A Real-World Comparison of Clinical Outcomes in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients Who Initiated Enzalutamide vs. Abiraterone Acetate (Abiraterone) in Flatiron Electronic Health Record (EHR) Database
Conditions: Prostatic Neoplasms, Castration-Resistant
Sponsor: Pfizer

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 1 of 4 7
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
A Real -W orl d C o m paris o n of Cli nical O utc o mes 
i n C he m ot hera p y- nai ve Metastatic 
Castrati o n- resista nt Pr ostate Ca ncer ( m C R P C) 
Patie nts W h o
I nitiate d E nzal uta mi de vs. 
A birater o ne Acetate (A birater o ne ) i n Flatir o n
Electr o nic Healt h Rec or d ( E H R ) data base 
Pr ot oc ol n u m ber
C 3 4 3 1 0 4 7
Pr ot oc ol versi o n i de ntifier
Versi o n 1 . 0
D ate
1 2 J u ne 2 0 2 3
Acti ve s u bst a nce
E nzal uta mi de
Me dici n al pr o d uct
Xta n di
Rese arc h q uesti o n a n d o bjecti ves
C o m pare c li nical o utc o mes of e nzal uta mi de vs. 
a birater o ne acetate i n c he m ot hera p y-nai ve m C R P C 
patie nts i n t he Flatir o n E H R
Pri mar y  o bjecti ve: T o c o m pare o verall s ur vi val
( O S) i n patie nts wit h c he m ot hera p y -nai ve m C R P C 
w h o i nitiate d e nzal uta mi de vs. a birater o ne
Sec o n dar y  o bjecti ve 1: T o c o m pare O S i n patie nts 
wit h c he m ot hera p y- nai ve m C R P C w h o recei ve d 
o nl y  e nzal uta mi de wit h o ut a n y  s u bse q ue nt t hera p y
vs. a birater o ne wit h o ut a n y s u bse q ue nt t hera py
Sec o n dar y  o bjecti ve 2: T o c o m pare treat me nt 
d urati o n a n d ti me t o s u bse q u e nt t hera p y i n 
c he m ot hera p y- nai ve m C R P C patie nts i nitiati n g 
e nzal uta mi de vs. a birater o ne 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)
C CI

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 2 of 4 7
A ut h or
 M A
Pfizer I nc.
T his d oc u me nt c o ntai ns c o nfi de ntial i nf or mati o n bel o n gi n g t o Pfizer. E xce pt as ot her w ise a gree d t o i n writi n g, 
b y acce pti n g or re vie wi n g t his d oc u me nt, y o u a gree t o h ol d t his i nf or mati o n i n c o nfi de nce a n d n ot c o p y or 
discl ose it t o ot hers (e xce pt w here re q uire d b y a p plica ble la w) or use it f or u na ut h orize d p ur p oses. I n t he e ve nt 
of a n y act ual or s us pecte d breac h of t his o bli gati o n , Pfizer m ust be pr o m ptl y n otifie d.
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)
C CI
P P D
P P D
P P D

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
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1. T A B L E O F C O N T E N T S
1. T A B L E O F C O N T E N T S .......................................................................................................3
2. LI S T O F A B B R E VI A T I O N S................................................................................................ 5
3. R E S P O N SI B L E P A R TI E S .................................................................................................... 7
4. A B S T R A C T ........................................................................................................................... 8
5. A M E N D M E N T S A N D U P D A T E S ....................................................................................... 8
6. MI L E S T O N E S ....................................................................................................................... 9
7. R A TI O N A L E A N D B A C K G R O U N D .................................................................................. 9
8. R E S E A R C H Q U E S TI O N A N D O BJ E C TI V E S ................................................................. 1 2
9. R E S E A R C H M E T H O D S .................................................................................................... 1 4
9. 1. St u d y  Desi g n...........................................................................................................1 4
9. 2. Setti n g ...................................................................................................................... 1 7
9. 2. 1. I ncl usi o n Criteria ........................................................................................ 1 7
9. 2. 2. E xcl usi o n Criteria ....................................................................................... 1 8
9. 2. 3. Treat me nt re gi me ns .................................................................................... 1 8
9. 2. 4. C o h ort creati o n ........................................................................................... 1 8
9. 3. Varia bles .................................................................................................................. 1 9
9. 3. 1. Baseli ne C haracteristics Varia bles ............................................................. 1 9
9. 3. 2. St u d y Peri o d Varia bl es ............................................................................... 2 3
9. 4. Data S o urces ............................................................................................................ 2 6
9. 5. St u d y  Size................................................................................................................ 2 6
9. 6. Data Ma na ge me nt ................................................................................................... 2 7
9. 7. Data A nal ys is .......................................................................................................... 2 7
9. 7. 1. Pri mar y  A nalys is ........................................................................................2 7
9. 7. 1. 1. S u m mar y  of Baseli ne C haracteristics a n d O S...........................2 7
9. 7. 1. 2. C o m parati ve a nal y sis of O S f or t he pri mar y o bjecti ve, 
a dj usti n g usi n g I PT W ........................................................................ 2 7
9. 7. 2. Sec o n dar y  A nalys is 1 .................................................................................2 8
9. 7. 2. 1. C o m parati ve A nal y sis of O S f or t he Sec o n dar y O bjecti ve 
1, A dj usti n g Usi n g I PT W .................................................................. 2 8
9 . 7. 3. Sec o n dar y A nalys is 2 .................................................................................2 9
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
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9. 7. 3. 1. C o m parati ve A nal y ses of Treat me nt D urati o n a n d Ti me t o 
S u bse q ue nt Treat me nt T hera p y f or t he Sec o n dar y O bjecti ve 2, 
A dj usti n g Usi n g I PT W ...................................................................... 2 9
................................................................................. 2 9
................................................................................. 3 0
9. 8. Q ualit y  C o ntr ol........................................................................................................ 3 0
9. 9. L i mitati o ns of t he Researc h Met h o ds...................................................................... 3 1
9. 1 0. Ot her As pects ........................................................................................................ 3 1
1 0. P R O T E C TI O N O F H U M A N S U BJ E C T S ........................................................................ 3 1
1 0. 1. Patie nt I nf or mati o n ................................................................................................ 3 1
1 0. 2. Patie nt C o nse nt ...................................................................................................... 3 1
1 0. 3. I nstit uti o nal Re vie w B oar d (I R B)/I n de pe n de nt Et hics C o m mittee (I E C) ............ 3 1
1 0. 4. Et hical C o n d uct of t he St u d y ................................................................................ 3 1
1 1. M A N A G E M E N T A N D R E P O R TI N G O F A D V E R S E E V E N T S/ A D V E R S E 
R E A C TI O N S ...................................................................................................................... 3 2
1 2. P L A N S F O R DI S S E M I NA TI N G A N D C O M M U NI C A TI N G S T U D Y R E S U L T S ........ 3 2
1 3. R E F E R E N C E S .................................................................................................................. 3 3
1 4. LI S T O F T A B L E S ............................................................................................................. 3 6
1 5. LI S T O F FI G U R E S ........................................................................................................... 3 6
A N N E X 1. LI S T O F S T A N D -A L O N E D O C U M E N T S ......................................................... 3 6
A N N E X 2. E N C E P P C H E C K LI S T F O R S T U D Y P R O T O C O L S ......................................... 3 6
A N N E X 3. A D DI TI O N A L  IN F O R M A TI O N ......................................................................... 3 7
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)
C CI

