
Medicus Economics, 
LLC
2 Stonehill Ln, Milton, 
MA 02186
Andrew J. Epstein, PhD
Principal
Medicus Economics, 
LLC
2 Stonehill Ln, Milton, 
MA 02186
090177e1a240b63e\Approved\Approved On: 27-Nov-2024 16:17 (GMT)

E nzal uta mi de
C 3 4 3 1 0 4 9 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
A me n d me nt 3 , Versi o n 4 . 0, 0 4 N o ve m ber 2 0 2 4
P FI Z E R C O N FI D E N TI A L
C T 2 4- WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 
Pa ge 9 of 4 0
4. A M E N D M E N T S A N D U P D A T E S
Versi o n 
I de ntifier
D ate
A m e n d me nt 
T y pe(s u bst a nti al 
or a d m i nistr ati ve)
Pr ot oc ol 
Secti o n(s) 
C h a n ge d
S u m m ar y of 
A m e n d me nt(s)
Re as o n
2 . 0
0 4 
A u g ust 
2 0 2 3
S u bsta ntial
Title pa ge
Secti o n 7
Secti o n 8. 7
T he pri ma ry o bjecti ve was 
c ha n ge d fr o m c o m paris o n 
of d urati o n of t hera p y 
bet wee n e nzal uta mi de a n d 
a birater o ne t o a 
descri pti ve a nal ysis of 
d urati o n of t hera p y wit h 
first-li ne n o vel h or m o nal 
t hera p y (N H T ;
a birater o ne, a pal uta mi de, 
or e nzal uta mi de) i n 
metastatic cast rati o n-
se nsiti ve pr ostate ca ncer 
(m C S P C ).
T he pri mar y 
o bjecti ve was 
c ha n ge d t o a 
descri pti ve 
a nal ysis of 
d urati o n of 
t hera p y wit h first-
li ne N H T beca use 
of u ncertai nt y 
a b o ut a de q u ate 
sa m ple size a n d 
a vaila bilit y of 
s ufficie nt f oll o w 
u p f or pr o d uct 
s pecific 
c o m paris o n of 
d urati o n of 
t hera p y. 
2 . 0
0 4 
A u g ust 
2 0 2 3
A d mi nistrati ve
Title pa ge
Title c ha n ge d t o “ N o vel 
h or m o nal t hera pies 
( N H Ts) f or t he treat me nt 
of metastatic castrati o n-
se nsiti ve pr ostate ca ncer 
( m C S P C) i n t he Me dicare 
p o p ulati o n” .
C ha n ge t o reflect 
a me n d me nt t o 
pri mar y 
o bjecti ve .
2. 0
0 4 
A u g ust 
2 0 2 3
A d mi nistrati ve
Secti o n 5
A me n d me nts t o ti meli nes 
t o reflect ne w e x pecte d 
st u d y start a n d ti meli ne.
U p dates t o reflect 
ne w e x pe cte d 
st u d y start a n d 
ti meli ne.
2 . 0
0 4 
A u g ust 
2 0 2 3
A d mi nistrati ve
Secti o n s 8. 1, 8. 2, 
8. 3, 8. 4, 8. 5, a n d 
8. 9
Clarif yi n g t hat t he e n d of 
i n de x i de ntificati o n peri o d 
will be o n 3 1 Dece m ber 
2 0 2 0 or 1 year bef ore e n d 
of data a vaila bilit y.
Clarif yi n g t hat t he e nd of 
data a vaila bilit y at prese nt 
is 3 1 Dece m ber 2 0 2 1.
U p date t o all o w 
use of m ore 
rece nt data if 
a vaila ble (e g, 
data t hr o u g h 
2 0 2 2).
2. 0
0 4 
A u g ust 
2 0 2 3
A d mi nistrati ve
Secti o n 8. 7  
A me n d me nts t o met h o ds 
t o reflect c ha n ges t o 
pri mar y a n d e x pl orat or y 
o bjecti v es.
C ha n ge t o reflect 
a me n d me nts t o 
pri mar y a n d 
e x pl orat or y 
0 9 0 1 7 7 e 1 a 2 4 0 b 6 3 e\ A p pr o v e d\ A p pr o v e d O n: 2 7- N o v- 2 0 2 4 1 6: 1 7 ( G M T)
C CI

Enzalutamide
C3431049 NON-INTERVENTIONAL STUDY PROTOCOL
Amendment 3, Version 4.0, 04 November 2024
PFIZER CONFIDENTIAL
CT24-WI-GL02-RF02 5.0 Non-Interventional Study Protocol Template For Secondary Data Collection Study 
Page 10 of 40
Version 
Identifier
Date
Amendment 
Type(substantial 
or administrative)
Protocol 
Section(s) 
Changed
Summary of 
Amendment(s)
Reason
objectives.
2.0
04 
August 
2023
Administrative
Sections 9.1, 9.2
Updates to language for 
consistency with CT24 
version 5 template for 
non-interventional study 
protocol template for 
secondary data collection 
study effective on 01 
August 2023
Updates to align 
with version 5 of 
protocol template 
that became 
effective since 
initial protocol 
approval
2.0
04 
August 
2023
Administrative
Footnotes
Updated footnotes to 
reflect footnote in CT24 
version 5 template for 
non-interventional study 
protocol template for 
secondary data collection 
study effective on 01 
August 2023
Updates to align 
with version 5 of 
protocol template 
that became 
effective since 
initial protocol 
approval
3.0
05
January 
2024
Administrative
Section 6
Deletion of a comma
Typo correction
3.0
05
January 
2024
Substantial
Sections 8.1, 8.2, 
8.2.1
Updated the start date of 
the index identification 
window to 01 January 
2020
Start date of 
index 
identification 
window updated 
so that 
abiraterone, 
apalutamide, and 
enzalutamide 
were all approved 
for use in mCSPC
3.0
05
January 
2024
Administrative
Sections 8.2 and 
8.4
Updated study period start 
date
Update of the 
potential start 
date of baseline 
period to reflect 
the update to start 
date of index 
identification 
window
3.0
05
January 
2024
Substantial
Section 8.2.2
Noted that patients with 
use of 1st generation 
antiandrogens 90 to 365 
days before index date or 
within 28 days after index 
date will be excluded from 
the analyses
Ensure that 
patients’ index 
NHT treatment is 
first-line 
treatment for 
mCSPC
3.0
05
January 
2024
Administrative
Section 8.2.2
Exclude patients with use
of lutetium Lu 177 
vipivotide tetraxetan prior 
to index date or within 28 
days after index date
Lutetium is only 
approved for use
in mCRPC and its 
use may indicate 
that patients have 
mCRPC. As the 
approval was in 
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E nzal uta mi de
C 3 4 3 1 0 4 9 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
A me n d me nt 3 , Versi o n 4 . 0, 0 4 N o ve m ber 2 0 2 4
P FI Z E R C O N FI D E N TI A L
C T 2 4- WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 
Pa ge 1 1 of 4 0
Versi o n 
I de ntifier
D ate
A m e n d me nt 
T y pe(s u bst a nti al 
or a d m i nistr ati ve)
Pr ot oc ol 
Secti o n(s) 
C h a n ge d
S u m m ar y of 
A m e n d me nt(s)
Re as o n
2 0 2 2, t his c ha n ge 
is n ot e x pecte d t o 
i m pact t he st u d y 
p o p ulati o n.
3. 0
0 5
Ja n uar y 
2 0 2 4
A d mi nistrati ve
Secti o n 8. 2. 3 
Ta ble 2
A d de d a d diti o nal c o des 
w hic h ma y be use d t o 
i de ntif y treat me nts
U p dates f or 
c o m plete ness
3. 0
0 5
Ja n uar y 
2 0 2 4
A d mi nistrati ve
Secti o n 8. 3 Ta ble 
3
U p dates t o baseli ne 
varia bles:
-Clarificati o n of defi niti o n 
of de n o v o m C S P C
-A d de d baseli ne varia ble 
f or l o n g-ter m 
c ortic oster oi d use a n d 
ti me fr o m i nitial pro state 
ca ncer dia g n osis t o 
metastasis
A d de d baseli ne 
varia bles re p orte d 
i n ot her st u dies
4. 0
0 4 
N o ve m
ber 
2 0 2 4
S u bsta ntial
St u d y 
i nf or mati o n title 
pa ge, Secti o n 7
4. 0
0 4 
N o ve m
ber 
2 0 2 4
A d mi nistrati ve
Secti o n 8. 1
Delete d “(at prese nt 3 1 
Dece m ber 2 0 2 1)” 
At t he ti me of 
a nal yses data 
were a vaila ble 
t hr o u g h 2 0 2 2
4. 0
0 4 
N o ve m
b e r
2 0 2 4
S u bsta ntial
Secti o n 8. 3 Ta ble 
3
4. 0
0 4 
N o ve m
ber 
2 0 2 4
S u bsta ntial
Secti o n 8. 4
4. 0
0 4 
N o ve m
ber 
2 0 2 4
S u bsta ntial
Secti o n 8. 7
0 9 0 1 7 7 e 1 a 2 4 0 b 6 3 e\ A p pr o v e d\ A p pr o v e d O n: 2 7- N o v- 2 0 2 4 1 6: 1 7 ( G M T)
C CI
C CI