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 5 of 4 7
2. LI S T O F A B B R E VI A TI O N S
A b bre vi a ti o n
Defi niti o n
A D T
an dr o ge n de pri vati o n t hera p y
A E
ad verse e ve nt
A L P 
a l kali ne p h os p hatase
A S C O
A merica n S ociet y of C li nical O nc ol o g y  A n n ual M eeti n g
B MI
b o d y  mass i n de x
C CI
C harls o n C o m or bi dit y  In de x
CI
c o nfi de nce i nter val
C P T
curre nt pr oce d ural ter mi n ol o g y
C R P C
castrati o n-resista nt pr ostate ca ncer
C S P C
castrati o n-se nsiti ve pr ostate ca ncer
E C O G
Easter n C o o perati ve O nc ol o g y  Gr o u p
E H R
electr o nic healt h rec or d
E R
emer ge nc y  r o o m
F D A
F o o d a n d D r u g A d mi nist rati o n
G PI
Ge neric P r o d uct Ide ntifier 
H C P C S
Healt hcare C o m m o n P r oce d ure C o di n g S ys te m
H R
h azar d rati o
I C D- 9-C M
I nter nati o nal Classificati o n of Diseases, Ni nt h Re visi o n, Cli nical 
M o dificati o n
I C D- 1 0-C M
I nter nati o nal Classificati o n of Diseases, Te nt h R e visi o n, Cli nical 
M o dificati o n
L D H
lactate de h y d r o ge nase
I P T W
in verse pr o ba bilit y  of treat me nt wei g hti n g
K M
Ka pla n -Meier
L H R H
l utei nizi n g h or m o ne-releasi n g h or m o ne
L O T
li ne of t hera py
m C R P C
m etastatic castrati o n-resista nt pr ostate ca ncer
m C S P C
m etastatic castrati o n-se nsiti ve pr ostate ca ncer
N CI
Nati o nal C a ncer Instit ute
N H T
n o vel h or m o ne t hera p y
O S
o verall s ur vi val
P C
p r ostate ca ncer
P C S
p r oce d ures
P S A
p r ostate-s pecific a nti ge n
R W E
real-w orl d e vi de n ce
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
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A b bre vi a ti o n
Defi niti o n
S S DI
S ocial S ec urit y Deat h I n de x
U S
U nit e d States
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 7 of 4 7
3. R E S P O N SI B L E P A R TI E S
P ri nci p al I n vesti g at or (s) of t he Pr ot oc ol
N a me, de gree(s)
J o b Title
Affili ati o n
A d dress
Jas mi na Iva n o va, 
M A
Se ni or Direct or, 
Val ue & E vi de nce -
Xta n di
Pfizer I nc.
6 6 H u ds o n Bl v d East, 
Ne w Y or k, N Y 1 0 0 0 1
Kris h na n 
Ra mas wa m y, P h D
Se ni or Direct or, 
Val ue & E vi de nce 
U S L ea d, O nc ol o g y
Pfizer I nc.
6 6 H u ds o n Bl v d East, 
Ne w Y or k, N Y 1 0 0 0 1
Bett y T h o m ps o n , 
P h D
Me dical Direct or, 
Pr ostate Ca ncer
Pfizer I nc.
6 6 H u ds o n Bl v d East, 
Ne w Y or k, N Y 1 0 0 0 1
J o nat ha n Assa ya g, 
P h D
Direct or / R W E 
Scie ntist - Prescisi o n 
Me dici ne/ O nc ol o g y  
Pfizer I nc.
6 6 H u ds o n Bl v d East, 
Ne w Y or k, N Y 1 0 0 0 1
Be nja mi n Li , P h D
Direct or, 
Bi ostatistics
Pfizer I nc.
1 0 0 U S R o ute 2 0 6 N ort h, 
Pea pac k , NJ 0 7 9 7 7
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 8 of 4 7
4. A B S T R A C T
S ta n dal o ne d oc u me nt A N N E X 1 .
5. A M E N D M E N T S A N D U P D A T E S
N o ne .
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 9 of 4 7
6. MI L E S T O N E S
M ilest o ne
Pl a n ne d d ate
Start of data c ollecti o n
0 1 A u g ust 2 0 2 3
E n d of data c ollecti o n
3 1 Dece m ber 2 0 2 3
Fi nal st u d y  re p ort
3 0 N o ve m ber 2 0 2 4
7. R A TI O N A L E A N D B A C K G R O U N D
m C R P C a n d tre at me nt wit h e nz al ut a mi de a n d a bir ater o ne
Pr ostate ca ncer is t he m ost c o m m o n ca ncer (e xcl u di n g n o n mela n o ma s ki n ca ncer) a n d t he 
sec o n d lea di n g ca use of ca ncer deat h a m o n g me n i n t he U nite d States (U S ). T he A merica n 
Ca ncer S ociet y esti mates t hat i n 2 0 2 2 t here will be 2 6 8, 4 9 0 ne w cases a n d 3 4 , 5 0 0 deat hs 
fr o m pr ostate ca ncer.1 T he maj orit y  of me n wit h ne wl y dia g n ose d pr ostate ca ncer prese nt 
wit h l ocalize d disease a n d u n der g o acti ve s ur veilla nce, ra dical pr ost atect o m y a n d/ or ra diati o n
t hera py. W hile t he l o n g -ter m o utl o o k is fa v orable f or earl y-sta ge pr ostate ca ncer, s ur vi val 
rates drasticall y decrease o nce t he disease has s prea d be yo n d t he pr ostate gla n d or w he n t he 
disease bec o mes castrati o n resista nt.2 ,3 F or t h ose eit her wit h m ore a d va nce d disease or w h ose 
t u m or rec urs after treat me nt, t he sta n dar d first-li ne s yste mic t hera p y is an dr o ge n de pri vati o n 
t hera py (A D T ).4 Pr ostate ca ncer pr e vi o usl y u ntreate d b y  or res p o n di n g t o A D T is calle d 
castrati o n-se nsiti ve pr ostate ca ncer (C S P C ). O ver ti me, me n wit h a d va nce d disease ma y  st o p 
res p o n di n g t o A D T a n d de vel o p castrati o n-resista nt pr ostate ca ncer (C R P C ). C R P C is 
pr ostate ca ncer t hat pr o gress es cli nicall y, ra di o gra p hicall y or bi oc he micall y des pite 
mai ntai ni n g castrate le vels of ser u m test oster o ne.5 Me dia n ti me t o m C R P C a m o n g patie nts 
wit h m etastatic castrati o n -sensiti ve pr ostate ca ncer (m C S P C ) treate d wit h A D T al o ne has 
bee n esti mate d t o be 1 1. 7 m o nt hs, wit h a p pr o xi matel y  8 0 % of patie nts pr ogressi n g t o 
m C R P C wit hi n 3 y ears.6 Esti mates of me dia n O S fr o m ti me of m C R P C dia g n osi s var y base d 
o n treat me nt recei ve d a n d tre at me nt setti n g a n d ra n ge fr o m 1 3 t o 3 5 m o nt hs acr oss 
st u dies.7 -1 0
O ver t he past deca de, se veral t hera pies f or m C R P C t hat s h o w a n i nc rease i n O S ha ve gai ne d 
re g ulat or y a p pr o val i n t he U S, i ncl u di n g n o vel h or m o ne t hera pies (N H Ts ) a birater o ne acetate 
(hereafter referre d t o as a birater o ne 1 1 ,1 2) a n d e nzal uta mi de,7 ,1 3 c he m ot hera pies 
(e g, d oceta xel ,1 0 ca bazita xel 1 4), i m m u n ot hera pies (e g, si p ule ucel - T1 5), a n d ra di ot hera pies 
(e g, ra di u m- 2 2 31 6). Ola pari b a n d ruca pari b are p ol y ( A D P-ri b ose) p oly m erase ( PA R P) 
i n hi bit ors a p pr o ve d f or a d ult patie nts wit h deleteri o us or s us pecte d deleteri o us ger mli ne or 
s o matic h o m ol o g o us rec o m bi nati o n re pair ge ne-m utate d m C R P C w h o ha ve disease 
pr o gressi o n o n N H Ts .1 7 ,1 8 N H Ts, partic ularl y e nzal uta mi de a n d a birater o ne, ha ve s h o w n 
str o n g efficac y i n t he m C R P C setti n g. E nzal uta mi de was i nitiall y a p pr o ve d b y t he F o o d a n d 
dr u g a d mi nistrati o n ( F D A ) i n 2 0 1 2 f or c he m ot hera p y-e x perie nce d m C R P C,1 9 w hile 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 1 0 of 4 7
a birater o ne was a pp r o ve d i n 2 0 1 1 f or t he sa me i n dicati o n.2 0 E nzal uta mi de a n d a birater o ne 
were s u bse q ue ntl y a p pr o ve d f or c he m ot hera p y -nai ve m C R P C ( 1 0 Se pte m ber 2 0 1 4 f or 
e nzal uta mi de; 1 0 D ecem ber 2 0 1 2 f or a birater o ne ) a n d are t he o nl y a p pr o ve d N H Ts i n t his 
i n dicati o n. B ot h dr u gs were als o s u bse q ue ntl y  a p pr o ve d f or use i n m C S P C 
( 1 6 D ece m ber 2 0 1 9 f or e nzal uta mi de; 0 7 F e br uar y 2 0 1 8 f or a birater o ne); h o we ver, e vi de nce 
s u p p orti n g t he efficac y of a birater o ne i n m C S P C was disse mi nate d at t he America n S ociet y 
of Cli nical O nc ol o g y  A n n ual Meeti n g ( A S C O) bet wee n 0 2- 0 6 J u ne 2 0 1 7. B ot h treat me nts 
tar get t he a n dr o ge n a xis wit h differe nt mec ha nis ms of acti o n: e nzal uta mi de i n hi bits t he 
a n dr o ge n rece pt or, s u bse q ue ntl y  re d uci n g n uclear tra nsl ocati o n of t he a n dr o ge n rece pt or 
c o m ple x a n d D N A bi n di n g, w hereas a birater o ne bl oc ks c y t oc hr o me P 4 5 0-1 7 t o i n hi bit 
a n dr o ge n s y nt hesis. 
B ot h e nzal uta mi de a n d a birater o ne pr o vi de i m pr o ve d O S i n pat ie nts wit h m C R P C i n b ot h 
c he m ot hera p y- nai ve 7 ,9 a n d c he m ot hera p y- e x perie nce d setti n gs. I n t he setti n g of 
c he m ot hera p y- nai ve m C R P C, t he P R E V AI L ( N = 1 7 1 7) st u d y  de m o nstrate d t hat patie nts 
recei vi n g e nzal uta mi de wit h o n g oi n g A D T ha d a statisticall y  si g nifica nt i m pr o ve me nt i n O S 
( me dia n O S of 3 5. 3 m o nt hs vs. 3 1. 3 m o nt hs; H R 0. 7 7 ; 9 5 % CI 0. 6 7- 0.8 8 ; p = 0. 0 0 0 2 ; 
0 1 J u ne 2 0 1 4 data c ut off ) c o m pare d t o patie nts recei vi n g place b o.7 Si milarl y , the 
C O U -A A -3 0 2 ( N = 1 0 8 8) trial of patie nts wit h m C R P C w h o were c he m ot hera p y- nai ve als o 
s h o we d statisticall y si g nifica nt i m pr o ve me nt i n O S f or patie nts recei vi n g a birater o ne a n d 
pre d ni s o ne wit h o n g oi n g A D T c o m pare d t o patie nts o nl y  recei vi n g pre d nis o ne wit h o n g oi n g 
A D T ( 3 4. 7 m o nt hs vs. 3 0. 3 m o nt hs, H R 0. 8 1; 9 5 % CI 0. 7 0-0. 9 3; p = 0. 0 0 3 ; 3 1 M arc h 2 0 1 4 
data c ut off ).9 O n t he stre n gt h of t his e vi de nce, t he Nati o nal C o m pre he nsi ve Ca ncer Net w or k 
g ui deli nes rec o m me n d b ot h e nz al uta mi de a n d a birater o ne as Cate g or y  1, preferre d treat me nt 
o pti o n s f or me n i n b ot h pre-d oceta xel a n d p ost -d oceta xel m C R P C p o p ulati o ns .5
E nzal uta mi de a n d a birater o ne are t he m ost c o m m o nl y use d N H T s i n patie nts wit h 
c he m ot hera p y -nai ve m C R P C i n real-w orl d cli nical practice . A st u d y  of patie nts wit h m C R P C 
i n t he U S usi n g t he Flatir o n E H R data ( 2 0 1 3 Q 1 - 2 0 1 7 Q 4) re p orte d t hat o ver half of patie nts 
o n m C R P C treat me nt recei ve d eit her a birater o ne or e nzal uta mi de i n t he first a n d sec o n d-li ne 
setti n gs (a birater o ne first-li ne: 3 7 %, sec o n d-li ne: 2 0 %; e nzal uta mi de first-li ne: 2 8 %, sec o n d-
li ne: 34 %) .2 1
C o m p ar ative effective ness of e nz al ut a mi de a n d a bir ater o ne
T h ere ha ve o nl y bee n t hree, s mall, hea d-t o- hea d ra n d o mize d c o ntr olle d trials c o m pari n g 
e nz al uta mi de a n d a birater o ne.2 2 ,2 3 ,2 4 A ra n d o mize d, P hase 3 st u d y fr o m Japa n wit h 2 0 3 
patie nts wit h castrati o n -resista nt pr ostate ca ncer di d n ot fi n d a statisticall y si g nifica nt 
differe nce i n O S bet wee n patie nts i nitiati n g e nzal uta mi de vs. a birater o ne ( H R 1. 1 7 , 9 5 % CI 
0. 7 2 , 1. 88 , p = 0.5 3). A ra n d o miz e d, o pe n-la bel, P hase 2, cr os s-o ver trial of 2 0 2 patie nts di d 
n ot fi n d a statisticall y  si g nifica nt differe nce i n O S bet wee n patie nts i nitiati n g e nzal uta mi de 
vs. a birater o ne ( H R 1. 2 7, 9 5 % CI 0. 8 6, 1. 8 5, p = 0. 2 3) .2 4 T he ot her trial was a si n gle -ce nter, 
o pe n -la bel, P hase 4 trial of 1 7 0 patie nts t hat f oc use d o n q ualit y  of life, fati g ue a n d meta b olic 
si de effects b ut di d n ot c o m pare O S bet wee n.2 3
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 1 1 of 4 7
C o m parati ve effecti ve ness of e nza l uta mi de a n d a birater o ne i n patie nts wit h m C R P C i n 
cli nical practice has als o bee n e val uate d i n m ulti ple real-w orl d st u dies . Si x st u dies ha d 
o verall sa m ple sizes o ver 1 0 0 0 patie nts a n d t hese st u dies de m o n strate d fa v ora ble O S f or 
e nzal uta mi de c o m pare d t o a b irater o ne.2 5 -3 0 A p o p ulati o n- base d st u d y  of c he m ot hera p y-nai ve
patie nts wit h m C R P C ( n = 1 0 3 0 8) i n t he Fre nc h Nati o nal Healt h Data S y ste m o bser ve d 
e nzal uta mi de was ass ocia te d wit h l o n ger O S c o m pare d wit h a birater o ne ( H R 0. 9 0; 9 5 % CI 
0. 8 5- 0. 9 6). 2 5 A retr os p ecti ve c o h ort st u d y base d o n t he Flatir o n E H R data base of m C R P C 
patie nts w h o recei ve d first- li ne s yste mic t hera p y ( n = 3 8 0 8 ) o bserve d a birater o ne was 
ass ociated wit h s h orter O S c o m pare d wit h e nzal uta mi de a m o n g n o n -His pa nic W hite me n 
( H R 1. 2 1; 9 5 % CI 1. 0 6-1. 3 8) .2 8 T w o retr os pecti ve st u dies i n t he V H A data base als o s h o we d 
e nzal uta mi de was ass ocia te d wit h l o n ger O S t ha n a birater o ne.2 6 ,2 7 I n a st u d y of 
c he m ot hera p y- nai ve pati e nts wit h m C R P C ( n = 3 1 7 4), Ta ga wa et al. f o u n d t hat 
e nzal uta mi de-treate d patie nts ha d l o n ger me dia n O S c o m pare d t o a birater o ne-treate d patie nts 
( me dia n O S of 2 9. 6 vs. 2 5. 9 m o nt hs; H R 0. 8 4; 9 5 % CI 0. 7 6- 0. 9 4; p = 0. 0 0 1 2), after 
a dj ust me nt f or baseli ne differe nces i n a ge, i n di vi d ual c o m or bi dities a n d pri or use of ra diati o n 
t hera py a n d c ortic oster oi d t hera py bet wee n t he gr o u ps, a n d irres pecti ve of f oll o w -o n t hera p y 
f or m C R P C.2 7 Si milar treat me nt differe nces were o bser ve d i n se nsiti vit y  a nal yses 
a d diti o nall y a dj usti n g f or pr ostate-s pecific a nti ge n le vel, he m o gl o bi n, a n d al kali ne 
p h os p hatase (A L P) . A nal yses i n t he s u b gr o u p of patie nts w h o recei ve d o nl y first-li ne 
treat me nt wit h o ut s u bse q ue nt t hera py s h o we d greater O S be nefit f or e nzal uta mi de vs. 
a birater o ne c o m pare d t o t he O S differe nce o bser ve d i n all patie nts. A n i n de pe n de nt st u dy b y 
Sc h oe n et al [ 2 0 2 2]2 6 of patie nts wit h m C R P C ( n = 5 8 2 2 ) usi n g a m ore rece nt c ut of t he 
V H A data als o f o u n d a si milar s ur vi val be nefit ass ociate d wit h e nzal uta mi de vs. a birater o ne 
( H R 0.8 9 , 9 5 % CI  0. 8 4-0. 9 5 ) i n a nalys es of all patie nts, a n d i n t he s u b gr o u p of patie nts w h o 
recei ve d o nl y first-li ne treat me nt wit h o ut s u bse q ue nt t hera py. T w o st u dies usi n g Tai wa n 
Nati o nal Healt h I ns ura nce data als o s h o we d s u peri or O S wit h e nzal uta mi de vs 
a birater o ne. 2 9 ,3 0 I n a st u d y of 1 1 5 3 m C R P C patie nts, Li n et al. f o u n d t hat t he e nzal uta mi de 
treate d patie nts ha d a l o wer ris k of o verall m ortalit y  c o m pare d wit h a birater o ne [a dj uste d 
hazar d rati o (a H R) = 0. 7 1, 9 5 % CI : 0. 5 7– 0. 8 8, p = 0. 0 0 2 ].2 9 In a st u d y of 1 0 4 6 a birater o ne 
a n d 1 1 8 e nzal uta mi de patie nts wit h m C R P C, Li  et al f o u n d t hat e nzal uta mi de si g nifica ntl y 
re d uce d t he ris k of deat h for m C R P C w he n c o m pare d wit h a b irater o ne a H R = 0. 8 2 8; 
9 5 % CI  0. 7 3 1-0. 9 3 8]. 3 0
R ati o n ale f or t he c urre nt st u dy 
As a de q uatel y p o were d, hea d -t o- hea d, ra n d o mize d c o ntr olle d trials c o m pari n g O S bet wee n 
t hese 2 t hera pies are u nli kel y t o be c o n d ucte d, real w orl d e vi de nce (R W E ) ca n pr o vi de 
i m p orta nt i nf or mati o n t o g ui de treat me nt decisi o ns , partic ularly as se veral years of data o n 
t he use of e nzal uta mi de a n d a birater o ne i n real-w orl d setti n gs ha ve n o w accr ue d. T hese 
real-w orl d data ma y  all o w f or assess me nt of c o m parati ve effective ness of e nzal uta mi de vs. 
a birater o ne i n a lar ger a n d m ore br oa dl y re prese ntati ve p o p ulati o n of patie nts wit h m C R P C 
t ha n w o ul d be p ossi ble i n ra n d o mize d cli nical trials, w here racial a n d et h nic min orities a n d 
patie nts wit h cer tai n c o m or bi dities are ofte n u n derre prese nte d. S uc h c o m parati ve e vi de nce is 
partic ularl y i m p orta nt t o patie nts, prescri bers , a n d healt hcare pla ns, gi ve n t he a d va nce d sta ge 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 1 2 of 4 7
of t he disease a n d t he i m perati ve t o o pti mize i nitial treat me nt c h oice. A m o n g t he lar ge pri or 
R W E st u dies i n t his t hera pe utic area, t hree of t he m f oc use d o n n o n -U S p o p ulati o n s. T w o U S 
st u dies f oc use d o n t he vetera ns ’ p o p ulati o n, w hic h ma y n ot be ge neraliza ble t o U S 
p o p ulati o n of pr ostate ca ncer patie nts. T he Marar et al . U S st u d y  usi n g Flatir o n E H R f oc use d 
m ore o n t h e differe nces of first- li ne treat me nt bet wee n race/et h nicit y gr o u ps, i ncl u de d b ot h 
c he m ot hera p y naï ve a n d patie nts pre vi o usl y treate d wit h d oceta xel , a n d ha d a relati vel y s h ort 
me dia n f oll o w u p of a p pr o xi matel y 1 3 m o nt hs.2 8
T his retr os pecti ve R W E st u d y usi n g Flatir o n E H R will ai m t o c o m pare t he effecti ve ness of 
e nzal utami de vs. a birater o ne a m o n g patie nts wit h c he m ot hera p y- nai ve m C R P C. T his st u d y  
will i ncl u de m ore rece nt data t ha n t he st u d y  pre vi o usl y p u blis he d b y Marar et al.2 8 a n d will 
use met h o d ol o g y  c o nsiste nt wit h t hat i n t he p u blis he d st u d y b y Ta ga wa et al.2 7 usi n g V H A 
data as well as t he met h o d ol o g y i n a n o n g oi n g st u d y  i n t he Me dicare p o p ulati o n.
8. 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
Pri m ary o bjective:
T o c o m pare O S i n patie nts wit h c he m ot hera p y -nai ve m C R P C w h o i nitiate d e nzal uta mi de vs. 
a birater o ne. 
T his o bjecti ve will be a d dr esse d wit h a n i nte nti o n -t o-treat st yl e of a nal ys is c o m pari n g O S 
o ver t he e ntiret y  of t he st u d y’s f oll o w-u p peri o d a m o n g all eli gi ble patie nts i nitiati n g 
e nzal uta mi de a n d a birater o ne. T his a nal ys is will i ncl u de all c he m ot hera p y- nai ve patie nts 
i nitiati n g first-li ne e nzal uta mi de vs. a birater o ne f or m C R P C, irres pecti ve of a n y s u bse q ue nt 
treat me nt. 
Sec o n d ary o bjective 1:
T o c o m pare O S i n patie nts wit h c he m ot hera p y- nai ve m C R P C w h o recei ve d o nl y  
e nzal uta mi de wit h o ut a n y s u bse q ue nt t hera p y vs. a birater o ne wit h o ut a n y s u bse q ue nt 
t hera py. Patie n ts recei vi n g o nly e nzal uta mi de will be defi ne d as patie nts w h o i nitiate 
e nzal uta mi de wi t h o ut s witc hi n g t o or a d di n g a n ot her m C R P C treat me nt. Patie nts recei vi n g 
o nl y  a birater o ne will be defi ne d as patie nts w h o i nitiate a birater o ne wit h o ut s witc hi n g t o or 
a ddi n g a n ot her m C R P C treat me nt. 
T he sec o n dar y  o bjecti ve will see k t o assess t he treat me nt effect attri b uta ble t o t he first N H T 
recei ve d. Gi ve n m C R P C is c o nsi dere d a n e n d-sta ge disease wit h li mite d e x pecte d s ur vi val, 
t he c h oice of w hic h N H T t o i nitiate first is partic ularl y i m p orta nt. I dentif y i n g t he treat me nt 
effect attri b uta ble t o t he first N H T recei ve d is of partic ular i nterest beca use R W E s h o ws t hat 
a maj orit y of patie nts wit h c he m ot hera py- nai ve m C R P C i n t he U S d o n ot recei ve s u bse q ue nt 
t hera py. A b o ut 5 1 % of patie nts wit h m C R P C i n a re ce nt E H R -base d a nal ys is recei ve d o nly 
o ne li ne of life - pr ol o n gi n g t hera pies s uc h as N H Ts d uri n g a mea n f oll o w-u p ti me of 
1 4. 6 m o nt hs .2 1 P ossi ble reas o ns fo r t his ma y i ncl u de patie nts bei n g t o o ill t o recei ve 
s u bse q ue nt t hera py, patie nts’ ref usal of f urt her t hera p y, deat h bef ore recei vi n g a sec o n d -li ne 
t hera py, or i nc o m plete rec or di n g of p ost -first li ne t hera pies, d ue t o e n d of st u d y f oll o w-u p or 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 1 3 of 4 7
recei pt of sec o n d-li ne t hera p y i n a n ot her healt h pla n n ot c o vere d b y  t he data base.2 1 T he V H A 
st u dies b y Ta ga wa et al. a n d Sc h oe n et al. als o o bser ve d t hat a p pr o xi matel y half of all 
patie nts recei ve d o nl y e nzal uta mi de or a birat er o ne wit h o ut s u bse q ue nt t hera p y . B ot h st u dies 
o bser ve d t here was a lar ger differe nce i n O S bet wee n e nzal uta mi de a n d a birater o ne i n t his 
s u b gr o u p of patie nts t ha n a m o n g all patie nts. 2 6 ,2 7
Sec o n d ary o bject ive 2:
T o c o m pare treat me nt d urati o n a n d ti me t o s u bse q ue nt t hera py i n che m ot hera p y- nai ve
m C R P C patie nts i nitiati n g e nzal uta mi de vs. a birater o ne. 
T his o bjecti ve will be a d dresse d wit h a n i nte nti o n- t o-treat styl e of a nal ys is co m pari n g ti me t o 
disc o nti n uati o n a n d ti me t o s u bse q ue nt t hera py o ver t he e nt iret y of t he st u d y’s f oll o w-u p 
peri o d a m o n g all eli gi ble patie nts i nitiati n g e nzal uta mi de a n d a birater o ne. Treat me nt d urati o n 
is i nte n de d t o pr o vi de s u p p orti ve e vi de nce of c o m parat i ve ti me o n t he in de x t hera p y . A 
s h orter treat me nt d urati o n ma y  be i n dicati ve of s h orter pr o gressi o n free s ur vi val or of 
t olera bilit y iss ues, a n d ma ybe c orrelate d wit h O S. 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)
C CI