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C3431049 NON-INTERVENTIONAL STUDY PROTOCOL
Amendment 3, Version 4.0, 04 November 2024
PFIZER CONFIDENTIAL
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Page 12 of 40
5. MILESTONES
Milestone
Planned Date
Start of data collection
10 September 2023
End of data collection
31 December 2024
Final study report
01 June 2025
6. RATIONALE AND BACKGROUND
Prostate cancer is the most common cancer and the second leading cause of cancer death 
among men in the United States (US). The National Cancer Institute estimates 268,490 new 
cases and 34,500 deaths of prostate cancer in 2022.1 While the long-term outlook is positive 
for early-stage prostate cancer, survival rates drastically decrease once the disease has spread 
beyond the prostate gland (ie, becoming metastatic) or when the disease becomes castration-
resistant.2
Metastatic castration-sensitive prostate cancer (mCSPC) is a form of metastatic prostate 
cancer among men who have never received or are sensitive to androgen deprivation therapy 
(ADT).3 The treatment landscape for mCSPC has evolved rapidly in recent years. Upfront 
intensified treatment with either docetaxel or novel hormonal therapy (NHT) added to a 
backbone of ADT has improved survival substantially.4-7 The US Food and Drug 
Administration (FDA) has approved the NHTs abiraterone, apalutamide, enzalutamide, and 
most recently darolutamide in combination with docetaxel for the treatment of mCSPC in 
February 2018, September 2019, December 2019, and August 2022, respectively.
Outside of clinical trials, little real-world evidence exists regarding the amount of time that 
mCSPC patients spend on NHTs prior to discontinuation. The LATITUDE phase III clinical 
trial assessing abiraterone acetate + prednisone in newly diagnosed high-risk mCSPC 
patients found a median treatment duration of 25.8 months, while median treatment duration 
in the TITAN phase III clinical trial for apalutamide in mCSPC patients on ADT was 
39.3 months.9,10 Another phase III study in metastatic hormone-sensitive prostate cancer, 
ARCHES, found a median treatment duration of 40.2 months for enzalutamide plus ADT, 
and that earlier initiation was associated with improved outcomes.6 These trials did not focus 
on directly comparing treatment duration across NHTs and evidence on how this may vary in 
real world applications is needed. In addition to time on treatment, research on real-world 
adherence to NHTs is limited by the fact that most of the published literature focuses on 
metastatic castration-resistant prostate cancer or more broadly on advanced prostate 
cancer.11,12 There are no known studies specifically assessing real-world NHT treatment 
adherence for mCSPC.
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E nzal uta mi de
C 3 4 3 1 0 4 9 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
A me n d me nt 3 , Versi o n 4 . 0, 0 4 N o ve m ber 2 0 2 4
P FI Z E R C O N FI D E N TI A L
C T 2 4- WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 
Pa ge 1 3 of 4 0
Gi ve n t hat 6 0 % of i nci de nt pr ostate ca ncer cases are dia g n ose d i n me n w h o are at least 
6 5 ye ars ol d a n d t hat Me dicare is t he pre d o mi na nt i ns urer a m o n g pe o ple a ge d 6 5 +, Me dicare 
is a ke y pla yer f or pr ostate ca ncer treat me nt .1 3 A m o n g t he m ore t ha n 6 1 milli o n i n di vi d uals 
e nr olle d i n Me dicare i n 2 0 1 9, 6 3 % were e nr olle d i n Ori gi nal Me di care ( w hile 3 7 % were 
e nr olle d i n Me dicare A d va nta ge) acc or di n g t o Ce nter f or Me dicare a n d Me dicai d Ser vices 
(C M S ) statistics.1 4
As t here is a n a bse nce of p u blis he d st u dies o n N H T treat me nt a d here nce f or m C S P C, t his 
st u d y see ks t o fill t hat ga p usi n g a d mi nistrati ve clai ms data fr o m F ee - F or- Ser vice Me dicare.
7. R E S E A R C H Q U E S TI O N A N D O B J E C TI V E S
T he st u d y o bjecti ves are t he f oll o wi n g :
Pri mar y
1.
Descri be treat me nt d urati o n a m o n g patie nts i nitiati n g first -li ne treat me nt wit h N H T 
(a birater o ne, a pal uta mi de, or e nzal utami de) f or m C S P C .
E x pl orat or y
1.
 
 
2.
Descri be ti me t o ne xt t hera p y f or patie nts i nitiati n g first -li ne treat me nt wit h N H T f or 
m C S P C
 
 
3.
Descri be a d here nce f or patie nts i nitiati n g first-li ne treat me nt wit h N H T f or m C S P C 
 
4.
Descri be baseli ne c haracteristics (i ncl u di n g de m o gra p hics, disease c haracteristics, 
pr ostate ca ncer hist or y , c o m or bi dities, a n d res o urce use) o verall f or patie nts i nitiati n g 
first-li ne treat me nt wit h N H T a n d c o m pare t he m acr oss treat me nt c o h orts.
5.
Descri be t he ne xt treat me nt recei ve d a m o n g t he o verall c o h ort of patie nts i nitiati n g 
first-li ne treat me nt wit h N H T f or m C S P C a n d se parately f or patie nts wit h first -li ne 
treat me nt wit h a birater o ne, a pal uta mi de, or e nzal uta mi de.
0 9 0 1 7 7 e 1 a 2 4 0 b 6 3 e\ A p pr o v e d\ A p pr o v e d O n: 2 7- N o v- 2 0 2 4 1 6: 1 7 ( G M T)
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C3431049 NON-INTERVENTIONAL STUDY PROTOCOL
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PFIZER CONFIDENTIAL
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8. RESEARCH METHODS 
8.1. Study Design
This will be a non-interventional cohort study using existing administrative data from 
Original Medicare. Consistent with study objectives, the analytic goals will be to characterize 
treatment duration, time to next therapy, adherence, and next treatment received by drug in 
mCSPC patients initiating first-line NHT treatment. To account for the lack of 
mCSPC-specific ICD-10-CM (International Classification of Diseases, 10th Revision, 
Clinical Modification) codes, a modified version of a previously developed diagnostic 
algorithm for use in claims data will be implemented to identify the patient population of 
interest.15 Patients with ≥8 weeks of continuous ADT use between 90 and 365 days prior to 
the index first-line NHT claim will be excluded from the analyses because they may be 
initiating treatment for mCRPC. Patients’ index date will be assigned based on their first
observed claim for relevant first-line NHTs during the index window (01 January 2020 to 
31 December 2020 (or 1 year prior to end of data availability) and baseline covariates will be 
measured during the 365-day period prior to this date (Figure 1). The study exposure will be 
the NHT prescribed at index date (index NHT) stratified by the therapies of interest 
(abiraterone, enzalutamide, and apalutamide). Outcomes will be measured during a follow-up 
period of at least 6 months (or until death), defined as the time from the index date through
the first of the following events: treatment switch, treatment discontinuation, death, or end of 
data availability. Study analyses will include fitting adjusted and unadjusted statistical
models, with adjustment in the former based on relevant characteristics captured in the 
Medicare data as identified in the empirical literature. 
Figure 1.
Diagram of Study Period
090177e1a240b63e\Approved\Approved On: 27-Nov-2024 16:17 (GMT)