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 1 4 of 4 7
9. R E S E A R C H M E T H O D S 
9. 1. St u d y D esi g n
A retr os pecti ve o bser vati o nal c o h ort desi g n usi n g Flatir o n E H R data base will be c o n d ucte d 
t o a d dress t he pri mar y a n d sec o n dar y o bjecti ves of t he st u d y. T he st u d y desi g n is 
su m marize d i n Fi g ure 1 bel o w a n d descri be d i n m ore detail i n t he s u bse q ue nt secti o ns.
Patie nts will be classifie d i nt o eit her t he e nzal uta mi de or a birater o ne gr o u ps, base d o n 
i nitiati o n of o ne of t hese t w o dr u gs duri n g t he i n de x peri o d of t his st u d y. Patie nts’ i n de x date 
will be defi ne d as t he date of i nitiati o n of e nzal uta mi de or a birater o ne a n d t heir i n de x date is 
re q uire d t o occ ur d uri n g t he i n de x peri o d. 
T he pr o p ose d i n de x peri o d f or t his st u d y  ra n ges fr o m 1 0 Se pte m ber 2 0 1 4 t o 
3 1 Dece m ber 2 0 1 9 ( or 3 years bef ore t he e n d of data a vaila bilit y i n t he E H R at t he ti me of 
a nal ys is start). T he start date of t he i n de x peri o d, 1 0 Se pte m ber 2 0 1 4, is base d o n t he date of 
F D A a p pr o val of e nzal uta mi de i n patie nts wit h c he m o t hera py -nai ve m C R P C . At t his ti me 
a birater o ne ha d alrea d y bee n a p pr o ve d f or use i n patie nts wit h c he m ot hera p y -nai ve m C R P C. 
T he e n d date of 3 1 Dece m ber 2 0 1 9 as t he e n d of t he i n de x peri o d all o ws f or t he p ote ntial of 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)
C CI

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 1 5 of 4 7
at least 3 y ears of f oll o w u p u ntil t he en d of data a vaila bilit y. W hile
cli nical trial data a b o ut 
a birater o ne use i n m C S P C was first prese nte d i n J u ne 2 0 1 7 a n d patie nts ma y ha ve starte d t o 
use a birater o ne i n m C S P C after t hat date, t he Flat ir o n E H R data base ca pt ures dia g n osis of 
metastasis a n d C R P C a bstracte d fr o m u ns tr uct ure d data . T hese data ca n be use d t o e ns ure 
t hat o nl y patie nts i nitiati n g e nzal uta mi de a n d a birater o ne f or m C R P C are i ncl u de d i n t he 
a nal ys es a n d t hat t he st u d y d oes n ot i ncl u de patie nts treate d f or m C S P C w h o w o ul d ha ve 
l o n ger s ur vi val. 
Baseli ne c haracteristi cs i ncl u di n g de m o gra p hics, disease c haracteristics, c o m or bi dities, a n d 
pri or treat me nts will be assesse d base d o n data pri or t o or o n t he i n de x date or d uri n g t he 
1 2- m o nt h peri o d pri or t o t he i n de x da te. A preli mi nar y list of baseli ne c haracteristics t o be
assesse d is i ncl u de d i n Secti o n 9. 3 . Patie nts will be f oll o we d fr o m t heir i n de x date t o t he 
earliest of patie nt deat h or e n d of data a vaila bilit y . P ote ntial d urati o n of f oll o w-u p f or 
patie nts i n t hese data will be m ore t ha n 3 ye ars f or al m ost all patie nts gi ve n t he e n d of t he 
i n de x peri o d of 3 1 Dece m ber 2 0 1 9 a n d c o vera ge of t he data c ut u ntil Dece m ber 2 0 2 2. O S 
o ver t he f oll o w -u p peri o d will be c o m pare d bet wee n e nz al uta mi de a n d a birater o ne gr o u ps, 
a dj usti n g f or differe nces i n baseli ne c haracteristics bet wee n t he t w o gr o u ps. T his st u d y  will 
be a n o n -i nter ve nti o nal retr os pecti ve c o h ort st u d y t hat d oes n ot i m p ose a treat me nt pr ot oc ol, 
a n y dia g n ostic/i nter ve nti o nal pr oce d ures ( P C S), or a visit sc he dule. 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 1 6 of 4 7
Fi g ure 1.
St u d y Desi g n
I n cl u si o n A s s e s s m e nt Wi n d o w
( Di a g n o si s of m C R P C )
D a y s  [- A n yt i m e, 1 4 d a y s ]
E x cl u si o n A s s e s s m e nt Wi n d o w
( C h e m ot h er a p y, N H T, i m m u n ot h er a p y, r a di u m-2 2 3, 
P A R P ) D a y s  [- A n yt i m e, -1 d a y ]
D a y s  [- A n yt i m e, -1 d a y ] 
C o nf o u n d er s A s s e s s m e nt Wi n d o w
(Pri or tr e a t m e nt s f or o pi o d s, 
c orti c o st er oi d s , k et o c o n a z ol e)
D a y s  [-3 6 5, -1 d a y ]
I n d e x d at e: T h e i niti ati o n d at e of e n z al uta mi d e or a bir at er o n e 
d uri n g t h e i n d e x p eri o d of 1 0 S e pt e m b er 2 0 1 4 -
3 1 D e c e m b er 2 0 1 9 ( or 3 y e ar s b ef or e e n d of d at a a v ail a bilit y)
I n d e x d at e will b e d efi n e d a s D a y  0
I n cl u si o n A s s e s s m e nt Wi n d o w
( M al e, A g e ≥1 8)
D a y s  [ 0, 0]
Ti m
Earliest of deat h, last patie nt c o ntact, a n d e n d of data a vaila bilit y.
C o nf o u n der Assess me nt Wi n d o w
( De mo gr a p hics)
D a ys [ 0, 0]
F oll o w u p W i n d o w
D a y s [ 0, e v e nt/ c e n s or
a
]
I n cl u si o n A s s e s s m e nt Wi n d o w
( Di a g n o si s of pr o st at e c a n c er)
D a y s  [- A n yt i m e, 0 d a y ]
C o nf o u n d er s A s s e s s m e nt Wi n d o w
( Di s e a s e c h ar a ct eri sti c s, c o m or bi diti e s)
D a y s  [-A n yt i m e, 0 d a y ]
E x cl u s io n A s s e s s m e nt Wi n d o w
( C a n c er s ot h er t h a n n o n-m el a n o m a s ki n c a n c er , m ali g n a nt 
n e o pl a s m wit h o ut s p e cifi c ati o n of sit e, a n d m ali g n a n t 
n e o pl a s m of t h e b o n e a n d arti c ul ar c artil a g e )
D a y s  [-D at e of s e c o n d ar y  m et a st a s e s, 0]
E x cl u si o n A s s e s s m e nt Wi n d o w
(E N Z or A B I i n co m bi n ati o n wit h ot h er 
tr e at m e nt s)
D a y s [ 0 , 2 8 ]
E x cl u si o n A s s e s s m e nt Wi n d o w
( C a n c er s ot h er t h a n n o n-m el a n o m a s ki n c a n c er)
D a y s  [- A n yt i m e, D at e of s e c o n d ar y m et a st a s e s]
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 1 7 of 4 7
9. 2. Setti n g
Patie nts i n t he Flatir o n E H R data base wit h m C R P C w h o i nitiate d treat me nt wit h 
e nzal uta mi de or a birater o ne a n d w h o ha ve n ot pre vi o usl y  recei ve d c he m ot hera p y will be 
selecte d f or t his st u d y. T he i ncl usi o n a n d e xcl usi o n criteria bel o w will be a p plie d t o i de ntif y  
patie nts.
9. 2. 1. I ncl usi o n C riteri a
Patie nts m ust meet all t he f oll o wi n g criteria t o be eli gi ble f or i ncl usi o n i n t he st u d y :
1.
Male wit h a metastatic pr ostate ca nc er dia g n osis a n d C R P C dia g n osi s. T he later of 
( 1) date of metastatic dia g n osis or ( 2) t he date of dia g n osis wit h castrati o n -resista nt 
pr ost ate ca ncer will be defi ne d as t he m C R P C dia g n osis date.
2.
Ha ve i nitiate d e nzal uta mi de or a birater o ne ( 1) wit hi n 1 4 da y s pri or t o or o n or after 
t he m C R P C dia g n osis date, a n d ( 2) d uri n g t he i n de x peri o d of 1 0 S e pte m ber 2 0 1 4 -
3 1 Dece m ber 2 0 1 9 ( or at least 3 years pri or t o t he e n d of data a vaila bilit y at t he ti me 
of a nal ys is start). I nitiati o n will be defi ne d as t he first e ver use of e nzal uta mi de or 
a birater o ne. T he i nitiati o n date of e nzal uta mi de or a birater o ne will be defi ne d as t he 
i n de x date. 

E nzal uta mi de a n d a birater o ne were a p pr o ve d f or c he m ot hera p y- nai ve m C R P C at 
differe nt ti mes ( 1 0 S e pte m ber 2 0 1 4 f or e nzal uta mi de; 1 0 D ece m ber 2 0 1 2 f or 
a birater o ne). T heref ore, 1 0 S e pte m ber 2 0 1 4 is selecte d as t he start date of t he 
i n de x peri o d, as at t his date b ot h e nzal uta mi de a n d a birater o ne beca me p ote ntial 
treat me nt c h oices f or patie nts wit h c he m ot hera p y -naï ve m C R P C. T he e n d date
3 1 Dece m ber 2 0 1 9 was selecte d t o all o w f or at least 3 years of p ote ntial f oll o w u p 
bef ore t he e n d of data a vaila bilit y.
3.
At least 1 8 years ol d at t he i n de x date .
4.
I nitial patie nt c o ntact i n t he E H R (w hic h c o ul d be rec or di n g of vital i nf or mati o n, 
visit, a me di cati o n a d mi nistrati o n, or a lab orat or y  test/res ult bei n g re p orte d, last 
a bstracte d oral t hera p y date, or last cli nically-rele va nt a bstracte d date [ e g, f or 
s peci me n c ollecti o n, pr oce d ure]) at least 1 8 0 da ys bef ore t he i n de x date t o e ns ure t hat 
patie nts were treate d at t he practice, ha ve treat me nt i nf or mati o n bef ore t he i n de x date, 
a n d t hat t he i n de x date is t h e i nitiati o n of first -li ne a birater o ne or e nzal uta mi de f or 
m C R P C.
5.
E vi de nce of c o ntact wit h patie nt i n t he E H R wit hi n 1 8 0 da y s after t he i n de x date t o 
e ns ure t hat t he patie nt was acti vel y e n ga ge d i n care at t he data pr o vi di n g i nstit uti o n.
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 1 8 of 4 7
9. 2. 2. E xcl usi o n C riteria
Patie nts 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.
Recei ve d c he m ot hera p y, N H T (ie, a birater o ne, a pal uta mi de, dar ol uta m i de, or 
e nzal uta mi de), ra di u m 2 2 3 a n d/ or i m m u n ot hera p y , ola pari b/ r uca pari b at a n y ti me 
pri or t o t he i n de x date.

 
2.
Recei ve d a n o t her N H T/ c he m ot hera p y/ i m m u n ot hera p y/ ra di u m
2 2 3/ ket oc o naz ole/ o la pari b/ r uca pari b wit hi n 2 8 da ys o n/ after t he i n de x date.
3.
Ha d a pri or hist or y  of ot her ca ncers e xce pt f or n o n-mela n o ma s ki n ca ncer pri or t o t he 
date of metastas is dia g n osis .
4.
Ha d a pri or hist or y  of ot her ca ncers e xce pt f or n o n-mela n o ma s ki n ca ncer, mali g na nt 
ne o plas m wit 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 metastasis dia g n osis a n d t he i n de x date.
Rele va nt di a g n osis, pr oce d ure a nd dr u g c o des nee de d t o o perati o nalize t he criteria a b o ve are 
i ncl u de d i n A p pe n di x 1 . 
9. 2. 3. Tre at me nt re gi me ns
N ot a p plica ble .
9. 2. 4. C o h ort cre ati o n
C o h orts (or tre at me nt c o h orts) for p ri m ar y objecti ve , sec o n d ar y o bjecti ve 2 
 

E nz al ut a mi de c o h ort : m C R P C patie nts w h o i nitiate d e nzal uta mi de o n t he i n de x date

A bir ater o ne c o h ort: m C R P C patie nts w h o i nitiate d a birater o ne o n t he i n de x date
C o h orts f or s ec o n d ar y objecti ve 1
: 

E nz al ut a mi de o nl y c o h ort: m C R P C patie n ts w h o i nitiate d e nzal uta mi de o n t he 
i n de x date a n d di d n ot recei ve s u bse q ue nt s yste mic a nti- ne o plastic t hera p y

A bir ater o ne o nl y c o h ort: m C R P C patie nts w h o i nitiate d a birater o ne o n t he i n de x 
date a n d di d n ot recei ve s u bse q ue nt s yste mic a nti-ne o plastic t hera p y
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)
C CI
C CI
C CI

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 1 9 of 4 7
9. 3. V ari a bles
9. 3. 1. B aseli ne C h ar acteristics V ari a bles
Baseli ne varia bles ( Ta ble 1 ) will be meas ure d f or t he 3 6 5 da y s pri or t o t he i n de x date u nless 
ot her wise s pecifie d .
T a ble 1.
B aseli ne D e m o gr a p hic a n d C li nic al C h ar acteristic V v ari a bles
V ari a ble
O per ati o n al defi niti o n
A ge
A ge will b e defi ne d as of t he i n de x date a n d retai ne d i n t he dataset as a 
c o nti n u o us varia ble a n d a cate g orical varia ble : ≤6 4, 6 5 - 6 9, 7 0-7 4, 7 5 -7 9, 
8 0 -8 4, ≥8 5 years ol d .
R ace /et h nicit y
Pr o p orti o n of patie nts t hat were Asia n, Blac k o r Africa n A merica n, 
His pa nic or L ati n o, W hite, Ot her Race will be e val uate d .
I n de x ye ar
Varia ble w ill be create d f or t he i n de x cale n dar year.
Ge o gr a p hic R e gi o ns
Pr o p orti o n of patie nts t hat li ve d i n N ort heast , Mi d west, S o ut h, West areas , 
a n d ot her/ u n k n o w n create d base d o n patie nt state o f resi de nce a n d U S 
Ce ns us Re gi o n defi niti o ns .
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)
C CI

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 2 0 of 4 7
T a ble 1.
B aseli ne D e m o gr a p hic a n d C li nic al C h ar acteristic V v ari a bles
V ari a ble
O per ati o n al defi niti o n
I ns ur a nce
Pr o p orti o n of patie nts wit h Me dicai d, Me dicare, C o m mercial Healt h Pla n, 
W or kers C o m pe nsati o n, Ot her G o ver n me nt Pr o gra m, Patie nt Assista nce 
Pr o gra m, Self P a y , Ot her Paye r - T y pe U n k n o w n base d o n t he p atie nt’s 
latest rec or de d pa yer cate g or y
Pr actice t y pe
Pr o p orti o n of patie nts treate d i n aca de mic a n d c o m m u nit y practice
S oc i al deter mi n a nts of he alt h ( S E S 
q ui ntile)
Pr o p orti o n of patie nts i n differe nt S E S I n de x q ui ntiles f or a patie nt's bl oc k 
gr o u p base d o n 2 0 1 5 -2 0 1 9 Ce ns us data .
Gle as o n sc ore at i niti al di a g n osis
Varia ble w ill be create d f or Gleas o n sc ore at i nitial dia g n osis: Less t ha n or 
e q ual t o 6, 4 + 3 = 7, 3 + 4 = 7, 7 ( w he n brea k d o w n n ot a vaila ble), 8, 9, 
1 0, U n k n o w n / N ot d oc u me nte d.
Site of Me t ast asis 
Fla gs will be create d f or patie nts t hat ha d a metastatic dia g n osis a n y ti me 
pri or t o or o n t he i n de x date at t he f oll o wi n g sites: viscera, b o ne o nl y, 
n o de o nl y, b o ne a n d n o de o nl y, a n d ot her .
Ti me fr o m Met ast atic Di a g n osis 
D ate t o I n de x D ate
Ti m e fr o m t he first metastatic dia g n osis date i n t he data t o t he i n de x date 
will be e val uate d.
Ti me fr o m P C Di a g n osis D ate t o 
I n de x D ate
Ti m e fr o m t he first o bser ve d P C date i n t he data t o t he i n de x date will be 
e val uate d.
T i me fr o m P C Di a g n osis t o m C R P C
Di a g n osis D ate 
Ti m e fr o m t he first o bser ve d P C dia g n osis t o m C R P C dia g n osis date will 
be e val uate d.
Ti me fr o m m C R P C Di a g n osis D ate 
to I n de x D ate
Ti m e fr o m t he first m C R P C dia g n osis date i n t he data t o t he i n de x date 
will be e val uate d.
C R P C di a g n osis bef or e first 
M e t ast atic Di a g n osis 
Pr o p orti o n of patie nts w h o ha d C R P C dia g n osis bef ore first metastatic
dia g n osis.
Ti me bet wee n A D T a n d i n de x d ate
Ti m e fr o m t he first o bser ve d rec or d f or me dical or s ur gical castrati o n t o 
i n de x da te.
R a dic al pr ost atect o m y
A b i nar y varia ble ( yes/ n o) will be create d f or patie nts wit h a clai m f or 
ra dical pr ostatect o m y bef ore i n de x date .
First -ge ner ati o n a nti - a n dr o ge ns 
( bic al ut a mi de, fl ut a mi de, 
nil ut a mi de)
A bi nar y varia ble ( yes/ n o) w ill be created f or patie nts w it h use of first-
ge nerati o n a nti -a n dr o ge ns wit hi n a year bef ore i n de x date (fr o m 
E n ha nce d _ Met P C _ Orals .
D ocet a xel use
A bi nar y va ria ble ( yes/ n o) will be create d f or patie nts wit h d oceta xel use 
pri or t o m C R P C
.
C hr o nic c ortic oster oi d use
A bi nar y varia ble ( yes/ n o) w ill be create d f or patie nts wit h c hr o nic 
c ortic oster oi d use wit hi n a year pri or t o i n de x date, defi ne d as ha vi n g o ne 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)
C CI

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 2 1 of 4 7
T a ble 1.
B aseli ne D e m o gr a p hic a n d C li nic al C h ar acteristic V v ari a bles
V ari a ble
O per ati o n al defi niti o n
of t he f oll o wi n g:

At least t w o c ortic oster oi d me dicati o n or d ers wit h at least 9 0 da ys 
a part w it hi n a year pri or t o i n de x date

At least t w o c ortic oster oi d a d mi nistrati o ns wit h at least 9 0 da ys a part 
wit hi n a year pri or t o i n de x date
O pi oi d a n al gesics
A bi nar y varia ble ( yes/ n o) w ill be create d f or patie nts wit h m e dicati o n 
or der f or o pi oi d a nal gesics wit hi n a year pri or t o i n de x date.
Ket oc o n az ole
A bi nar y varia ble ( yes/ n o) w ill be create d f or patie nts wit h use of
ket oc o naz ole wit hi n a year pri or t o i n de x date (fr o m 
E n ha nce d _ Met P C _ Orals ).
M o difie d N CI C CI Sc ore
T he N CI versi o n of t he C CI sc ore w ill be create d base d o n dia g n oses a n y 
ti me pri or t o or o n t he i n de x date. As a n ote E H R data ma y ca pt ure o nl y 
date of first dia g n osis or ma y ha ve m ulti ple rec or ds f or t he sa me dia g n osis 
at differe nt ti mes. Bi nar y varia bles ( yes/ n o) will be create d t o fla g patie nts 
w h o ha ve clai ms f or eac h of t he i n di vi d ual c o m or b i dities wit hi n t he N CI. 
Ca ncer will be e xcl u de d fr o m C CI sc ore. 
H y perte nsi o n
A bi nar y varia ble ( yes/ n o) will be create d f or patie nts w it h dia g n osis f or 
h y perte nsi o n b ef ore or o n t he i n de x date .
S tr o ke
A bi nar y varia ble ( yes/ n o) will be create d f or patie nts w it h dia g n osis f or 
str o ke bef ore or t he i n de x date .
Ac ute C or o n ar y S y n dr o m e
A bi nar y varia ble ( yes/ n o) will be create d f or patie nts w it h clai ms f or 
ac ute c or o na r y s y n dr o me bef ore or o n t he i n de x date .
A n gi n a Pect oris
A bi nar y varia ble ( yes/ n o) will be create d f or patie nts w it h clai ms f or 
a n gi na pect oris bef ore or o n t he i n de x date .
Arr h yt h mi a
A bi nar y varia ble ( yes/ n o) will be create d f or patie nts w it h clai ms for 
arr h yt h mia bef ore or o n t he i n de x date .
M y oc ar di al I nf arcti o n
A bi nar y varia ble ( yes/ n o) will be create d f or patie nts w it h clai ms f or 
m y ocar dial i nfracti o n bef ore or o n t he i n de x date .
C o n gesti ve He art F ail ure
A bi nar y varia ble ( yes/ n o) will be create d f or patie nts w it h clai ms f or 
c o n gesti ve heart fail ure bef ore or o n t he i n de x date .
H y perli pi de mi a
A bi nar y varia ble ( yes/ n o) will be create d f or patie nts w it h clai ms f or 
h y perli pi de mia bef ore or o n t he i n de x date .
L o wer -e xtre mit y Arteri al Occl usi ve 
Dis e ase
A bi nar y varia ble ( yes/ n o) w ill be create d f or patie nts wit h clai ms f or l o w-
e xtre mit y arterial occl usi ve disease bef ore or o n t he i n de x date .
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 2 2 of 4 7
T a ble 1.
B aseli ne D e m o gr a p hic a n d C li nic al C h ar acteristic V v ari a bles
V ari a ble
O per ati o n al defi niti o n
T y pe 2 Di a betes
A bi nar y varia ble ( yes/ n o) will be create d f or patie nt s wit h clai ms f or t ype 
2 dia betes bef o re or o n t he i n de x date .
C hr o nic O bstr ucti ve P ul m o n ar y 
Dise ase
A bi nar y varia ble ( yes/ n o) will be create d f or patie nts w it h clai ms f or
c hr o nic o bstr ucti ve p ul m o nar y disease bef ore or o n t he i n de x date .
I nfl a m m at or y Bo wel Dise ase
A bi nar y varia ble ( yes/ n o ) will be create d f or patie nts wit h clai ms f or
i nfla m mat or y b o wel disease bef ore or o n t he i n de x date .
A ne mi a
A bi nar y varia ble ( yes/ n o) will be create d f or patie nts w it h clai ms f or
a ne mia bef ore or o n t he i n de x date .
Seiz ures 
A bi nar y varia ble ( yes/ n o) wi ll be create d f or patie nts with clai ms f or
seiz ures bef ore or o n t he i n de x date .
Uri n ar y tr act i nfecti o n
A bi nar y varia ble ( yes/ n o) will be create d f or patie nts w it h clai ms f or
uri nar y tract i nfecti o n bef ore or o n t he i n de x date .
Re n al dise ase
A bi nar y v aria ble ( yes/ n o) will be creat e d f or patie nts wit h clai ms f or
re nal disease bef ore or o n t he i n de x date .
Li ver dise ase
A bi nar y varia ble ( yes/ n o) will be create d f or patie nts w it h clai ms f or li ver 
disease bef ore or o n t he i n de x date .
R he u m at ol o gic dis e ase
A bi nar y varia ble ( yes/ n o) w ill be create d f or patie nts wit h clai ms f or
r he u mat ol o gic disease bef ore or o n t he i n de x date.
H e m i ple gi a
A bi nar y varia ble ( yes/ n o) will be create d f or patie nts w it h clai ms f or
h e mi ple gia bef ore or o n t he i n de x date .
P ar al y sis
A bi nar y varia ble ( yes/ n o) will be create d f or patie nts w it h clai ms f or
p aral ysis bef ore or o n t he i n de x date .
Pe ptic ulcer dise ase
A bi nar y varia ble ( yes/ n o) will be create d f or patie nts w it h clai ms f or
p e ptic ulcer disease bef ore or o n t he i n de x dat e.
AI Ds
A bi nar y varia ble ( ye s/ n o) will be create d f or patie nts w it h clai ms f or
AI D S bef ore or o n t he i n de x date .
I m p ote nce
A bi nar y varia ble ( yes/ n o) will be create d f or patie nts w it h clai ms f or
i mp ote nce bef ore or o n t he i n de x date .
B o d y m ass i n de x ( BMI )
B o d y  mass i n de x ( wei g ht i n k g/( hei g ht i n meters) ^ 2) w ill be calc ulate d 
base d o n m ost rece nt meas ure of hei g ht a n d wei g ht pri or t o or o n i n de x 
date. B MI w ill be calc ulate d as a c o nti n u o us varia ble a n d f or t he 
f oll o wi n g cate g ories: < 1 8. 5, 1 8. 5 t o < 2 5, 2 5 t o < 3 0, 3 0 t o < 3 5, 3 5 t o < 4 0, 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 2 3 of 4 7
T a ble 1.
B aseli ne D e m o gr a p hic a n d C li nic al C h ar acteristic V v ari a bles
V ari a ble
O per ati o n al defi niti o n
a n d ≥4 0.
E C O G
Varia ble w ill be create d f or E C O G base d o n t he m ost rece nt assess me nt 
pri or t o or o n i n de x date. E C O G w ill be re p orte d as a cate g orical varia ble: 
0, 1, 2, 3, 4, u n k n o w n .
Pr ost ate -s pecific a nti ge n (P S A )
P S A w ill be calc ulate d base d o n t he m o st rece nt assess me nt pri or t o or o n 
t he i n de x date a n d retai ne d i n t he dataset as a c o nti n u o us varia ble. 
De pe n di n g o n c o m plete ness of a vaila ble P S A at i n de x, a cate g oria l
varia ble f or P S A ma y be create d base d o n P S A distri b uti o n wit h a 
cate g or y f or u n k n o w n P S A at i n de x.
Al b u mi n
Varia ble w ill be create d f or al b u mi n base d o n t he m ost rece nt assess me nt 
pri or t o or o n t he i n de x data a n d will be retai ne d as a c o nti n u o us varia bles 
or cate g orical varia ble base d o n c ut offs f or n or m al ra n ge i n t he data.
A L P
Varia b le will be create d f or A L P base d o n t he m ost rece nt assess me nt 
pri or t o or o n t he i n de x data a n d will be retai ne d as a c o nti n u o us varia bles 
or cate g orical varia ble base d o n c ut offs f or n or mal ra n ge i n t he data.
H e m o gl o bi n
Var ia ble will be create d f or he m o gl o bi n base d o n t he m ost rece nt 
assess me nt pri or t o or o n t he i n de x data a n d will be retai ne d as a 
c o nti n u o us varia bles or cate g orical varia ble base d o n c ut offs f or n or mal 
ra n ge i n t he data.
L act ate de h y dr o ge n ase (L D H )
Var ia ble will be create d f or L D H bas e d o n t he m ost rece nt assess me nt 
pri or t o or o n t he i n de x data a n d will be retai ne d as a c o nti n u o us varia bles 
or cate g orical varia ble base d o n c ut offs f or n or mal ra n ge i n t he data.
9. 3. 2. St u d y P eri o d V ari a bles
St u d y  peri o d variable s (Ta ble 2 ) are s u m marize d bel o w. 
T a ble 2.
St u d y P eri o d V ari a bles  
V ari a ble
O per ati o n al defi niti o n
F oll o w -u p ti me
T he f oll o w -u p peri o d w ill be defi ne d as t he ti me fr o m t he i n de x date t o 
t he earliest of  deat h , e n d of data a vaila bili t y (e g, 2 0 2 2 Q 4) , or last 
patie nt c o ntact defi ne d as t he date of m ost rece nt c o ntact i n t he data, 
w hic h c o ul d be rec or di n g of vital i nf or mati o n, visit, a me dicati o n 
a d mi nistrati o n, or a la b orat or y test/res ult bei n g re p orte d , last a bstracte d 
oral t hera p y da te, or last cli nicall y-rele va nt a bstracte d date (e g, f or 
s peci me n c ollecti o n, pr oce d ure) .
O S ( ti me t o de at h )
Ti m e t o deat h will be defi ne d as t he ti me fr o m t he i nitiati o n of 
e nzal uta mi de or a birater o ne (ie, i n de x date) t o t he date of deat h. Patie nts 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 2 4 of 4 7
T a ble 2.
St u d y P eri o d V ari a bles  
V ari a ble
O per ati o n al defi niti o n
w h o d o n ot die w ill be ce ns ore d at t heir last a vaila ble f oll o w-u p, w hic h 
will be defi ne d as t he earlier of e n d of d ata a vaila bilit y or last patie nt 
c o ntact.
Date of deat h. I n m ost Flatir o n deli vera bles, deat h data is deli vere d w it h
a mo nt h gra n ularit y. 
Date of deat h is a c o nse ns us varia ble acr oss t he t hree data s o urces ( E H R, 
S ocial Sec urit y Deat h I n de x ( S S DI ) a n d o bituar y data). Flatir o n 
ge nerates t he varia ble acc or di n g t o t he f oll o wi n g r ules a n d hierarc h y 
( prefere nce is base d on c o m parati ve a nal yses wit h t he N ati o nal Deat h 
I n de x as t he g ol d sta n dar d):
Use a bstracte d dates o ver str uct ure d dates w he n t he a bstracte d date
gra n ularit y is at t he da y le vel.
Use t he f oll o wi n g r ules w he n t here are m ulti ple str uct ure d dates of deat h:
If all t hree dates are i n a gree me nt, t hat date of deat h is selecte d
If a n y t w o dates are i n a gree me nt, t hat date of deat h is selecte d
If n o ne of t he dates are i n a gree me nt, t he n t he ra n k or der t o w hic h t he 
date of deat h is selecte d is: S S DI O bit uar y data E H R
Li n e of t her a p y ( L O T) st art d ate

T he i n de x date a n d t he start date f or t he first L O T is t he i nitiati o n of 
e nzal uta mi de or a birater o ne wit hi n 1 4 da ys bef ore or o n or after t he 
m C R P C dia g n osis date .