E nzal uta mi de
C 3 4 3 1 0 4 9 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
A me n d me nt 3 , Versi o n 4 . 0, 0 4 N o ve m ber 2 0 2 4
P FI Z E R C O N FI D E N TI A L
C T 2 4- WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 
Pa ge 1 5 of 4 0
8. 2. Setti n g
Patie nts resi di n g i n t he U S will be i de ntifie d a n d a nal yses c o n d ucte d usi n g cla i ms a n d 
e nr oll me nt data c o veri n g t he peri o d fr o m 0 1 J a n uar y 2 0 1 9 t o e n d of data a vaila bilit y (at 
prese nt 3 1 Dece m ber 2 0 2 1 ), wit h t he i de ntificati o n wi n d o w fr o m 0 1 Ja n uar y 2 0 2 0 t o 3 1 
Dece m ber 2 0 2 0 ( or 1 year bef ore t he e n d of data a vaila bilit y). T he start o f t he i de ntificati o n 
wi n d o w was selecte d s o t hat a birater o ne, a pal uta mi de, a n d e nzal uta mi de were all a p pr o ve d 
f or use i n m C S P C. Clai ms data e xte n di n g bac k t o 1 Ja n uar y 2 0 1 6 will be use d t o assess 
i ncl usi o n a n d e xcl usi o n criteria. T he case defi niti o n f or m C S P C will be base d o n t he 
pre vi o usl y refere nce d dia g n ostic al g orit h m (see I ncl usi o n Criteria a n d E xcl usi o n Criteria 
bel o w) wit h rele va nt a da ptati o ns a p plie d w here necessar y  t o ali g n wit h st u d y sc o pe.1 5
8. 2. 1. I ncl usi o n C riteri a
P atie nts m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or i ncl usi o n i n t he 
st u d y, wit h o nl y  i n patie nt h os pitalizati o n, o ut patie nt facilit y, a n d carrier clai ms use d t o 
i de ntif y m C S P C patie nts:
I ncl usi o n criteria:
1.
Male patie nts wit h ≥1 clai m ( 0 1 Ja n uar y 2 0 2 0 t o 3 1 Dece m ber 2 0 2 0 [ or 1 year bef ore 
t he e n d of data a vaila bilit y]) f or a birater o ne, a pal uta mi de, or e nzal uta mi de (earliest is 
t he i n de x date) (Ta ble 1 ). 
2.
≥1 clai m wit h a dia g n osis c o de i n a n y p ositi o n f or pr ostate ca ncer (I C D - 1 0-C M: C 6 1) 
pri or t o t he i n de x date 
3.
≥1 clai m wit h a dia g n osis c o de f or sec o n dar y  metastasis o n or after t he i nitial pr ostate 
ca ncer dia g n osis (I C D-1 0 - C M c o des C 7 7 (e xcl u di n g C 7 7. 5), C 7 8, C 7 9, C 7 B)
4.
I n de x date wit hi n 3 0 da ys pri or t o or a n y ti me after t he first clai m f or metastatic 
disease 
5.
≥1 clai m f or A D T treat me nt i n t he 9 0 da y s pri or t o or wit hi n 3 0 da ys f oll o wi n g t he 
i n de x date (Ta ble 2 )
6.
≥6 5 y ears ol d 1 2 m o nt hs pri or t o t he i n de x date ( baseli ne peri o d) 
7.
C o nti n u o us e nr oll me nt i n Me dicare Parts A, B, a n d D t hr o u g h o ut t he baseli ne peri o d
8.
C o nti n u o us e nr oll me nt i n Me dicare Parts A, B, a n d D f or ≥6 m o nt hs f oll o wi n g t he 
i n de x date ( u nless deat h) (f oll o w-u p peri o d)
0 9 0 1 7 7 e 1 a 2 4 0 b 6 3 e\ A p pr o v e d\ A p pr o v e d O n: 2 7- N o v- 2 0 2 4 1 6: 1 7 ( G M T)
C CI

E nzal uta mi de
C 3 4 3 1 0 4 9 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
A me n d me nt 3 , Versi o n 4 . 0, 0 4 N o ve m ber 2 0 2 4
P FI Z E R C O N FI D E N TI A L
C T 2 4- WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 
Pa ge 1 6 of 4 0
8. 2. 2. E xcl usi o n C riteri a
Patie nt s meeti n g a n y of t he f oll o wi n g criteria will n ot be i ncl u de d i n t he st u d y :
1.
≥1 clai m wit h a dia g n osis c o de f or ot her ca ncers pri or t o or o n t he i n de x date, 
e xcl u di n g n o n-mela n o ma s ki n ca ncer at a n y ti me pri or, a n d mali g na nt ne o plas m 
wi t h o ut s pecificati o n of site a n d mali g na nt ne o plas m of t he b o ne a n d artic ular 
cartila ge bet wee n t he date of metastatic disease a n d t he i n de x date .1 4
2.
C lai ms i n dicati n g ≥8 wee ks of c o nti n u o us A D T use bet wee n 9 0 a n d 3 6 5 da y s pri or t o 
t he i n de x date or clai ms i n dicati n g 1 st ge nerati o n a nti -a n dr o ge n use bet wee n 9 0 a n d 
3 6 5 da y s pri or t o t he i n de x date
3.
E vi de nce of pr ostate ca ncer treat me nt i ncl u di n g c he m ot hera p y, N H T, P A R P 
i n hi bit or, i m m u n ot hera p y, ra di u m- 2 2 3, luteti u m L u 1 7 7 v i pi v oti de tetra xeta n, 
s ur gical castrati o n ( defi ne d as ≥1 bilateral orc hiect o m y  or ≥2 u nilateral 
orc hiect o mies) , or castrati o n resista nce dia g n osis (I C D - 1 0-C M c o de Z 1 9. 2) at a n y  
ti me pri or t o t he i n de x date (Ta ble 2 )
4.
E vi de nce of pr ostate ca ncer treat me nt i ncl u di n g c he m ot hera p y, n o n- i n de x N H T, 1 st
ge nerati o n a nti -a n dr o ge n, P A R P i n hi bit or, i m m u n ot hera p y, ra di u m- 2 2 3, or luteti u m 
L u 1 7 7 v i pi v oti de tetra xeta n wit hi n 2 8 da y s o n/after i n de x date. 
5.
≥1 clai m wit h a c o de i n dicati n g partici pati o n i n a cli nical trial o n or aft er t he i n de x 
date (I C D -1 0- C M: Z 0 0. 6; Healt hcare C o m m o n Pr oce d ure C o di n g S ys te m [H C P C S ]
m o difiers: Q 0, Q 1) 
6.
L ocate d o utsi de t he 5 0 states or Was hi n gt o n, D C d uri n g t he baseli ne a n d f o ll o w- u p 
peri o ds
7.
E nr oll me nt i n Me dicare A d va nta ge ( Me dicare Part C) d uri n g t he baseli ne or 
f oll o w-u p peri o d s
0 9 0 1 7 7 e 1 a 2 4 0 b 6 3 e\ A p pr o v e d\ A p pr o v e d O n: 2 7- N o v- 2 0 2 4 1 6: 1 7 ( G M T)
C CI

Enzalutamide
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8.2.3. Inclusion/Exclusion Criteria Detailed Definitions
Table 1.
NHTs Approved for mCSPC During Index Window
Novel hormonal therapy
National Drug Code (NDC)
Apalutamide
59676060012
Abiraterone
00093112589, 00143959721, 00378692078, 00378692191, 00904694804, 
16714096301, 42291002412, 42292005701, 42292005703, 43598035804, 
47335040181, 51407018112, 57894015012, 57894015512, 57894019506, 
60505432701, 60687045511, 60687045521, 64679002101, 64980041812, 
69238116507, 69238175406, 72205003092, 72606056601
Enzalutamide
00469012599, 00469062599, 00469072560
Table 2.
Other Prostate Cancer Treatments
Hormonal 
therapy
NDC
HCPCS/Current Procedural 
Terminology [CPT]
ADT (LHRH agonists/antagonists)
Goserelin
00310095036, 00310095130, 00310096036, 
00310096130, 70720095036, 70720095130
J9202
Histrelin
54092063775, 55592050001, 67979000201, 
67979050001
J1675, J9225, J9226, S0133, Q2020
Leuprolide
00024022205, 00024059707, 00024059722, 
00024060545, 00024061030, 00024079375, 
00026971101, 00074210803, 00074228203, 
00074244003, 00074334603, 00074347303, 
00074364103, 00074364203, 00074366303, 
00074368303, 00074377903, 00074969403,
00182315499, 00185740014, 00185740085, 
00300210601, 00300210801, 00300227001,
00300228201, 00300243701, 00300244001, 
00300333601, 00300334301, 00300334601, 
00300361224, 00300361228, 00300362624, 
00300362628, 00300362901, 00300362906, 
00300363901, 00300363906, 00300364101, 
00300364201, 00300366301, 00300367301, 
00300368301, 00703401418, 00703401419, 
00703402419, 00781400332, 17314450001, 
41616093640, 47335093640, 49884036826, 
49884036845, 54569271300, 54569454700, 
54569478500, 54569498200, 55390051505, 
62935015350, 62935022104, 62935022205, 
62935022305, 62935030230, 62935030330, 
62935045245, 62935045345, 62935075275, 
62935075375, 62935075474, 64523010001, 
64523010002
C9430, J1950, J1951, J1952, J1954, 
J9217, J9218, J9219, Q0057
Triptorelin
00009521501, 00009521901, 00009766401, 
00023590203, 00023590204, 00023590411, 
00023590412, 00023590622, 00023590623, 
24338015020, 52544009276, 52544015302, 
52544015376, 52544015402, 52544015476, 
C9016, J3315, J3316
090177e1a240b63e\Approved\Approved On: 27-Nov-2024 16:17 (GMT)