T he start date f or t he sec o n d a n d later L O Ts will be defi n e d as t he 
date of t he first clai m f or a s yste mic treat me nt f oll o wi n g t he e n d of 
t he prece di ng L O T .
L O T re gi me n
A L O T will i ncl u de all s yste mic treat me nts starte d wit hi n 2 8 da ys of t he 
L O T start date . T his gr o u p of treat me nts starte d wit hi n 2 8 da ys of t he 
start date will be referre d t o as t he L O T re gi me n. As a n ote, t his st u d y 
will f oll o w Flatir o n m P C re gi me n r ules a n d will e xcl u de t he f oll o wi n g 
fr o m t he re gi me ns: ra diati o n a n d s ur ger y, lutei nizi n g h or m o ne -releasi n g 
h or m o ne ( L H R H) a g o nists/a nta g o nists , bica l uta mi de, nil uta mi de, 
fl uta mi de, de n os u ma b , z ole dr o nic aci d, m e gestr ol, a n d m e gestr ol acetate.
L O T e n d d ate
Ge nerall y t his st u d y will use t he Flatir o n L O T defi niti o n r ules f or m P C. 
A L O T will e n d w he n o ne of t he f oll o wi n g occ urs :

A ne w s yste mic treat me nt is starte d m ore t ha n 2 8 da ys after t he L O T 
start date
E xce pti o n f or ra di u m -2 2 3 2 1
o
Starti n g ra di u m -2 2 3 wit hi n 9 0 da ys of t he L O T start date d oes 
n ot e n d a L O T
o
Starti n g ra di u m -2 2 3 m ore t ha n 9 0 da ys after t he L O T start dat e 
d oes e n d a L O T

A d diti o n of s elect beta e mitters ( Str o nti u m -8 9, Sa mari u m -1 5 3, 
R he ni u m -1 8 8) t o a re gi me n d oes n ot a d va nce t he L O T. A d diti o n of 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 2 5 of 4 7
T a ble 2.
St u d y P eri o d V ari a bles  
V ari a ble
O per ati o n al defi niti o n
l uteti u m 1 7 7 vi pi v oti de tetra xeta n t o a re gi me n > 2 8 da ys after t he 
start of t he re gi me n d oes a d va nce t he L O T.

W he n a ga p i n dr u g e pis o des of m o re t ha n 9 0 da ys occ urs, t he li ne 
n u m ber is a d va nce d .
L O T e n d date w ill be defi ne d as t he earliest of 1) deat h, 2) last patie nt 
c o ntact, 3) da y bef ore t he start of ne xt L O T, 4 ) e n d of data a vaila bilit y
Tre at m e nt d ur ati o n ( ti me t o 
disc o nti n u ati o n) 
Treat me nt d urati o n of t he i n de x treat me nt will be defi ne d as t he ti me 
fr o m t he i nitiati o n of e nzal uta mi de or a birater o ne (ie, i n de x date) t o t he 
disc o nti n uati o n date. Disc o nti n uati o n will be defi ne d as t he earliest of 1)
deat h, 2) a b stracte d e n d date f or last e nzal uta mi de or a birater o ne dr u g 
e pis o de t hat starts wit hi n t he i n de x treat me nt L O T (dr u g e pis o des f or 
a bstracte d oral t hera pies fr o m t he Flatir o n Dr u g E pis o de ta ble) , or 3) da y 
bef ore t he start of ne xt L O T . Patie nts w h o d o n o t disc o nti n ue will be 
ce ns ore d at t heir last a vaila ble f oll o w-u p, w hic h will be defi ne d as t he 
earlier of e n d of data a vaila bilit y or last patie nt c o ntact . T he treat me nt 
d urati o n defi niti o n f oll o ws Flatir o n’s g ui da nce o n “ Strate gies f or 
Esti mati n g Real -W or l d Ti m e t o Treat me nt Disc o nti n uat i o n (r wT T D) 
Usi n g A bstracte d Disc o nti n uati o n I nf or mati o n” a vaila ble t hr o u g h 
Flatir o n K n o wle d ge Ce nter .
Ti me t o s u bse q ue nt t her a p y
Ti m e t o s u bse q ue nt t hera p y will be defi ne d as t he ti me fr o m t he i nitiati o n 
of e nzal uta mi de o r abirater o ne (ie, i n de x date) t o t he start of ne xt L O T. 
Patie nts w h o d o n ot start a ne w L O T will be ce ns ore d at t he earliest of 1) 
deat h, 2) e n d of data a vaila bilit y or 3) last patie nt c o ntact .
Tre at m e nt se q ue nce
Treat me nt se q ue nces will i ncl u de i n de x tr eat me nt ie, e nzal uta mi de or 
a birater o ne, ne xt treat me nt r e gi me n f oll o wi n g t he i n de x treat me nt 
(ie, sec o n d treat me nt), a n d s u bse q ue nt treat me nt re gi me n f oll o wi n g t he 
sec o n d treat me nt if a n y (ie, t hir d treat me nt).
T he f oll o w i n g a ge nts will be c o nsi dere d as s u bse q ue nt treat me nt re gi me n 
p ost e nzal uta mi de or a birater o ne:

N H T

C he m ot hera p y

I m m u n ot hera p y

Ra di u m -2 2 3

Ket oc o naz ole

Ola pari b

R uca pari b
A D T a n d a nti -a n dr o ge n ( bical uta mi de, fl uta mi de, nil uta mi de) w ill n ot be 
c o nsi dere d as s u bse q ue nt treat me nt re gi me ns p os t enzal uta mi de or 
a birater o ne
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 2 6 of 4 7
9. 4. D at a S o urces
De -i de ntifie d patie nt-le vel data fr o m patie nts wit h m P C will be e x tracte d fr o m t he Flatir o n 
Healt h Electr o nic Healt h Rec or d data base. T he Flatir o n data base c o nsists of nati o nall y  
re prese ntati ve real-w orl d data fr om c o m m u nit y practices a n d aca d e mic me dical ce nters fr o m 
2 0 1 3 t hr o u g h t he prese nt a n d c o ntai ns str uct ure d a n d u nstr uct ure d data c urate d via 
tec h n ol o g y-e na ble d a bstracti o n a n d s u p ple me nte d wit h t hir d -part y  deat h i nf or mati o n.
9. 5. St u d y S ize
Ta ble 3 be l o w s h o ws sa m ple sizes nee de d t o detect a ra n ge of hazar d rati os ( H R) f or O S 
fr o m 0. 80 t o 0. 90 bet wee n e nzal uta mi de a n d a birater o ne wit h 8 0 % p o wer a n d a o ne-si de d 
al p ha le vel of 0. 0 2 5, v ar y i n g t he perce nta ge of deat hs d uri ng t he st u d y f oll o w -u p peri o d 
( 5 0 %, 5 5 % a n d 6 0 %). Calc ulati o ns are base d o n t he met h o d b y  Sc h oe nfel d ( 1 9 8 3).3 1 I n t he 
p u blis he d Marar et al .2 8 Flatir o n st u d y , t here were 2 7 8 5 m C R P C patie nts i nitiati n g first -li ne 
treat me nt wit h si n gle a ge nt e nzal uta mi de or a birater o ne , a n d a p pr oxi matel y 2 5 0 0 were 
c he m ot hera p y -naï ve . O ur st u d y  will use m ore rece nt data a n d ha ve l o n ger f oll o w u p a n d ma y 
ha ve a lar ger sa m ple of patie nts. If we ha ve a si milar n u m ber of patie nts we e x pect t hat we 
will be a ble t o detec t at H R ≤0. 8 5 wit h 8 0 % p o wer.
T a ble 3.
S a m ple S izes t o D etect a R a n ge of O S H Rs f or E nz al ut a mi de vs 
A bir ater o ne wit h 8 0 % P o wer
1: 1 r ati o of p atie nts recei vi n g 
e nz al ut a mi de t o a bir ater o ne
2: 3 r ati o of p atie nts recei vi n g 
e nz al ut a mi de t o a bir ater o ne
H R
5 0 % 
de at hs
5 5 % 
de at hs
6 0 % 
de at hs 
5 0 % 
de at hs 
5 5 % 
de at hs 
6 0 % 
de at hs 
0. 8 0 
1 2 6 2  
1 1 4 7  
1 0 5 2  
1 3 1 4  
1 1 9 5  
1 0 9 5 
0. 8 1 
1 4 1 6  
1 2 8 7  
1 1 8 0  
1 4 7 4  
1 3 4 0  
1 2 2 8 
0. 8 2 
1 5 9 6  
1 4 5 1  
1 3 3 0  
1 6 6 2  
1 5 1 1  
1 3 8 5 
0. 8 3 
1 8 1 0  
1 6 4 5  
1 5 0 8  
1 8 8 4  
1 7 1 3  
1 5 7 0 
0. 8 4 
2 0 6 6  
1 8 7 8  
1 7 2 2  
2 1 5 2  
1 9 5 6  
1 7 9 3 
0. 8 5 
2 3 7 8  
2 1 6 2  
1 9 8 2  
2 4 7 8  
2 2 5 3  
2 0 6 5 
0. 8 6 
2 7 6 2  
2 5 1 1  
2 3 0 2  
2 8 7 6  
2 6 1 5  
2 3 9 7 
0. 8 7 
3 2 3 8  
2 9 4 4  
2 6 9 8  
3 3 7 4  
3 0 6 7  
2 8 1 2 
0. 8 8 
3 8 4 4  
3 4 9 5  
3 2 0 3  
4 0 0 4  
3 6 4 0  
3 3 3 7 
0. 8 9 
4 6 2 4  
4 2 0 4  
3 8 5 3  
4 8 1 6  
4 3 7 8  
4 0 1 3 
0. 9 0 
5 6 5 8  
5 1 4 4  
4 7 1 5  
5 8 9 2  
5 3 5 6  
4 9 1 0 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 2 7 of 4 7
9. 6. D at a M a n a ge me nt 
A clea n, patie nt -le vel dataset will be ge nerate d f or use t hr o u g h o ut t he st u dy. T his pr ocess 
will e ntail basic e x pl orat or y  c hec ks t o e ns ure data i nte grity;  clea ni n g a n d ref or matti n g t he 
ra w data as nee de d; a n d creati n g varia bles f or all ke y  st u d y meas ures, i ncl u di n g patie nt 
c haracteristics, treat me nt start a n d e n d dates, a n d classificati o n of treat me nts a n d me dicati o n . 
All data will be st ore d a n d mai ntai ne d o n a sec ure e ncr ypte d n o n -cl o u d-base d ser ver a n d 
accesse d o ver a sec ure i nter nal pri vate wi de area net w or k. T he data will be ma de accessi ble 
o nl y  t o i n di vi d uals w or ki n g o n t he c urre nt st u d y. N o atte m pt will be ma de t o i de ntif y 
i n di vi d ual patie nts, h os pitals, or p h ysicia ns. A nalyses will be c o n d ucte d usi n g S A S 9. 4 ( S A S 
I nstit ute, Car y N C).
9. 7. D at a A n al ysis
9. 7. 1. Pri m ar y A n al ysis
T he pri mar y  a nalys is, a d dressi n g t he pri mar y o bjecti ve, will c o m pare O S i n patie nts wit h 
c he m ot hera p y- nai ve m C R P C i n Flatir o n i nitiati n g e nzal uta mi de vs. a birater o ne, a dj usti n g f or 
baseli ne c o nf o u n ders usi n g I P T W as descri be d bel o w.
9. 7. 1. 1. S u m m ar y of B aseli ne C h ar acteristics a n d O S
Baseli ne c haracteristics i ncl u di n g de m o gra p hics, i ns ura nce stat us, race, disease 
c haracteristics, ti me fr o m first P C dia g n osis t o m C R P C dia g n osis, ti me fr o m m C R P C 
dia g n o sis t o i n de x date, ti me fr o m first A D T t o i n de x date, E C O G, baseli ne la b val ues, pri or 
pr ostate ca ncer treat me nts, a n d c o m or bi dities will be c o m pare d bet wee n e nzal uta mi de a n d 
a birater o n e gr o u ps. 
S u m mar y  statistics f or baseli ne c haracteristics will be re p orte d, i ncl u di n g fre q ue ncies a n d 
perce nta ges f or cate g orical varia bles, a n d mea ns, sta n dar d de viati o ns, a n d me dia ns f or 
c o nti n u o us varia bles. 
Descri pti ve a nal ys es of O S will be d o ne usi n g K M a nal y ses t o descri be t he pr o ba bilit y of 
s ur vi val o ver ti me i n eac h c o h ort. T he me dia n f oll o w-u p ti me, n u m ber of deat hs a n d me dia n 
O S (a n d 9 5 % CI ) will be re p orte d f or eac h gr o u p. U na dj uste d C o x pr o p orti o nal hazar d 
m o dels will al s o be fit f or descri pti ve p ur p oses o nl y .
9. 7. 1. 2. C o m p ar ati ve a n al ysis of O S f or t he pri m ar y o bjecti ve , a dj usti n g usi n g I P T W
T he pri mar y  a nalys is, a d dressi n g t he pri mar y o bjecti ve, will c o m pare O S i n c he m ot hera py-
nai ve m C R P C patie nts i nitiati n g e nzal uta mi de vs. a birater o ne a dj usti n g f or c o nf o u n di n g as 
descri be d bel o w. I P T W will be use d t o a dj ust f or differ ences bet wee n t he t w o treat me nt 
c o h orts o n t he pre -s pecifie d c o nf o u n di n g fact ors liste d i n A p pe n di x 2 Ta ble 1 . T hese 
p ote ntial c o nf o u n di n g fact ors were base d o n p u blis he d articles re p orti n g pr o g n ostic fact ors 
f or O S. I PT W will be ba se d o n pr o pe nsity sc ores esti mate d as descri be d bel o w. 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 2 8 of 4 7
Pr o pe nsity sc ore c alc ul ati o n
Pr o pe nsit y  sc ores will be o btai ne d base d o n a l o gistic re gressi o n m o del t hat i ncl u des 
treat me nt gr o u p (e nzal uta mi de or a birater o ne) as t he de pe n de nt varia ble, a n d t he pre-
s pecifie d set of c o nf o u n ders liste d i n A p pe n di x 2 Ta ble 1 as i n de pe n de nt varia bles. A 
pr o pe nsit y  sc ore, defi ne d as t he pr o ba bilit y of i nitiati n g e nzal uta mi de as o p p ose d t o 
a birater o ne, c o n diti o nal o n baseli ne c haracteristics, will be esti mate d fr o m t his m o del f or 
eac h patie nt. T he distri b uti o n of pr o pe nsit y  sc ores i n t he t w o treat me nt c o h orts will be 
c o m pare d usi n g de nsit y pl ots t o e ns ure a de q uate o verla p.
I P T W
Patie nts’ wei g hts will be a f u ncti o n of t he pr o pe nsit y sc ore: wei g hts f or e nzal uta mi de 
patie nts will be 1/( pr o ba bilit y  of i nitiati n g e nzal uta mi de), w hereas wei g hts f or a birater o ne 
patie nts will be 1/( 1- pr o ba bilit y  of i nitiati n g e nzal uta mi de). T o a d dress t he p ossi bilit y of 
e xtre me wei g ht val ues, patie nts’ wei g hts will be sta bilize d b y t he mar gi nal pr o ba bilit y of 
bei n g i n t heir treat me nt gr o u p. 3 2 T he distri b uti o n of t he sta bilize d wei g ht s will be e xa mi ne d, 
a n d if nee de d, e xtre me wei g hts ma y  be tr u ncate d s uc h t hat wei g hts e xcee di n g a particular 
t hres h ol d are eac h set t o t hat t hres h ol d.3 3
Ba la nce of t he baseli ne c haracteristics bet wee n e nzal uta mi de a n d a birater o ne gr o u ps i n t he 
wei g hte d sa m ple will be assesse d usi n g sta n dar dize d differe nces. Baseli ne c haracteristics 
will be c o nsi dere d t o be a de q uatel y bala nce d if t he a bs ol ute val ue of sta n dar dize d differe nces 
is less t ha n 0. 1. 3 4 If i m bala nces re mai n, a d diti o nal c o variates ma y be i ncl u de d i n t he 
s u bse q ue nt IP T W - adj uste d C o x pr o p orti o nal hazar ds re gressi o n m o del.
K a pl a n -Meier a n alysis a n d C ox pr o p orti o n al -h az ar d s m o del
O S will be c o m pare d bet wee n e nzal uta mi de a n d a birater o ne -treate d patie nts i n t he wei g hte d 
sa m ple usi n g wei g hte d K M a nal yses. T o c o m pare t he hazar d o f deat h bet wee n patie nts w h o 
i nitiate d e nzal uta mi de a n d patie nts w h o i nitiate d a birater o ne, a wei g hte d C o x pr o p orti o nal 
hazar ds m o del wit h a n i n de pe n de nt varia ble f or treat me nt gr o u p will be fitte d, usi n g a r o b ust 
varia nce esti mat or. H Rs wit h c orres p o n di n g 9 5 % CI s a n d p-val ues will be re p orte d.
9. 7. 2. Sec o n d ar y A n al ysis 1
9. 7. 2. 1. C o m p ar ati ve A n al ysis of O S f or t he S ec o n d ar y O bjecti ve 1 , A dj usti n g U si n g 
I P T W
T he sec o n dar y  a nal ysis will f oc us o n t he s u b gr o u p of patie nts w h o recei ve d e nzal uta mi de or 
a birater o ne wit h o ut s u bs eq ue nt t hera p y (ie, i ncl u di n g o nly patie nts w h o di d n ot s witc h t o or 
a d d a n ot her m C R P C treat me nt). Patie nt c haracteristics a n d O S will be s u m marize d f or t his 
s u b gr o u p as d o ne i n t he pri mar y a nalys is, descri be d i n Secti o n 9. 7. 1. 1 . O S bet wee n t hese t w o 
gr o u ps will be c o m pare d usi n g a n I P T W -a dj uste d a nalys is. Pr o pe nsit y  sc ores a n d bala nce of 
pre -s pecifie d c o nf o u n ders i n t his s u b gr o u p of patie nts will be assesse d. If s u bsta ntial 
i m bala nces e xist, pr ope nsit y  sc ores ma y be re-esti mate d f or t his s u b gr o u p of patie nt s, usi n g 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 2 9 of 4 7
t he sa me pre-s pecifie d c o nf o u n ders a n d pr o pe nsity sc ore esti mati o n met h o d as descri be d f or 
t he pri mar y a nal ysis i n Secti o n 9. 7. 1. 2 . 
9. 7. 3. Sec o n d ar y A n al ysis 2
9. 7. 3. 1. C o m p ar ati ve A n al yses of T re at me nt D ur ati o n a n d T i me t o S u bse q ue nt 
T re at me nt T her a p y f or t he S ec o n d ar y O bjecti ve 2, A dj usti n g U si n g I P T W
T he sec o n dar y  a nal ysis 2, a d dressi n g t he sec o n dar y o bjecti ve 2, will c o m pare treat me nt 
d urati o n of t he i n de x treat me nt a n d ti me t o s u bse q ue nt t hera py i n patie nts wit h 
c he m ot hera p y -nai ve m C R P C i nitiati n g e nzal uta mi de vs. a birater o ne, a dj usti n g f or baseli ne 
c o nf o u n ders usi n g I P T W as descri be d i n Secti o n 9. 7. 1. 2 .
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)
C CI