Enzalutamide
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Hormonal 
therapy
NDC
HCPCS/Current Procedural 
Terminology [CPT]
52544018876, 52544018976, 74676590200, 
74676590201, 74676590400, 74676590401, 
74676590601
Degarelix
55566830101, 55566830102, 55566830301, 
55566840101, 55566840102, 55566840301
J9155
Relugolix
72974012001
First Generation anti-androgens
Bicalutamide
00093022001, 00093022056, 00310070510, 
00310070530, 00310070539, 00378701705, 
00378701793, 00781540901, 00781540931, 
00781540964, 00904601946, 00904601960, 
16714057101, 16714057102, 16714081601, 
16714081602, 16729002301, 16729002310, 
41616048583, 41616048588, 42291016830, 
42291016850, 47335048583, 47335048588, 
51079069201, 51079069203, 51991056001, 
52152052602, 52152052630, 60429017701, 
60429017705, 60429017730, 60505264201, 
60505264203, 62559068030, 62559089030, 
67253019103, 67253019110, 68084037411, 
68084037421, 68084061211, 68084061221, 
68382022401, 68382022405, 68382022406, 
68382022410
Flutamide
00085052503, 00085052505, 00085052506, 
00093712005, 00093712086, 00172496058, 
00172496070, 00185112505, 00185112518, 
00185112588, 00555087004, 00555087063, 
00591222718, 00591246618, 49884075305, 
49884075313, 54868462800, 58016017000, 
58016017030, 58016017060, 58016017090, 
58016017099, 60429027218, 69097091591
2140244000
Nilutamide
00088111035, 00088111114, 24987011114, 
59212011114, 62559017331, 66993021238
Chemotherapy
NDC
HCPCS
Taxane 
Chemotherapy
Cabazitaxel
00024582411
C9276, J9043
Docetaxel
00069914111, 00069914122, 00069914211, 
00069914222, 00069914411, 00075800120, 
00075800180, 00075800301, 00075800404, 
00143920401, 00143920501, 00409020102, 
00409020110, 00409020120, 00409020125, 
00409020126, 00409020127, 00409036601, 
00409036701, 00409036801, 00703572001, 
00703573001, 00955102001, 00955102104, 
00955102208, 16714046501, 16714050001, 
16729012049, 16729022850, 16729023163, 
16729023164, 16729023165, 16729026763, 
16729026764, 16729026765, 25021022201, 
25021022204, 25021022207, 25021024501, 
J9170, J9171
090177e1a240b63e\Approved\Approved On: 27-Nov-2024 16:17 (GMT)

Enzalutamide
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Hormonal 
therapy
NDC
HCPCS/Current Procedural 
Terminology [CPT]
25021024504, 39822212001, 39822218001, 
39822220001, 42367012121, 42367012125, 
42367012129, 43066000101, 43066000601, 
43066001001, 43598025811, 43598025940, 
43598038957, 43598061040, 43598061111, 
45963073452, 45963073454, 45963073474, 
45963076552, 45963079056, 47335028541, 
47335028641, 47335032340, 47335089540, 
47335093940, 50742046316, 63739093211, 
63739097117, 66758005001, 66758005002, 
66758005003, 66758095002, 66758095003, 
66758095004, 67457053102, 67457053208, 
67457053316, 67457078108, 72485021401, 
72485021504, 72485021608
Other 
Chemotherapy
Carboplatin
00015321030, 00015321130, 00015321176, 
00015321230, 00015321329, 00015321330, 
00015321429, 00015321430, 00015321529, 
00015321530, 00015321630, 00015323011, 
00015323111, 00015323211, 00015323311, 
00409112910, 00409112911, 00409112912, 
00591221911, 00591222011, 00591333626, 
00591333712, 00591333889, 00591345460, 
00591368711, 00703324411, 00703324611, 
00703324811, 00703324911, 00703326401, 
00703326601, 00703326801, 00703326871, 
00703327401, 00703327601, 00703327801, 
00703423901, 00703423981, 00703424401, 
00703424481, 00703424601, 00703424681, 
00703424801, 00703424881, 00703424891, 
10019091201, 10019091202, 10019091203, 
10019091501, 10019091601, 10019091615, 
10019091701, 10139006005, 10139006015, 
10139006045, 10518010110, 10518010111, 
10518010112, 15210006112, 15210006312, 
15210006612, 15210006712, 16729029512, 
16729029531, 16729029533, 16729029534, 
25021020205, 25021020215, 25021020245, 
25021020251, 47335015040, 47335015140, 
47335028440, 47335030040, 47781060320, 
47781060427, 47781060594, 47781060694, 
50111096576, 50111096676, 50111096776, 
50742044505, 50742044615, 50742044745, 
50742044860, 55150033501, 55150038601, 
55390015001, 55390015101, 55390015201, 
55390015301, 55390015401, 55390015501, 
55390015601, 55390022001, 55390022101, 
55390022201, 61703033918, 61703033922, 
61703033950, 61703033956, 61703033961, 
61703033962, 61703033963, 61703036018, 
61703036022, 61703036050, 63323016610, 
J8530, J9070, J9080, J9090, J9091, 
J9092, J9093, J9094, J9095, J9096, 
J9097
090177e1a240b63e\Approved\Approved On: 27-Nov-2024 16:17 (GMT)

Enzalutamide
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Amendment 3, Version 4.0, 04 November 2024
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Hormonal 
therapy
NDC
HCPCS/Current Procedural 
Terminology [CPT]
63323016720, 63323016721, 63323016800, 
63323016905, 63323016915, 63323016945, 
63323017205, 63323017215, 63323017245, 
63323017260, 66758004701, 66758004702, 
66758004703, 66758004704, 67457049154, 
67457049215, 67457049346, 67457049461, 
67457060820, 69448000512, 69448000531, 
69448000533, 69448000534, 69448000538, 
71288010005, 71288010015, 71288010045, 
71288010051
Cisplatin
00003307297, 00015307020, 00015307220, 
00015322022, 00015322026, 00015322122, 
00015322126, 00069008101, 00069008407, 
00143950401, 00143950501, 00703574711, 
00703574811, 10019091001, 10019091002, 
16729028811, 16729028838, 44567050901, 
44567051001, 44567051101, 44567053001, 
47781060925, 47781061023, 49452207801, 
49452207802, 49452207803, 55390009901, 
55390011250, 55390011299, 55390018701, 
55390041450, 55390041499, 63323010351, 
63323010364, 63323010365, 67457042410, 
67457042551, 68001028324, 68001028327, 
68001028332, 68001028333, 70860020650, 
70860020651
J9045
Oxaliplatin
00024059010, 00024059120, 00024059240, 
00024059602, 00024059704, 00069006701, 
00069007001, 00069007201, 00069007401, 
00069101001, 00703398501, 00703398601, 
00781331570, 00781331780, 00781931570, 
00781931780, 00955102720, 00955172510, 
00955172720, 00955173110, 00955173320, 
16714072701, 16714072801, 16729033203, 
16729033205, 25021021120, 25021021250, 
25021023310, 25021023320, 41616017640, 
41616017840, 43066001401, 43066001801, 
45963061153, 45963061159, 45963063749, 
45963063858, 47335004640, 47335004740, 
47335017640, 47335017840, 47781059122, 
47781059229, 51991021898, 51991021998, 
51991092298, 51991092398, 55150033101, 
55150033201, 60505613206, 60505613207, 
60505613208, 61703036318, 61703036322, 
61703036330, 61703036331, 61703036332, 
61703036340, 63323017530, 63323017650, 
63323021110, 63323021220, 63323065010, 
63323065017, 63323065020, 63323065027, 
63323075010, 63323075020, 66758005301, 
66758005302, 67457044220, 67457046910, 
67457047610, 68001034128, 68001034129, 
68001034136, 68001034137, 68001046836, 
68001046837, 70860020110, 70860020120, 
J9263
090177e1a240b63e\Approved\Approved On: 27-Nov-2024 16:17 (GMT)

Enzalutamide
C3431049 NON-INTERVENTIONAL STUDY PROTOCOL
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Hormonal 
therapy
NDC
HCPCS/Current Procedural 
Terminology [CPT]
71288010110, 71288010120, 72266012501, 
72266012510, 72266012601, 72266012610, 
72266016101, 72266016201, 72603010101, 
72603030101
Mitoxantrone 
00205939336, 00205939372, 00703468001, 
00703468091, 00703468501, 00703468591, 
00703468601, 00703468691, 10518010510, 
10518010511, 10518010512, 15210040335, 
44087152001, 44087152501, 44087153001, 
55390008301, 55390008401, 55390008501, 
58406064003, 58406064005, 58406064007, 
61703034318, 61703034365, 61703034366, 
63323013210, 63323013212, 63323013215
J9293
Etoposide
00013733691, 00013734694, 00013735688, 
00013736673, 00015306120, 00015306124, 
00015306220, 00015306224, 00015308420, 
00015309145, 00015309520, 00015309530, 
00015309595, 00015340420, 00074148501, 
00074148502, 00074148503, 00143937601, 
00143951001, 00143951101, 00143951201, 
00186157131, 00364302853, 00378326694, 
00703564301, 00703564601, 00703565301, 
00703565601, 00703565691, 00703565701, 
00703565791, 00703565801, 00703566701, 
00703566801, 10019093001, 10019093002, 
16729011408, 16729011411, 16729011431, 
16729026231, 51079096501, 51079096505, 
53905029101, 55390029101, 55390029201, 
55390029301, 55390049101, 55390049201, 
55390049301, 58406071112, 58406071418, 
61269041020, 63323010405, 63323010425, 
63323010450, 68001026525, 68001026526, 
68001026527
J8560, J9181
Immunotherap
y
NDC
HCPCS
Pembrolizumab
00006302601, 00006302602, 00006302604, 
00006302901, 00006302902
J9271, C9027
Sipuleucel-T
30237890006
Q2043, C9273
Radiotherapy
NDC
HCPCS
Radium-223
50419020801
A9606
Lutetium Lu 177 
Vipivotide 
Tetraxetan
69488001061
A9607
PARP 
Inhibitors
NDC 
HCPCS
Olaparib
00310065758, 00310066812, 00310066860, 
00310067912, 00310067960
Rucaparib
69660020191, 69660020291, 69660020391
Talazoparib
00069029630, 00069119530
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Hormonal 
therapy
NDC
HCPCS/Current Procedural 
Terminology [CPT]
Niraparib
69656010330, 69656010390
Surgical 
Castration
ICD-10 Procedure Coding System (ICD-10-PCS)
CPT Codes
Bilateral 
orchiectomy
0VTC4ZZ, 0VTC0ZZ
54520, 54522, 54530, 54535, 54690
Unilateral 
orchiectomy
0VT90ZZ, 0VT94ZZ, 0VTB0ZZ, 0VTB4ZZ
8.3. Variables
Variables that will be included in this analysis are listed in Table 3, with additional detail 
regarding operational definitions provided where relevant. All variables will be constructed 
from the Medicare enrollment and claims data described in Section 8.4.
Table 3.
Study Variables
Variable
Description
Exposure
Index NHT compound
First NHT (abiraterone, enzalutamide, or apalutamide) used during the index window 
as defined by the presence of a claim containing one of the NDC codes listed in
Table 1.
Follow-up Period Outcomes
Treatment duration
Length of time (in days) that a patient uses NHT treatment. A patient will be 
considered “on treatment” from their initial claim date until the end of observation for 
any of the following reasons (earliest of dates below): 
!
The end of data availability (at present December 31, 2021)
!
The patient’s date of death 
!
The day before a treatment switch
!
The day of treatment discontinuation (a 90-day gap in days supply will be
considered as discontinuation)
!
Alternative definitions of discontinuation (ie, 30-day and 60-day gaps) 
will be explored in sensitivity analyses. 
Discontinuation
An indicator for discontinuation of index treatment during the follow-up period, 
determined by the presence of a gap in treatment coverage of more than 90 days from 
the last day of medication availability (last observed claim + the days’ supply for that 
claim).16 -18 The impact of varying this time period on study results will be explored 
via sensitivity analysis. 
Treatment switch
Defined as the initiation of another prostate cancer treatment not given in 
conjunction with index treatment (Table 2 at any point following the index 
date.
Time to next therapy
Length of time (in days) from a patient’s index date to first observed claim
for another prostate cancer treatment (Table 2).
Adherence
The number of days supplied of an NHT over the total days of follow-up elapsed in a 
given period (eg, 3-month, 6-month, etc.) expressed as a percentage as the proportion 
of days covered (PDC), with the maximum value capped at 100% and overlapping 
prescriptions carried forward.19
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Variable
Description
Follow up for overall survival 
Length of time (in days) from a patient’s index date to date of death or cutoff 
date for mortality data availability.
Overall survival
Length of time (in days) from a patient’s index date to date of death. Patients 
who did not die will be censored as of the cutoff date for mortality data 
availability.
Demographic and socioeconomic characteristics
Age
Age as of index date in years will be calculated based on the beneficiary’s birth date 
and index date. 
Age group
Age group will be a categorical variable for age defined as one of 65–74, 75–84, 85+.
Census region
Census region will be a categorical variable defined by categorizing the beneficiary’s 
state of residence into Census regions (Northeast, South, Midwest, West) from the 
enrollment record covering the index date.
Index year
Index year will be defined as the year of the index date.
Race
Race will be a categorical variable for the beneficiary’s self-reported race/ethnicity 
taking the categories Non-Hispanic White, Black or African-American, Asian/Pacific 
Islander, Hispanic, and Other (including other, American Indian/Alaska Native, and 
unknown race) from the enrollment record covering the index date.
Dual eligibility 
Dual eligibility will be a binary indicator of whether a patient received dual-eligibility 
benefits for both Medicare and Medicaid.
Clinical characteristics
Bone metastasis
Bone metastasis will be identified from inpatient, outpatient and Carrier claims with a 
diagnosis code for bone metastasis: 
ICD-10-CM: C79.51
Brain metastasis
Brain metastasis will be identified from inpatient, outpatient and Carrier claims with a 
diagnosis code for brain metastasis: 
ICD-10-CM: C79.31
Visceral metastasis
Visceral metastasis (including liver, lung, adrenal, peritoneal, and brain metastases) 
will be identified from inpatient, outpatient and Carrier claims with a diagnosis code 
for visceral metastasis:
ICD-10-CM: C78.0x, C78.6x, C78.7x, C79.31, C79.7x
Baseline comorbidity score
Baseline comorbidity score will be a continuous Charlson Comorbidity Index based on 
research by.20 The conditions in this index and their score weights are:
-
Myocardial infarction (1),
-
Congestive heart failure (1),
-
Peripheral vascular disease (1),
-
Cerebrovascular disease (1),
-
Chronic obstructive pulmonary disease (1),
-
Dementia (1),
-
Hemiplegia or paraplegia (2),
-
Diabetes without chronic complication (1),
-
Diabetes with chronic complication (2),
-
Moderate or severe renal disease (2),
-
Mild liver disease (1),
-
Moderate or severe liver disease (3),
-
Peptic ulcer disease (1)
-
Rheumatic disease (1),
-
AIDS/HIV (6).
Long-term corticosteroid use
Binary indicator for having long-term corticosteroid use, including hydrocortisone, 
prednisone, prednisolone, and dexamethasone during the baseline period: 1) treatment 
duration of ≥90 days with a gap of no more than 30 days between consecutive 
pharmacy claims (ie, less than 30 days between the end of the days supply of one 
claim and the start of the next claim) or, 2) at least two corticosteroid procedure claims 
(per Part B data) with at least 90 days apart during the baseline period.
Evidence of de novo mCSPC
Binary indicator for whether the earliest claim with a secondary metastasis diagnosis 
(ICD-10-CM codes C77 (excluding C77.5), C78, C79, C7B) following the initial 
prostate cancer diagnosis (ICD-10-CM: C61) was within 3 months of the initial 
prostate cancer diagnosis. 
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Variable
Description
ADT claim within 90 days prior to index 
date
Binary indicator for the presence of an ADT claim in the 90 days prior to the index 
date.
Time from first prostate cancer diagnosis 
to metastasis
Length of time (in months) from a patient’s initial prostate cancer diagnosis to first 
metastatic diagnosis.
Time from first metastatic diagnosis to 
index date
Length of time (in months) from a patient’s first metastatic diagnosis to the index date.
Time from ADT initiation to index date
Length of time (in months) from a patient’s first ADT claim to the index date. If the 
patient initiated ADT after the index date, the time will be 0.
Time from ADT claim within 90 days 
before or 30 days after index date to 
index date
Length of time (in months) from a patient’s first ADT claim within 90 days before or 
30 days after the index date to the index date. If the patient initiated ADT after the 
index date, the time will be 0. This variable is intended to capture potential delay in 
NHT start relative to ADT potentially due to coverage reasons.
Baseline healthcare resource use
Any inpatient admission
Binary variable representing any record of an inpatient admission during the 365-day 
baseline period.
Any emergency department visit
Binary variable representing any record of an emergency department visit during the 
365-day baseline period.
Number of unique days with an 
outpatient claim
Cumulative number of days where an outpatient claim was submitted during the 
baseline period.
Nursing home category
Nursing home category will be a categorical variable for nursing home residence 
status defined by categorizing a beneficiary’s use of nursing home services during the 
baseline period as none, short-stay only, any long stay.
Total healthcare spending 
Total healthcare spending will be calculated for the baseline period as the total amount 
paid by all parties (Medicare, other payers, patient out-of-pocket).
8.4. Data Sources
The study will use a 100% census of data from the United States federal Medicare program 
on beneficiaries aged 65+ consistently enrolled in Original (also known as traditional or 
fee-for-service) Medicare insurance coverage for hospital (Part A), physician (Part B) and 
pharmacy (Part D) claims. These data are made available by the US Centers for Medicare 
and Medicaid Services (CMS). As of July 2019, there were over 38 million beneficiaries in 
Original Medicare, of whom 28 million qualified for Medicare benefits based on their age 
and were enrolled in Parts A and B and over 25 million had prescription drug coverage 
through Part D.14 Part D coverage started on 01 January 2006, and the study will focus on 
enrollment and claims data from 01 January 2019 through end of data availability (at present 
31 December 2021) but will use claims back to 01 January 2016 to assess medical history 
(eg, first metastatic diagnosis). 
The research-identifiable data files provide a comprehensive and longitudinal picture of 
health care use among individuals aged 65 years and older. The Medicare data contractor 
assigns a unique beneficiary identification number to everyone who receives Medicare 
coverage and uses that number to identify an individual’s records in all Medicare data files. 
This number does not change during a beneficiary’s lifetime and each number is used only 
once.
The enrollment file contains monthly information on beneficiaries’ enrollment in each part of 
Medicare as well as demographic information, residential location (at the 5-digit ZIP Code 
level), and date of death (from Medicare administrative files). 
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Claims data are available for all medical services covered by the program and are organized 
into data files based on the nature and source of the claim. The Inpatient, Outpatient and 
Skilled Nursing Facility files include institutional claims from hospitals for inpatient and 
outpatient services and from nursing homes for short-stay “skilled” admissions. The Carrier 
file includes fee-for-service claims submitted by professional providers, including 
physicians, physician assistants, clinical social workers, nurse practitioners. (Claims for some 
organizational providers, such as free-standing facilities, are also found in the Carrier file. 
Examples include independent clinical laboratories, ambulance providers, free-standing 
ambulatory surgical centers and free-standing radiology centers).  There are separate files for 
claims for durable medical equipment, home health visits and hospice care. 
CMS receives death information from a number of sources. The main sources CMS uses to 
develop its death information are:
!
Medicare claims data from the Medicare Common Working File (CWF)
!
Online date of death edits submitted by family members
!
Benefit information used to administer the Medicare program collected from the 
Railroad Retirement Board (RRB) and the Social Security Administration (SSA)
8.5. Study Size
A previous feasibility assessment using the available 100% Medicare claims data from 
January 2016 through December 2020 identified a sample of approximately 1,600 patients 
meeting the inclusion criteria. This number is expected to increase with the addition of 
Medicare data from 2021.
The impact of restricting the index window to the period when all 3 NHTs of interest were 
approved and available from 01 January 2020 to 31 December 2020 (or 1 year before end of 
data availability) on study results will be additionally assessed in additional sensitivity 
analyses.21
8.6. Data Management 
Pursuant to requirements guiding participation in the CMS Virtual Research Data Center 
(VRDC) Innovator program, Medicus Economics staff will access the Medicare claims and 
enrollment data only through the VRDC. As such, Medicus staff will not directly possess any 
beneficiary-level CMS data, and the only data to be downloaded from the VRDC will be 
summary-level statistics.
All data manipulation and analysis will be conducted on the CMS VRDC environment 
remotely by Medicus staff. Data manipulation and analysis will be conducted using SAS 
software (SAS Institute, Cary, NC) and R Statistical Software (v4.2.2; R Core Team 2023). 
8.7. Data Analysis 
Primary
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1. Describe treatment duration among patients initiating first-line treatment with NHT 
(abiraterone, apalutamide, or enzalutamide) for mCSPC
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E nzal uta mi de
C 3 4 3 1 0 4 9 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
A me n d me nt 3 , Versi o n 4 . 0, 0 4 N o ve m ber 2 0 2 4
P FI Z E R C O N FI D E N TI A L
C T 2 4- WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 
Pa ge 2 7 of 4 0
E x pl orat or y
1.
 