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 3 0 of 4 7
9. 8. Q u alit y C o ntr ol
Best practice g ui deli nes will be f oll o we d t o e ns ure pr oject q ualit y, i ncl u di n g str uct ure d 
or ga nizati o n of pr oject materials (e g, data e xtracts, statistical s oft ware pr o gra ms, o ut p ut 
ta bles) a n d sta n dar d i nter nal a u dit pr ocess. T he a u dit pr ocess b ot h c o nfir ms t he vali dit y of 
t he a nalyt ical a p pr oac h a n d e ns ures t hat all pr o gra ms a n d res ults are acc urate.
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)
C CI

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 3 1 of 4 7
9. 9. Li mit ati o ns of t he R ese arc h M et h o ds
T he a nal y ses c o n d ucte d as part of t his st u d y  are s u bject t o t he f oll o wi n g li mitati o ns, w hic h 
will be a d dresse d i n a n y write -u p of t he st u d y:

Flatir o n data c ollects patie nt i nf or mati o n m ostl y  fr o m c o m m u nit y o nc ol o g y ce nters.

C ertai n c o variates m a y  ha ve bee n i nc o m pletely c o de d d ue t o inc o nsiste nt electr o nic 
healt h rec or d d oc u me ntati o n (e g , c o m or bi dities), a n d i nf or mati o n a b o ut s o me 
varia bles affecti n g pr o g n osis a n d o utc o mes were n ot a vaila ble i n t he data base.
9. 1 0. Ot her A s pects
N ot a p plica ble .
1 0. P R O T E C TI O N O F H U M A N S U B J E C T S
T his st u d y  i n v ol ves data t hat e xist i n a n o n y mize d str uct ure d f or mat a n d c o ntai n n o patie nt 
pers o nal i nf or mati o n. 
1 0. 1. P atie nt Inf or m ati o n 
T his st u d y  i n v ol ves data t hat e xist i n a n o n ymize d str uct ure d f or mat a n d c o ntai n n o patie nt 
pers o nal i nf or mati o n . 
1 0. 2. P atie nt C o nse nt
As t his st u d y  i n v ol ves a n o n ymize d str uct ure d data, w hic h acc or di n g t o a p plica ble le gal 
re q uire me nts d o n ot c o ntai n data s u bject t o pri vac y la ws, o btai ni n g i nf or me d c o nse nt fr o m 
patie nts b y  Pfizer is n ot re q uire d.
1 0. 3. I nstit uti o n al R e vie w B o ar d (I R B)/I n de pe n de nt Et hics C o m mi ttee (I E C)
T he I R B a p pr o val of t his o bser vati o nal st u d y  wit h sec o n dar y data use fr o m a n e xisti n g E H R 
data base is c o vere d b y I R B a p pr o val o n Flatir o n pare nt pr ot oc ol. Data pr o vi de d b y Flatir o n 
t o t hir d parties were de-i de ntifie d a n d pr o visi o ns were i n place t o pre ve nt re -i de ntificati o n i n 
or der t o pr otect patie nts’ c o nfi de ntialit y . T his st u d y is e xe m pt fr o m i nstit uti o nal re vie w b oar d 
a p pr o val beca use it is retr os pecti ve, n o n -i nter ve nti o nal, a n d will use a n o n y mize d data 
pr o vi de d b y  Flatir o n.
1 0. 4. Et hic al C o n d u ct of t he S t u d y
T he st u d y  will be c o n d ucte d i n acc or da nce wit h le gal a n d re g ulat or y re q uire me nts, as well as 
wit h scie ntific p ur p ose, val ue a n d ri g or a n d f oll o w ge nerall y acce pte d researc h practices 
descri be d i n G ui deli nes f or G o o d P har mac oe pi de mi ol o g y  Practices ( G P P). P u blic P olic y 
C o m mittee, I nter nati o nal S ociet y  of P har mac oe pi de mi ol o g y.  P har mac oe pi de mi ol o g y a n d 
Dr u g Safet y 2 0 1 6; 2 5: 2 - 1 0. htt ps :// o nli neli brar y. wile y.c o m/ d oi/f ull/ 1 0. 1 0 0 2/ p ds. 3 8 9 1.
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 3 2 of 4 7
1 1. M A N A G E M E N T A N D R E P O R TI N G O F A D V E R S E E V E N T S/ A D V E R S E 
R E A C TI O N S 
T his st u d y  i n v ol ves data t hat e xist as str ucture d data b y t he ti me of st u d y start . I n t his data 
s o urce, i n di vi d ual patie nt data are n ot retrie ve d or vali date d, a n d it is n ot p ossi ble t o li n k (ie, 
i de ntif y a p ote ntial ass ociati o n bet wee n) a partic ular pro d uct a n d me dical e ve nt f or a n y  
i n di vi d ual. T h us, t he mi ni m u m criteria f or re p orti n g a n a d verse e ve nt ( A E) (ie, i de ntifia ble 
pat ie nt, i de ntifia ble re p orter, a s us pect pr o d uct, a n d e ve nt) ca n n ot be met.
1 2. P L A N S F O R DI S S E MI N A T I N G A N D C O M M U NI C A TI NG S T U D Y R E S U L T S
Base d o n t he a nal ys is res ults, a st u d y re p ort s u m marizi n g t he bac k gr o u n d, o bjecti ves, 
met h o ds, res ults, a n d c o ncl usi o n of t he st u d y will be pre pare d . T he st u d y  re p ort ma y be 
disse mi nate d wit hi n Pfizer b ut is n ot e x pecte d t o be e xter nall y c o m m u nicate d. In t he e ve nt of 
a n y pr o hi biti o n or restricti o n i m p ose d (e g, cli nical h ol d) b y a n a p plica ble c o m pete nt 
a ut h orit y i n a ny area of t he w orl d, or if t he i n vesti gat or is a ware of a n y  ne w i nf or mati o n 
w hic h mi g ht i nfl ue nce t he e val uati o n of t he be nefits a n d ris ks o f a Pfizer pr o d uct, Pfizer 
s h o ul d be i nf or me d i m me diately. U p o n st u d y c o m pleti o n a n d fi nalizati o n of t he st u d y re p ort, 
t he res ults of t his n o n-i nter ve nti o nal st u dy will be s u b mitte d f or p u blicati o n or c o nfere nce 
prese ntati o n , pe n di n g o n disc ussi o n a n d a gre eme nt of all parties i n v ol ve d i n t he a nal ys is.
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 3 3 of 4 7
1 3. R E F E R E N C E S
1.  
Nati o nal Ca ncer I nstit ute. S E E R Ca ncer Stat Facts: Pr ostate Ca ncer. 2 0 2 2 ; 
htt ps://seer.ca ncer. g o v/statfacts/ ht ml/ pr ost. ht ml . Accesse d Fe br uar y  2 1, 2 0 23.
2.
Nati o nal Ca ncer I nstit ute. Pr ostate ca ncer treat me nt: healt h pr ofessi o nal versi o n. 2 0 1 6; 
htt p:// w w w.ca ncer. g o v/t y pes/ pr ostate/ h p / pr ostate-treat me nt- p d q. Accesse d J ul y 2 1, 
2 0 2 1.
3.
Kir b y  M, Hirst C, Cra wf or d E D. C haracterisi n g t he castrati o n-resista nt pr ostate ca ncer 
p o p ulati o n: a s y ste matic re vie w. I nt J Cli n Pr act. 2 0 1 1; 6 5( 1 1): 1 1 8 0 - 1 1 9 2.
4.  
He L, Fa n g H, C he n C, et al. Metastatic castra ti o n-resista nt pr ostate ca ncer: Aca de mic 
i nsi g hts a n d pers pecti ves t hr o u g h bi bli o metric a nal ysis. Me dici ne ( B alti m ore). 
2 0 2 0; 9 9( 1 5):e 1 9 7 6 0.
5.
Nati o nal C o m p re he nsi ve Ca ncer Net w or k. Pr ostate Ca ncer. . 2 0 2 3; Versi o n 
1. 2 0 2 3: htt ps:// w w w. ncc n. or g/ pr ofessi o nals/ p h ys icia n _ gls/ p df/ pr ostate. pdf . Accesse d 
Fe br uar y  2 3, 2 0 2 3.
6.
S wee ne y  CJ, C he n Y H, Car d ucci M, et al. C he m o h or m o nal T hera py i n Metastatic 
H or m o ne -Se nsiti ve P rostate Ca ncer. N E n gl J Me d. 2 0 1 5; 3 7 3( 8): 7 3 7 -7 4 6.
7.
Beer T M, Ar mstr o n g AJ, Rat h k o pf D, et al. E nzal uta mi de i n me n wit h c he m ot hera p y-
nai ve metastatic castrati o n -resista nt pr ostate ca ncer: e xte n de d a nalys is of t he p hase 3 
P R E V AI L st u d y. E ur o pe a n ur ol o gy. 2 0 1 7; 7 1( 2): 1 5 1 - 1 5 4.
8.  
M oreira D M, H o war d L E, S o ur beer K N, et al. Pre dicti n g Ti me Fr o m Metastasis t o 
O verall S ur vi val i n Castrati o n - Resista nt Pr ostate Ca ncer: Res ults Fr o m S E A R C H. Cli n 
Ge nit o uri n C a ncer. 2 0 1 7; 1 5( 1): 6 0 -6 6 e 6 2.
9.
R y a n CJ, S mit h M R, Fizazi K, et al. A b irater o ne acetate pl us pre d nis o ne vers us place b o 
pl us pre d nis o ne i n c he m ot hera p y -nai ve me n wit h metast atic castrati o n-resista nt pr ostate 
ca ncer ( C O U -A A -3 0 2): fi nal o verall s ur vi val a nal y sis of a ra n d o mise d, d o u ble-bli n d, 
place b o -c o ntr olle d p hase 3 st u d y . L a ncet O nc ol. 2 0 1 5; 1 6( 2): 1 5 2 -1 6 0.
1 0.
Ta n n oc k I F, de Wit R, Berr y  W R, et al. D oceta xel pl us pre d nis o ne or mit o xa ntr o ne pl us 
pre d nis o n e f or a d va nce d pr ostate ca ncer. N E n gl J Me d. 2 0 0 4; 3 5 1( 1 5): 1 5 0 2 - 1 5 1 2.
1 1.
de B o n o J S, L o g ot hetis CJ, M oli na A, et al. A birater o ne a n d i ncrease d s ur vi val i n 
metastatic pr ostate ca ncer. N E n gl J Me d. 2 0 1 1; 3 6 4( 2 1): 1 9 9 5 - 2 0 0 5.
1 2.
R y a n CJ, S mit h M R, de B o n o J S, et al. A birater o ne i n metastatic pr ostate ca ncer 
wit h o ut pre vi o us c he m ot hera p y. N E n gl J Me d. 2 0 1 3; 3 6 8( 2): 1 3 8 - 1 4 8.
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 3 4 of 4 7
1 3.
Sc her HI, Fizazi K, Saa d F, et al. I ncrease d s ur vi val wit h e nzal uta mi de i n pr ostate 
ca ncer after c he m ot hera p y. N E n gl J Me d. 2 0 1 2; 3 6 7( 1 3): 1 1 8 7 - 1 1 9 7.
1 4.
O u dar d S, Fizazi K, Se n gel ø v L, et al. Ca bazita xel vers us d oceta xel a s first-li ne t hera py 
f or patie nts wit h metastatic castrati o n-resista nt pr ostate ca ncer: a ra n d o mize d p hase III 
trial— FI R S T A N A. J o ur n al of Cli nic al O nc ol o gy. 2 0 1 7; 3 5( 2 8): 3 1 8 9 - 3 1 9 7.
1 5.
Ka nt of f P W, Hi ga n o C S, S h ore N D, et al. Si p ule ucel-T i m m u n ot hera p y f or castrati o n-
resista nt pr ostate ca ncer. N E n gl J Me d. 2 0 1 0; 3 6 3( 5 ): 4 1 1- 4 2 2.
1 6.
Par ker C, Nilss o n S, Hei nric h D, et al. Al p ha e mitter ra di u m -2 2 3 a n d s ur vi val i n 
metastatic pr ostate ca ncer. Ne w E n gl a n d J o ur n al of Me dici ne. 2 0 1 3; 3 6 9( 3): 2 1 3 -2 2 3.
1 7.
de B o n o J, Mate o J, Fizaz i K, et al. Ola pari b f or metastatic castrati o n-resista nt p r ostate 
ca ncer. N E n gl J Me d. 2 0 2 0; 3 8 2( 2 2): 2 0 9 1 - 2 1 0 2.
1 8.
A bi da W, Pat nai k A, Ca m p bell D, et al. R uca pari b i n me n wit h metastatic ca strati o n-
resista nt pr ostate ca ncer har b ori n g a B R C A 1 or B R C A 2 ge ne alterati o n. J o ur n al of 
Cli nic al O nc ol o gy. 2 0 2 0; 3 8( 3 2): 3 7 6 3.
1 9.
Astellas P har ma U S. X T A N DI [ pac ka ge i nsert]. 2 0 1 2; 
htt ps:// w w w.astellas. us/ d ocs/ us/ 1 2 A 0 0 5 -E N Z -W PI. p df . Accesse d J ul y 2 1, 2 0 2 1.
2 0.
J ansse n Gl o bal Ser vices L L C. Z Y TI G A [ pac ka ge i nsert]. 2 0 1 1; 
htt ps:// w w w. ja nsse nla bels.c o m/ pac ka ge-i nsert/ pr o d uct-m o n o gra p h/ prescr ibi n g -
i nf or mati o n/ Z Y TI G A-pi. p df . Accesse d J ul y 2 1, 2 0 2 1.
2 1.
Ge or ge DJ, Sart or O, Miller K, et al. Treat me nt Patter ns a n d O utc o mes i n Patie nts Wit h 
Metastatic Castrati o n -resista nt Pr ostate Ca ncer i n a Real-w orl d Cli nical Practice Setti n g 
i n t he U nite d States. C li n Ge nit o uri n C a ncer. 2 0 2 0; 1 8( 4): 2 8 4 - 2 9 4.
2 2.
Iz u mi K, S hi ma T, Mita K, et al. E nzal uta mi de Vers us A birater o ne pl us Pre d nis ol o ne 
Be f ore C he m ot hera p y f or Castrati o n-resista nt Pr ostate Ca ncer: A M ultice nter 
Ra n d o mize d C o ntr olle d Trial . E ur Ur ol O pe n Sci. 2 0 2 2 Ma y 1 9; 4 1: 1 6- 2 3.
2 3.
Ter n o v et al. E A U 2 0 2 1: Fati g ue, Q ualit y -of -Life a n d Meta b olic C ha n ges i n Me n 
Treate d Wit h E nzal uta mi de Vers us A birater o ne Pl us Pre d nis o ne ( H E A T): A 
Ra n d o mize d Trial. 2 0 2 1; htt ps:// w w w. ur ot o da y .c o m/c o nfere nce-hi g hli g hts/ea u -
2 0 2 1/ea u - 2 0 2 1- prostate -ca ncer/ 1 3 0 7 5 4 -ea u- 2 0 2 1-fati g ue-q ualit y -of -life-a n d-meta b olic -
c ha n ges -i n-me n -treate d-wit h -e nzal uta mi de-vers us -a birater o ne-pl us -pre d nis o ne -heat -a-
ra n d o mize d-trial. ht ml. Accesse d A u g ust, 2 0 2 1.
2 4.
K halaf DJ, A n nala M, Taa vitsai ne n S, et al. O pti mal se q ue n ci n g of e nzal uta mi de a n d 
a birater o ne acetate pl us pre d nis o ne i n metastatic castrati o n -resista nt pr ostate ca ncer: a 
m ultice ntre, r a n d o mise d, o pe n -la bel, p hase 2, cr oss o ver trial. L a ncet O nc ol . 
2 0 1 9; 2 0( 1 2): 1 7 3 0 - 1 7 3 9.
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 3 5 of 4 7
2 5.
Scailte u x L -M, Ca m pill o -Gi me nez B, Ker bra t S, et al. O verall S ur vi val A m o n g 
C he m ot hera p y- Nai ve Patie nts Wit h Castrati o n -Resista nt Pr ostate Ca ncer U n der 
A birater o ne Vers us E nzal uta mi de: A Direct C o m paris o n Base d o n a 2 0 1 4 – 2 0 1 8 Fre nc h 
P o p ulati o n St u d y  (t he S P E A R C o h ort). A m J E pi de mi ol. 2 0 2 1; 1 9 0( 3) : 4 1 3- 4 2 2.
2 6.
Sc h oe n M W, Cars o n K R, L u o S, et al. S ur vi val of vetera ns treate d wit h e nzal uta mi de 
a n d a birater o ne i n a d va nce d pr ostate ca ncer. I n: W olters Kl u wer Healt h; 2 0 2 1.
2 7.
Ta ga wa S T, Ra mas wa m y K, H ua n g A, et al. S ur vi val o utc o mes i n patie nts wit h 
c he m ot herap y- nai ve metastatic castrati o n -resista nt pr ostate ca ncer treate d wit h 
e nzal uta mi de or a birater o ne acetate. Pr ost ate C a ncer Pr ost a tic Dis. 2 0 2 1.
2 8.
Marar M, L o n g Q, Ma mta ni R, Nara y a n V, Va pi wal a N, Pari k h R B. O utc o mes A m o n g 