 
2.
Descri be ti me t o ne xt t hera p y f or patie nts i nitiati n g first-li ne treat me nt wit h N H T f or 
m C S P C
 
 
3.
Descri be a d here nce f or patie nts i nitiati n g first-li ne treat me nt wit h N H T f or m C S P C 
 
4.
Descri be baseli ne c haracteristics (i ncl u di n g de m o gra p hics, disease c haracteristics, 
pr ostate ca ncer hist or y , c o m or bi dities, a n d res o urce use) o verall f or patie nts i nitiati n g 
first-li ne treat me nt wit h N H T a n d c o m pare t he m acr oss treat me nt c o h orts
5.
Descri be ne xt treat me nt recei ve d a m o n g t he o verall c o h ort of patie nts i nitiati n g first-
li ne treat me nt wit h N H T f or m C S P C a n d se paratel y  f or patie nts wit h first-li ne 
treat me nt wit h a birater o ne, a pal uta mi de, or e nzal uta mi de
Pri mar y  O bjecti ve
O bjecti ve 1
St u d y  o bjecti ve: D escri be treat me nt d urati o n a m o n g patie nts i nitiati n g first -li ne treat me nt 
wit h N H T (a birater o ne, a pal uta mi de, or e nzal uta mi de) f or m C S P C
T he a nal yt ic dataset f or t his o bjecti ve will be c o nstr ucte d at t he be neficiar y le vel a n d will 
i ncl u de t he e x p os ure of i n de x N H T (a birater o ne, a pal uta mi de, or e nzal uta mi de) as well as 
o utc o mes meas ure d fr o m t he i n de x date t hr o u g h t he first of t he f oll o wi n g e ve nts: treat me nt 
s witc h, treat me nt disc o nti n uati o n, deat h, or e n d of f oll o w u p. 
A nal y ses will i ncl u de:
0 9 0 1 7 7 e 1 a 2 4 0 b 6 3 e\ A p pr o v e d\ A p pr o v e d O n: 2 7- N o v- 2 0 2 4 1 6: 1 7 ( G M T)
C CI
C CI
C CI
C CI

E nzal uta mi de
C 3 4 3 1 0 4 9 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
A me n d me nt 3 , Versi o n 4 . 0, 0 4 N o ve m ber 2 0 2 4
P FI Z E R C O N FI D E N TI A L
C T 2 4- WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 
Pa ge 2 8 of 4 0

C o nstr ucti n g fre q ue nc y  ta bles of reas o n f or N H T treat me nt disc o nti n uati o n/e n d of 
f oll o w u p dis p ositi o n ( disc o nti n uati o n, deat h, treat me nt s witc h, e n d of i n de x wi n d o w) 
o verall. 

Calc ulati n g descri pti ve statistics fr o m Ka pla n -Meier ( K M) c ur ves (e g, n u m ber of 
patie nts wit h e ve nt/ce ns ore d, me dia n, 9 5 % C o nfi de nce I nter val ( CI), a n d i nter q uartile 
ra n ge) f or N H T treat me nt d urati o n a n d c o nstr ucti n g K M c ur ve wit h e n d of t he st u d y 
peri o d as a ce ns ori n g e ve nt .
E x pl orat or y  O bjecti ves
0 9 0 1 7 7 e 1 a 2 4 0 b 6 3 e\ A p pr o v e d\ A p pr o v e d O n: 2 7- N o v- 2 0 2 4 1 6: 1 7 ( G M T)
C CI

E nzal uta mi de
C 3 4 3 1 0 4 9 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
A me n d me nt 3 , Versi o n 4 . 0, 0 4 N o ve m ber 2 0 2 4
P FI Z E R C O N FI D E N TI A L
C T 2 4- WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 
Pa ge 2 9 of 4 0
E x pl orat or y  O bjecti ve 2
St u d y  o bjecti ve: Descri be ti me t o ne xt t hera p y  f or patie nts i nitiati n g first-li ne treat me nt wit h 
N H T f or m C S P C 
 
 
T he a nal yt ic dataset f or t his o bjecti ve will be c o nstr ucte d at t he be neficiar y le vel a n d will 
i ncl u de t he e x p os ure of i n de x N H T c o m p o u n d as well as t he ti me t o ne xt t hera py o utc o me 
meas ure d fr o m t he i n de x date t hr o u g h t he first of t he f oll o wi n g e ve nts: treat me nt s witc h, 
deat h, or e n d of f oll o w u p.
 
 
A nal y ses will i ncl u de:

Calc ulati n g descri pti ve statistics fr o m K M c ur ves (e g, n u m ber of patie nts wit h 
e ve nt/ce ns ore d, me dia n, 9 5 % CI , a n d i nter q uartile ra n ge) f or ti me t o ne xt t hera p y 
o verall 
a n d c o nstr ucti n g K M c ur ves 
 
 
 
 
 
 
E x pl orat or y  O bjecti ve 3
St u d y  o bjecti ve: Descri be a d here nce f or patie nts i nitiati n g first-li ne treat me nt wit h N H T f or 
m C S P C
 
T he a nal yt ic dataset f or t his o bjecti ve will be c o nstr ucte d at t he be neficiar y le vel a n d will 
i ncl u de t he e x p os ure of i n de x N H T (e nzal uta mi de vs a birater o ne a n d e nzal uta mi de vs 
a pal uta mi de) as well as o utc o mes meas ure d fr o m t he i n de x date t hr o u g h t he first of t he 
f oll o wi n g e ve nts: treat me nt s witc h, treat me nt disc o nti n uati o n, deat h, or e n d of f oll o w u p. 
 
 
0 9 0 1 7 7 e 1 a 2 4 0 b 6 3 e\ A p pr o v e d\ A p pr o v e d O n: 2 7- N o v- 2 0 2 4 1 6: 1 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI

E nzal uta mi de
C 3 4 3 1 0 4 9 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
A me n d me nt 3 , Versi o n 4 . 0, 0 4 N o ve m ber 2 0 2 4
P FI Z E R C O N FI D E N TI A L
C T 2 4- WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 
Pa ge 3 0 of 4 0
A nal y ses will i ncl u de:

Calc u lati n g descri pti ve statistics ( mea n, sta n dar d de viati o n, me dia n, a n d i nter q uartile 
ra n ge) f or a d here nce at t hree-m o nt h i nter vals o ver t he first y ear f oll o wi n g t he i n de x 
date o verall
. A vera ge a d here nce o verall
at eac h 
3 -m o n t h i nter val i n t he f oll o w-u p peri o d will be pl otte d t o pr o vi de a vis ual 
re prese ntati o n of tre n ds o ver ti me, wit h t he u n dersta n di n g t hat t he c o m p ositi o n of 
patie nts at eac h ti me p oi nt will be c ha n gi n g d ue t o s witc hi n g, deat h, etc. T he 
distri b uti o n of mea n a d here nce i n t he year f oll o wi n g t he i n de x date will a d diti o nall y  
be e xa mi ne d t o deter mi ne t he ma g nit u de of s ke w a n d k urt osis. T he pr o p orti o n of 
patie nts wit h a d here nce ≥8 0 % will als o be re p orte d.
0 9 0 1 7 7 e 1 a 2 4 0 b 6 3 e\ A p pr o v e d\ A p pr o v e d O n: 2 7- N o v- 2 0 2 4 1 6: 1 7 ( G M T)
C CI
C CI
C CI

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Exploratory Objective 4
Study objective: Describe baseline characteristics (including demographics, disease 
characteristics, prostate cancer history, comorbidities, and resource use) overall for patients 
initiating first-line treatment with NHT and compare them across treatment cohorts.
The analytic dataset for this objective will be constructed at the beneficiary level and include 
demographic, clinical, and resource use characteristics measured during the baseline period. 
Relevant summary measures are detailed below and will be generated for the overall patient 
sample and stratified by initial NHT therapy. 
Analyses will include:
!
Constructing frequency tables of treatment type by initial NHT compound.
!
Calculating descriptive statistics (mean, standard deviation, median, and interquartile 
range for continuous measures; count and proportion for categorical measures) of all 
included characteristics at baseline (a) overall for patients initiating NHTs, and (b) by 
NHT type. Stratified descriptive statistics tables will include statistical tests (Analysis 
of variance [ANOVA] for means, nonparametric tests of equality of medians, and χ2
tests for distributions of categorical variables) for each characteristic of the null 
hypothesis of joint equality across levels of the stratification variable. 
Exploratory Objective 5
Study objective: Describe next treatment received among the overall cohort of patients 
initiating first-line treatment with NHT for mCSPC and separately for patients with first-line 
treatment with abiraterone, apalutamide, or enzalutamide.
The analytic dataset for this objective will be constructed at the beneficiary level and will 
include the exposure of index NHT as well as first subsequent mCSPC treatment identified 
using NDC codes from 1 and 2. Patients that die or reach the end of follow-up without 
initiating a subsequent mCSPC therapy will be separately characterized.
Analyses will include:
!
Constructing frequency tables of next therapy type (eg, hormonal, chemo, other) 
overall and by initial NHT compound.
!
Within initial NHT compound, more granular presentations of next therapy by 
compound will be provided and the distribution of next therapies by treatment type 
will be visualized via stacked bar charts.
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E nzal uta mi de
C 3 4 3 1 0 4 9 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
A me n d me nt 3 , Versi o n 4 . 0, 0 4 N o ve m ber 2 0 2 4
P FI Z E R C O N FI D E N TI A L
C T 2 4- WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 
Pa ge 3 2 of 4 0
0 9 0 1 7 7 e 1 a 2 4 0 b 6 3 e\ A p pr o v e d\ A p pr o v e d O n: 2 7- N o v- 2 0 2 4 1 6: 1 7 ( G M T)
C CI

E nzal uta mi de
C 3 4 3 1 0 4 9 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
A me n d me nt 3 , Versi o n 4 . 0, 0 4 N o ve m ber 2 0 2 4
P FI Z E R C O N FI D E N TI A L
C T 2 4- WI -G L 0 2 -R F 0 2 5 . 0 N o n-I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 
Pa ge 3 3 of 4 0
8. 8. Q u alit y C o ntr ol
T he Me dicare a d mi nistrati ve data c ollecti o n occ urre d i n t he past, a n d access t o t he data will 
be o btai ne d fr o m C M S. N o a d diti o nal i nsi g ht i nt o t he data c ollecti o n pr oce d ures is a vaila ble 
be y o n d t hat w hic h has bee n p u blis he d b y  C M S. As a res ult, Me dic us staff rel y o n q ualit y 
c o ntr ol meas ures i m ple me nte d b y C M S d uri n g data c ollecti o n.
Me dic us has esta blis he d pr ot oc ols f or q ualit y c o ntr ol of a nal ys es. All a nal yses are a u dite d 
bef ore t he fi nalizati o n of res ults. T he a u dit or will i n de pe n de ntl y re vie w t he c o nce pt ual a n d 
tec h nical ele me nts of t he a nalys is a n d see k t o i de ntif y a ny fla ws or p ote ntial err ors.
T he a u dit or will u n dersta n d t he g oal of t he a nal y sis a n d t he e x pecte d res ults, a n d t he n re vie w 
eac h ste p of t he Me dic us data a nal ys is a u dit c h ec klist (a vaila ble u p o n re q uest). T he a u dit or 
will kee p a list of q uesti o ns or iss ues a n d t he n meet wit h t he pr oject lea d t o disc uss a n y  
fi n di n gs. If err ors or iss ues are f o u n d t hat c ha n ge t he res ults, t he a u dit or will perf or m a n 
i ncre me ntal a u dit t o e ns ure t hat c ha n ges ha ve bee n i m ple me nte d pr o perl y a n d a n y c ha n ge i n 
res ults ali g ns wit h e x pectati o ns a b o ut ma g nit u de a n d directi o n.
8. 9. Li mit ati o ns of t he R ese arc h M et h o ds
T here are se veral stre n gt hs t o t he st u d y  descri be d here, w hic h i ncl u de:

Use of t he ce ns us of i n di vi d uals e nr olle d i n Ori gi nal Me dicare a n d dia g n ose d wit h 
m C S P C e n ha nces ge neraliza bilit y  t o a ver y lar ge p orti o n of all m CS P C patie nts.
0 9 0 1 7 7 e 1 a 2 4 0 b 6 3 e\ A p pr o v e d\ A p pr o v e d O n: 2 7- N o v- 2 0 2 4 1 6: 1 7 ( G M T)
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!
Availability of data starting in 2005 to ensure ample opportunity to identify the 
occurrence of mCSPC and the ability to describe practice patterns through 2021 (at 
present).
!
Medicare data offer access to measures not typically available in commercial and 
open-source claims databases, including beneficiary mortality and race/ethnicity.
There are also several limitations, which include:
!
Possibly small sample sizes for some analyses, which would limit the statistical 
power to detect differences in outcomes across stratification levels.
!
Limited generalizability of results outside of the Original Medicare population or to 
experience later than 2021 (at present).
!
Relationships observed in statistical analyses may be an artifact of residual 
confounding due to an inability to capture certain factors in Medicare data, so results 
will be associational and not causal and subject to omitted variable bias. 
!
To prevent patient de-identification, outputs from CMS-provided data sources must 
be aggregated across at least 11 patients. Any outputs where N<11 must be redacted, 
and medians cannot be presented for any populations where N<50.
!
Inaccuracy stemming from the intrinsic nature of administrative claims, including 
lack of clinical fidelity and lack of information on patients prior to their entry into the 
database. 
!
The impact of these limitations will be assessed to the extent possible via sensitivity 
analyses.
8.10. Other Aspects
Not applicable.
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9. PROTECTION OF HUMAN PARTICIPANTS
9.1. Patient Information 
This study involves data that exist in deidentified/anonymized structured format and contain 
no patient personal information. 
9.2. Patient Consent
As this study involves deidentified/anonymized structured data, which according to 
applicable legal requirements do not contain data subject to privacy laws, obtaining informed 
consent from patients by Pfizer is not required.
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
This continuation of research activity is covered by a review of the WCG Institutional 
Review Board (IRB). On 01 March 2021, the WCG IRB determined that this research 
activity (identified as WCG IRB work order #1-1409624-1), as conducted by Medicus 
Economics, was exempt from IRB review under 45 CFR § 46.104(d)(4), because, although 
the research involves the use of identifiable private information, (1) that information is 
recorded by the investigator in such a manner that the identity of the human subjects cannot 
readily by ascertained directly or through identifiers linked to the subjects, (2) the 
investigator will not contact the subjects, and (3) the investigator will not re-identify subjects.
At the same time, WCG IRB also approved a full waiver of Health Insurance Portability and 
Accountability Act (HIPAA) authorization for use and disclosure of protected health 
information (PHI) based on adequate documentation that (1) the use or disclosure of the PHI 
involves no more than minimal risk to the individuals; (2) the research could not be 
practicably conducted without access to and use of the PHI; and (3) the research could not 
practicably be conducted without the waiver.
9.4. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in in Guidelines for Good Pharmacoepidemiology Practices issued by the 
International Society for Pharmacoepidemiology.
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10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This study involves data that exist as structured data by the time of study start. In these data 
sources, individual patient data are not retrieved or validated, and it is not possible to link (ie, 
identify a potential association between) a particular product and medical event for any 
individual. Thus, the minimum criteria for reporting an adverse event (AE) (ie, identifiable 
patient, identifiable reporter, a suspect product, and event) cannot be met.
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
The results of this study will be considered for dissemination in the form of scientific 
publications (eg, an abstract/poster for presentation at a national conference, a manuscript for 
submission to a peer-reviewed journal).
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately. 
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12. REFERENCES
1.
Prostate Cancer Treatment (PDQ®)–Patient Version - NCI [Internet]. 2023 [cited 2023 
Mar 2]. Available from: https://www.cancer.gov/types/prostate/patient/prostate-
treatment-pdq.
2.
Damodaran S, Kyriakopoulos CE, Jarrard DF. Newly diagnosed metastatic prostate 
cancer – has the paradigm changed? Urol Clin North Am. 2017 Nov;44(4):611–21. 
3.
S D, Jm L, Df J. Targeting Metastatic Hormone Sensitive Prostate Cancer: 
Chemohormonal Therapy and New Combinatorial Approaches. J Urol [Internet]. 2019 
May [cited 2023 Mar 2];201(5). Available from: 
https://pubmed.ncbi.nlm.nih.gov/30747897/.
4.
Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, et al. 
Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J 
Med. 2015 Aug 20;373(8):737–46. 
5.
Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. 
Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk 
metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival 
analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019 
May;20(5):686–700. 
6.
Armstrong AJ, Shore ND, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, et 
al. Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Metastatic 
Hormone-Sensitive Prostate Cancer by Pattern of Metastatic Spread: ARCHES Post 
Hoc Analyses. J Urol. 2021 May;205(5):1361. 
7.
Chi KN, Chowdhury S, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, 
et al. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: 
Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J 
Clin Oncol. 2021 Jul 10;39(20):2294–303. 
8.
Sayegh N, Swami U, Agarwal N. Recent Advances in the Management of Metastatic 
Prostate Cancer. JCO Oncol Pract. 2022 Jan;18(1):45–55. 
9.
Chi KN, Chowdhury S, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, 
et al. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: 
Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J 
Clin Oncol Off J Am Soc Clin Oncol. 2021 Jul 10;39(20):2294–303. 
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10.
Fizazi K, Tran N, Fein LE, Matsubara N, Rodríguez Antolín A, Ozguroglu M, et al. 
Final analysis of phase III LATITUDE study in patients (pts) with newly diagnosed 
high-risk metastatic castration-naïve prostate cancer (NDx-HR mCNPC) treated with 
abiraterone acetate + prednisone (AA+P) added to androgen deprivation therapy (ADT). 
J Clin Oncol. 2019 Mar;37(7_suppl):141–141. 
11.
Pilon D, LaMori J, Rossi C, Durkin M, Ghelerter I, Ke X, et al. Medication adherence 
among patients with advanced prostate cancer using oral therapies. Future Oncol Lond 
Engl. 2022 Jan;18(2):231–43. 
12.
Al-Ali BM, Eredics K, Madersbacher S, Schauer I. Abiraterone acetate, enzalutamide 
and their sequence for castration-resistant prostate cancer : Adherence, survival and 
hospitalization analysis of a medical claims database. Wien Klin Wochenschr. 2018 
Nov;130(21–22):659–64. 
13.
Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 
2023;73(1):17–48. 
14.
2019 Medicare Advantage and Part D Prescription Drug Program Landscape | CMS 
[Internet]. [cited 2023 Mar 2]. Available from: https://www.cms.gov/newsroom/fact-
sheets/2019-medicare-advantage-and-part-d-prescription-drug-program-landscape.
15.
Freedland SJ, Ke X, Lafeuille MH, Romdhani H, Kinkead F, Lefebvre P, et al. 
Identification of patients with metastatic castration-sensitive or metastatic castration-
resistant prostate cancer using administrative health claims and laboratory data. Curr 
Med Res Opin. 2021 Apr 3;37(4):609–22. 
16.
Appukkuttan S, Madaj K, Du Y, Azzolina J, Wilt W, Parkin J, et al. MP24-03 REAL-
WORLD UTILIZATION OF APALUTAMIDE AND ENZALUTAMIDE IN NON-
METASTATIC CASTRATE RESISTANT PROSTATE CANCER: A 
RETROSPECTIVE STUDY. J Urol. 2021 Sep;206(Supplement 3):e412. 
17.
Freedland SJ, Sandin R, Sah J, Emir B, Mu Q, Ratiu A, et al. Treatment patterns and 
survival in metastatic castration-sensitive prostate cancer in the US Veterans Health 
Administration. Cancer Med. 2021 Dec;10(23):8570–80. 
18.
Ryan CJ, Ke X, Lafeuille MH, Romdhani H, Kinkead F, Lefebvre P, et al. Management 
of Patients with Metastatic Castration-Sensitive Prostate Cancer in the Real-World 
Setting in the United States. J Urol. 2021 Dec;206(6):1420–9. 
19.
Loucks J, Zuckerman AD, Berni A, Saulles A, Thomas G, Alonzo A. Proportion of 
days covered as a measure of medication adherence. Am J Health-Syst Pharm AJHP 
Off J Am Soc Health-Syst Pharm. 2022 Mar 7;79(6):492–6. 
20.
Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and 
validating the Charlson comorbidity index and score for risk adjustment in hospital 
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discharge abstracts using data from 6 countries. Am J Epidemiol. 2011 Mar 
15;173(6):676–82. 
21.
Kessel A, Kohli M, Swami U. Current management of metastatic castration-sensitive 
prostate cancer. Cancer Treat Res Commun. 2021 Jan 1;28:100384. 
22.
Bland JM, Altman DG. The logrank test. BMJ. 2004 May 1;328(7447):1073. 
23.
Clark TG, Bradburn MJ, Love SB, Altman DG. Survival Analysis Part I: Basic concepts 
and first analyses. Br J Cancer. 2003 Jul 21;89(2):232–8. 
24.
Chen K, Cheng Y, Berkout O, Lindhiem O. Analyzing Proportion Scores as Outcomes 
for Prevention Trials: A Statistical Primer. Prev Sci Off J Soc Prev Res. 2017 
Apr;18(3):312–21. 
25.
Altman DG, Royston P. The cost of dichotomising continuous variables. BMJ. 2006 
May 4;332(7549):1080. 
26.
Altman DG, Lausen B, Sauerbrei W, Schumacher M. Dangers of using “optimal” 
cutpoints in the evaluation of prognostic factors. J Natl Cancer Inst. 1994 Jun 
1;86(11):829–35. 
27.
Tueller SJ, Deboeck PR, Van Dorn RA. Getting less of what you want: reductions in 
statistical power and increased bias when categorizing medication adherence data. J 
Behav Med. 2016 Dec 1;39(6):969–80. 
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13. LIST OF TABLES
Table 1.          NHTs Approved for mCSPC During Index Window 
Table 2.          Other Prostate Cancer Treatments
Table 3.          Study Variables
14. LIST OF FIGURES
FIGURE 1. DIAGRAM OF STUDY PERIOD.
ANNEX 1.
LIST OF STAND ALONE DOCUMENTS
Not applicable.
ANNEX 2.
ADDITIONAL INFORMATION
Not applicable.
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D o c u m e nt A p pr o v al R e c or d
D o c u m e nt N a m e:
D o c u m e nt Titl e:
Si g n e d B y:
D at e( G M T)
Si g ni n g C a p a cit y
0 9 0 1 7 7 e 1 a 2 4 0 b 6 3 e\ A p pr o v e d\ A p pr o v e d O n: 2 7- N o v- 2 0 2 4 1 6: 1 7 ( G M T)
P P D
P P D