Africa n A merica n a n d N o n -His pa nic W hite Me n Wit h Metastatic Castrati o n- Resista nt 
Pr ostate Ca ncer Wit h First -Li ne A birater o ne. J A M A net w ork o pe n. 
2 0 2 2; 5( 1):e 2 1 4 2 0 9 3 -e 2 1 4 2 0 9 3.
2 9.
Li n Y, H ua n g Y, Li u C. Treat me nt -E mer ge nt C o -M or bi d ities a n d S ur vi val i n Patie nts 
Wit h Metastatic Castrati o n -Resista n t Pr ostate Ca ncer Recei vi n g A birater o ne or 
E nzal uta mi de. Fr o nt P har mac ol. 2 0 2 1 Ma y  1 8; 1 2: 6 6 9 2 3 6.
3 0.
Li P Y, L u Y H, C he n C Y. C o m parati ve Effecti ve ness of A birater o ne a n d E nzal uta mi de 
i n Patie nts Wit h Metastatic Castrati o n -Resista nt Pr ostate Ca ncer i n Tai wa n . Fr o nt 
O nc ol. 2 0 2 2 Mar 7; 1 2: 8 2 2 3 7 5.
3 1.
Sc h oe nfel d D A. Sa m ple -Size F or m ula f or t he Pr o p orti o nal- Hazar ds Re gressi o n M o del . 
Bi o metrics . 1 9 8 3; 3 9( 2 ):4 9 9- 5 0 3.
3 2.
R o bi ns J M, Her na n M A, Br u m bac k B. Mar gi nal str uct ural m o dels a n d ca usal i nfere nce 
i n e pi de mi ol o g y. E pi de mi ol o g y. 2 0 0 0; 1 1( 5): 5 5 0 - 5 6 0.
3 3.
C ole S R, Her na n M A. C o nstr ucti n g i n verse pr o ba bilit y  wei g hts f or mar gi nal str uct ural 
m o dels. A m J E pi de mi ol. 2 0 0 8; 1 6 8( 6): 6 5 6 - 6 6 4.
3 4.
A usti n P C. A n I ntr o d ucti o n t o Pr o pe n sit y Sc ore Met h o ds f or Re d uci n g t he Effects of 
C o nf o u n di n g i n O bse rvati o nal St u dies. M ultiv ari ate Be h av Res. 2 0 1 1; 4 6( 3): 3 9 9 - 4 2 4.
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 3 6 of 4 7
1 4. LI S T O F T A B L E S 
Ta ble 1.
Baseli ne De m o gra p hic a n d Cli nical C haracteristic V varia bles ................1 9
Ta ble 2.
St u d y  Peri o d Varia bles............................................................................. 2 3
Ta ble 3.
Sa m ple Sizes t o Detect a Ra n ge of O S H Rs f or E nzal uta mi de vs 
A birater o ne wit h 8 0 % P o wer .................................................................... 2 6
1 5. LI S T O F FI G U R E S
Fi g ure 1.
St u d y  Desi g n............................................................................................. 1 6
A N N E X 1. LI S T O F S T A N D -A L O N E D O C U M E N T S
N u m ber
D oc u me nt refere nce 
n u m ber
D ate
Title
1
Secti o n 4
1 2 J u ne 2 0 2 3
A bstract
A N N E X 2. E N C E P P C H E C K LI S T F O R S T U D Y P R O T O C O L S
N ot a p plica ble.
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 3 7 of 4 7
A N N E X 3 . A D DI TI O N A L I N F O R M A TI O N
A p pe n di x 1.
A p pe n di x 1 T a ble 1. A d mi nistr ati ve c o des f or rele v a nt tre at me nts
H or m o n al t her a p y
G PI
H C P C S/ C P T
I C D
A D T
Orc hiect o m y
C P T
5 4 5 2 0, 5 4 5 2 2, 5 4 5 3 0, 5 4 5 3 5, 
5 4 6 9 0
I C D- 9-C M
V 4 5. 7 7
I C D- 1 0-C M
Z 9 0. 7 9
I C D- 9-P C S
6 2 3, 6 2 4 1, 6 2 4 2
I C D- 1 0-P C S
0 V 5 9 0 Z Z, 
0 V 5 9 3 Z Z, 
0 V 5 9 4 Z Z, 
0 V 5 B 0 Z Z, 
0 V 5 B 3 Z Z, 
0 V 5 B 4 Z Z, 
0 V 5 C 0 Z Z, 
0 V 5 C 3 Z Z, 
0 V 5 C 4 Z Z, 
0 V T 9 0 Z Z, 
0 V T 9 4 Z Z, 
0 V T B 0 Z Z, 
0 V T B 4 Z Z, 
0 V T C 0 Z Z, 
0 V T C 4 Z Z
      L H R H a g o nists/ a nt a g o nists
De gareli x
2 1 4 0 5 5 2 5
1 0
J 91 5 5
G osereli n
2 1 4 0 5 0 0 5
J 92 0 2
Histreli n
2 1 4 0 5 0 0 7
1 0
J 16 7 5, J 9 2 2 5, J 9 2 2 6, S 0 1 3 3
Le u pr oli de
2 1 4 0 5 0 1 0
J 19 5 0, J 9 2 1 7, J 9 2 1 8, J 9 2 1 9, 
Q 0 0 5 7
Tri p t oreli n
2 1 4 0 5 0 5 0
J 33 1 5
N H T
A pal uta mi de
2 1 4 0 2 4 1 0
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 3 8 of 4 7
A p pe n di x 1 T a ble 1. A d mi nistr ati ve c o des f or rele v a nt tre at me nts
0 0
A birater o ne
2 1 4 0 6 0 1 0
2 0
Dar ol uta mi de
2 1 4 0 2 4 2 5
0 0
E nzal uta mi de
2 1 4 0 2 4 3 0
0 0
First ge ner ati o n a nti -
a n dr o ge ns
Bical uta mi de
2 1 4 0 2 4 2 0
0 0
Fl uta mi de
2 1 4 0 2 4 4 0
0 0
Nil uta mi de
2 1 4 0 2 4 6 0
0 0
C he m ot her a p y
G PI
H C P C S
I C D
T a x a ne C he m ot her a p y
Ca bazita xel
2 1 5 0 0 0 0 3
0 0
C 9 2 7 6, J 9 0 4 3
D oceta xel
2 1 5 0 0 0 0 5
0 0
J 91 7 0, J 9 1 7 1
Ot her C he m ot her a p y
Car b o plati n
2 1 1 0 0 0 1 5
0 0
J 90 4 5
Cis plati n
2 1 1 0 0 0 2 0
0 0
J 90 6 0, J 9 0 6 2
O xali plati n
2 1 1 0 0 0 2 8
0 0
J 92 6 3
Mit o xa ntr o ne 
2 1 2 0 0 0 5 5
0 0
J 92 9 3
I m m u n ot her a p y
G PI
H C P C S
I C D
Si p ule ucel - T
2 1 6 5 1 0 7 0
0 0
Q 2 0 4 3, C 9 2 7 3
Pe m br oliz u ma b 
2 1 3 5 7 9 5 3
0 0
J 92 7 1, C 9 0 2 7
R a di u m
G PI
H C P C S
I C D
Ra di u m - 2 2 3
2 1 6 0 0 0 5 5
0 0
A 9 6 0 6
R a di ati o n t her a p y
G PI
H C P C S
I C D
Brac h yt h era p y
0 3 9 4 T - 0 3 9 5 T
C P T: 7 7 7 6 1- 7 7 7 6 3, 7 7 7 6 7 -
7 7 7 6 8, 7 7 7 7 0 -7 7 7 7 2, 7 7 7 7 8, 
7 7 7 8 9, 7 7 7 5 0, 7 7 7 9 0
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 3 9 of 4 7
A p pe n di x 1 T a ble 1. A d mi nistr ati ve c o des f or rele v a nt tre at me nts
C o n ve nti o nal e xter nal 
bea m ra diati o n treat me nt 
deli ver y
G 6 0 0 3 -G 6 0 1 4
C P T: 7 7 4 0 1- 7 7 4 1 6, 
I nte nsit y m o d ulate d 
ra diati o n t hera p y
G 6 0 1 5 -G 6 0 1 6 
C P T: 7 7 3 8 5- 7 7 3 8 6
Pr ot o n bea m t hera p y
C P T: 7 7 5 2 0- 7 7 5 2 5
Stere otactic b o d y ra diati o n 
t hera p y
C P T: 7 7 3 7 3
B o ne t ar geti n g a ge nts
G PI
H C P C S
IC D
De n os u ma b
3 0 0 4 4 5 3 0
0 0
J 08 9 7, C 9 2 7 2
I ba n dr o nate
3 0 0 4 2 0 4 8
1 0
J 17 4 0, C 9 2 2 9  
Z ole dr o nic aci d
3 0 0 4 2 0 9 0
0 0
J 34 8 9, Q 2 0 5 1, J 3 4 8 7 , J 3 4 8 8, 
Q 4 0 9 5
I C D- 9-P C S
V 5 8. 6 8
I C D- 1 0-P C S
Z 7 9. 8 3
Pa mi dr o nate dis o di u m
3 0 0 4 2 0 6 0
1 0
J 24 3 0
S ur ger y
G PI
H C P C S/ C P T
I C D
Pr ostatec t o m y
5 5 8 3 1, 5 5 8 4 0, 5 5 8 4 2, 5 5 8 4 5, 
5 5 8 6 6
I C D- 9-P C S
6 0 2 1, 6 0 2 9, 6 0 3, 
6 0 4, 6 0 5, 6 0 6 1, 
6 0 6 2, 6 0 6 9
I C D- 1 0-P C S
0 V T 0 0 Z Z, 
0 V T 0 4 Z Z, 
0 V T 0 7 Z Z, 
0 V T 0 8 Z Z, 
0 V B 0 0 Z Z, 
0 V B 0 3 Z Z, 
0 V B 0 4 Z Z, 
0 V B 0 7 Z Z, 
0 V B 0 8 Z Z, 
0 V 5 0 0 Z Z, 
0 V 5 0 3 Z Z, 
0 V 5 0 4 Z Z, 
0 V 5 0 7 Z Z, 
0 V 5 0 8 Z Z
Fr act ure a n d s kelet al -rel ate d 
e ve nts 1
G PI
H C P C S
I C D
B o ne s ur ger y
2 7 1 8 7, 2 7 2 3 5, 2 7 2 3 6, 2 7 2 4 4, 
2 7 2 4 5, 2 7 2 4 8, 2 7 2 6 9, 2 7 4 9 5, 
2 7 5 0 6, 2 7 5 0 7, 2 7 5 0 9, 2 7 5 1 1, 
2 7 5 1 3, 2 7 5 1 4, 2 3 6 1 5, 2 3 6 1 6, 
I C D- 9-P C S : 
7 8 1 5, 7 8 4 5, 7 8 5 5, 
7 9 1 5, 7 9 2 5, 7 9 3 5, 
7 9 9 5, 7 8 1 2, 7 8 4 2, 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 4 0 of 4 7
A p pe n di x 1 T a ble 1. A d mi nistr ati ve c o des f or rele v a nt tre at me nts
2 3 6 3 0, 2 4 4 9 8, 2 4 5 1 5, 2 4 5 1 6, 
2 4 5 3 8, 2 4 5 4 5, 2 4 5 4 6, 2 4 5 6 6, 
2 4 5 7 5, 2 4 5 7 9, 2 4 5 8 2 , 2 4 5 8 6, 
2 4 5 8 7, 2 4 6 3 5, 2 4 6 6 5, 2 4 6 6 6, 
2 4 6 8 5, 2 5 4 9 0, 2 5 4 9 1, 2 5 4 9 2, 
2 5 5 1 5, 2 5 5 2 5, 2 5 5 2 6, 2 5 5 4 5, 
2 5 6 0 6, 2 5 6 0 7, 2 5 6 0 8, 2 5 6 0 9, 
2 7 5 3 5, 2 7 5 3 6, 2 7 7 4 5, 2 7 7 5 6, 
2 7 7 5 8, 2 7 7 5 9, 2 7 7 6 6, 2 7 7 6 9, 
2 7 7 8 4, 2 7 7 9 2, 2 7 8 2 6, 2 7 8 2 7, 
2 2 3 2 5, 2 2 3 2 6, 2 2 3 2 7, 2 2 3 2 8, 
2 2 5 2 0, 2 2 5 2 1, 2 2 5 2 2, 2 2 5 3 2, 
2 2 5 3 3, 2 2 5 3 4, 2 2 5 4 8, 2 2 5 5 0, 
2 2 5 5 4, 2 2 5 5 5, 2 2 5 5 6, 2 2 5 5 8, 
2 2 5 6 5, 2 2 5 8 5, 2 2 5 9 0, 2 2 5 9 5, 
2 2 6 0 0, 2 2 6 1 0, 2 2 6 1 2, 2 2 6 1 4, 
2 2 6 1 5, 2 2 6 2 5, 2 2 6 3 0, 2 2 6 3 2, 
2 0 9 8 2, 2 3 4 9 0, 2 3 5 1 5, 2 3 5 8 5, 
2 7 2 1 5, 2 7 2 1 6, 2 7 2 1 7, 2 7 2 1 8, 
2 7 2 2 6, 2 7 2 2 7, 2 7 2 2 8, 2 7 5 2 4, 
2 7 5 4 0, 2 2 5 2 3, 2 2 5 2 4, 2 2 5 2 5,
2 2 5 2 6, 2 2 5 2 7, 2 5 5 7 4, 2 5 5 7 5
7 8 5 2, 7 9 1 1, 7 9 2 1, 
7 9 3 1, 7 9 9 1, 7 8 1 3, 
7 8 4 3, 7 8 5 3, 7 9 1 2, 
7 9 2 2, 7 9 3 2, 7 9 9 2, 
7 8 1 7, 7 8 4 7, 7 8 5 7, 
7 9 1 6, 7 9 2 6, 7 9 3 6, 
7 9 9 6, 0 3 5 3, 8 1 0 2, 
8 1 0 3, 8 1 0 4, 8 1 0 5, 
8 1 0 6, 8 1 0 7, 8 1 0 8,
7 8 1 0, 7 8 1 1, 7 8 1 6, 
7 8 1 9, 7 8 4 0, 7 8 4 1, 
7 8 4 6, 7 8 4 9, 7 8 5 0, 
7 8 5 1, 7 8 5 6, 7 8 5 9, 
7 9 1 0, 7 9 1 9, 7 9 2 0, 
7 9 2 9, 7 9 3 0, 7 9 3 9, 
7 9 9 0, a n d 7 9 9 9
B o ne palliati ve 
ra di ot hera p y
A 9 6 0 0, A 9 6 0 4, A 9 6 0 5, C 9 4 0 1, 
J 30 0 5, 7 7 4 0 1, 7 7 4 0 2, 7 7 4 0 3, 
7 7 4 0 4, 7 7 4 0 6, 7 7 4 0 7, 7 7 4 0 8, 
7 7 4 0 9, 7 7 4 1 1, 7 7 4 1 2, 7 7 4 1 3, 
7 7 4 1 4, 7 7 4 1 6, 7 7 4 1 8, 7 9 0 0 5, 
7 9 1 0 1, 7 9 2 0 0, 7 9 3 0 0, 7 9 4 0 0, 
7 9 4 0 3, 7 9 4 4 0, 7 9 4 4 5, 7 9 9 9 9
I C D- 1 0-P C S : 
D P 0 0 0 Z Z ‑ D P 0 C 6
Z Z
I C D- 9-C M : 
9 2 2 3, 9 2 2 4, 9 2 2 9
Pat h ol o gic fract ure
I C D- 9-C M : 
7 3 3. 1
I C D- 1 0-C M : 
M 8 4. 5
S pi nal c or d c o m pressi o n
6 3 0 5 0, 6 3 0 5 1, 2 2 5 5 1, 2 2 5 5 2, 
6 3 0 6 4, 6 3 0 6 6, 6 1 3 4 3, s 2 3 4 8, 
6 3 0 7 5- 8, s 2 3 5 0, s 2 3 5 1, 6 3 1 9 5, 
6 3 1 9 7, 6 3 1 9 9, 6 3 0 0 1, 6 3 0 0 3, 
6 3 0 0 5, 6 3 0 1 1, 6 3 0 1 5, 6 3 0 1 6, 
6 3 0 1 7, 6 3 1 7 0, 6 3 0 1 2, 6 3 0 4 5, 
6 3 0 4 6, 6 3 0 4 7, 6 3 0 4 8, 6 3 0 4 0, 
6 3 0 4 2, 6 3 0 4 3, 6 3 0 4 4, 6 3 0 2 0, 
6 3 0 3 0, 6 3 0 3 5, 2 2 2 2 4, 2 2 2 2 2, 
2 2 2 1 4, 2 2 2 1 2, 2 2 2 0 7, 2 2 2 0 6, 
0 2 7 4t, 0 2 7 5t, c 9 7 2 9, 0 2 0 2t, 
2 2 8 6 5, 0 1 6 4t, 0 0 9 4t, 0 0 9 7t, 
6 3 0 5 7, 6 3 0 5 6, 6 3 0 5 5, 6 3 0 8 1, 
I C D- 9-C M : 
3 3 6. 3, 3 3 6. 8, 
3 3 6. 9
I C D- 1 0-C M : 
G 5 5, G 9 5. 2, 
G 9 9. 2
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 4 1 of 4 7
A p pe n di x 1 T a ble 1. A d mi nistr ati ve c o des f or rele v a nt tre at me nts
6 3 0 8 2, 6 3 0 8 7, 6 3 0 8 8, 6 3 1 0 1, 
6 3 1 0 2, 6 3 1 0 3, 6 3 0 9 0, 6 3 0 9 1, 
6 3 0 8 6, 6 3 0 8 5
Ot her pr ost ate c a ncer dr u gs
G PI
H C P C S
I C D
Ket oc o naz ole
1 1 4 0 4 0 4 0
0 0
9 6 3 0 1 0 6 4
0 0
Ola pari b
2 1 5 3 5 5 6 0
R uca pari b
2 1 5 3 5 5 7 0
2 0
Ot her b ase li ne peri o d 
me dic ati o ns
G PI
H C P C S
I C D
C ortic oster oi ds
2 2, 8 9 1 0, 
8 9 1 5
P ai n me dic ati o ns ( a n al gesics)
N o n -narc otics
6 4
O pi oi ds
6 5
A nti- i nfla m mat or y 
me dicati o ns
6 6
A b bre vi ati o ns: C M: Cli nical M o dificati o n; C P T, C urre nt Pr oce d ural Ter mi n ol o g y; G PI: Ge neric Pr o d uct 
I de ntifier; H C P C S: Healt hcare C o m m o n Pr oce d ure C o di n g S yste m; I C D: I nter nati o nal Classificati o n of 
Diseases; L H R H: L utei nizi n g H or m o ne -Releasi n g H or m o ne; P C S: Pr oce d ures
N ote:
[1] S o urce: Al y A, O n u k w u g ha E, W o o ds C, et al. Meas ure m e nt of s keletal relate d e ve nts i n S E E R -Me dicare: a 
c o m paris o n of clai ms -base d met h o ds. B M C Me d Res Met h o d ol. 2 0 1 5; 1 5: 6 5. P u blis he d 2 0 1 5 A u g 1 9. 
d oi: 1 0. 1 1 8 6/s 1 2 8 7 4 -0 1 5 -0 0 4 7 -5
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 4 2 of 4 7
A p pe n di x 1 T a ble 2. A d mi nistr ati ve c o des f or site of met ast atic dise ase
Site o f met ast atic dise ase
I C D- 9-C M 
I C D- 1 0-C M 
L y m p h N o de
1 9 6 0- 1 9 6 3, 1 9 6 5, 1 9 6 6, 
1 9 6 8, 1 9 6 9
C 7 7 0 -C 7 7 5, C 7 7 8, C 7 7 9, C 7 B 0 1
Viscer al
Res pirat or y Or ga ns
1 9 7 0- 1 9 7 3
C 7 8 0 0 -C 7 8 0 2, C 7 8 1, C 7 8 2, C 7 8 3 0, 
C 7 8 3 9
Di gesti ve Or ga ns
Li ver
1 9 7 7
C 7 8 7 , C 7 B 0 2
Ot her di gesti v e 
or ga ns
1 9 7 4- 1 9 7 6, 1 9 7 8
C 7 8 4 -C 7 8 6 , C 7 8 8 0, C 7 8 8 9, C 7 B 0 4
B o ne
1 9 8 5
C 7 9 5 1, C 7 9 5 2, C 7 B 0 3
Ot her S pecifie d Sites
1 9 8 0- 1 9 8 4, 1 9 8 6- 1 9 8 7, 
1 9 8 8 1, 1 9 8 8 2, 1 9 8 8 9
C 7 9 0 0 -C 7 9 0 2, C 7 9 1 0, C 7 9 1 1, C 7 9 1 9, 
C 7 9 2, C 7 9 3 1, C 7 9 3 2, C 7 9 4 0, C 7 9 4 9, 
C 7 9 6 0 -C 7 9 6 2, C 7 9 7 0 -C 7 9 7 2, C 7 9 8 1, 
C 7 9 8 2, C 7 9 8 9, C 7 B 0 3, C 7 B 0 9, C 7 B 1, 
C 7 B 8
Wit h o ut S pecific ati o n of 
Site
1 9 9 0, 1 9 9 1
C 7 9 9, C 7 B 0 9, C 7 B 0 0
A b bre vi ati o ns: I C D- 9-C M, I nter nati o nal Classificati o n of Diseases, Ni nt h Re visi o n, Cli nical M o dificati o n; 
I C D-1 0 -C M, I nter nati o nal Classificati o n of Diseases , Te nt h Re visi o n, Cli nical M o dificati o n.
A p pe n di x 1 T a ble 3. A d mi nistr ati ve c o des f or c o m or bi dities
C o n diti o ns a n d c o m or bi dities
I C D- 9-C M 
I C D- 1 0-C M 
N CI c o m or bi dit y i n de x 1
Cere br o vasc ular disease
3 6 2. 3 4, 4 3 0 – 4 3 8
G 4 5, G 4 6 , H 3 4. 0, I 6 0 – I 6 9
C hr o nic p ul m o nar y disease
4 1 6. 8, 4 1 6. 9, 4 9 0 – 5 0 5, 
5 0 6. 4, 5 0 8. 1, 5 0 8. 8
I 2 7. 8, I 2 7. 9, J 4 0– J 4 7, J 6 0–
J 67, J 6 8. 4, J 7 0. 1, J 7 0. 3
C o n gesti ve heart fail ure
3 9 8. 9 1, 4 0 2. 0 1, 4 0 2. 1 1, 
4 0 2. 9 1, 4 0 4. 0 1, 4 0 4. 0 3, 
4 0 4. 1 1, 4 0 4. 1 3, 4 0 4. 9 1, 
4 0 4. 9 3, 4 2 5. 4 – 4 2 5. 9 , 4 2 8
I 0 9. 9, I 1 1. 0, I 1 3. 0, I 1 3. 2, 
I 2 5. 5, I 4 2. 0, I 4 2. 5– I 4 2. 9, 
I 4 3, I 5 0, P 2 9. 0
De me ntia
2 9 0, 2 9 4. 1, 3 3 1. 2
F 0 0 – F 0 3, F 0 5. 1, G 3 0, 
G 3 1. 1
Dia betes wit h c hr o nic c o m plicati o n
2 5 0. 4 – 2 5 0. 7
E 1 0. 2 – E 1 0. 5, E 1 0. 7, E 1 1. 2 –
E 1 1. 5, E 1 1. 7, E 1 2. 2 – E 1 2. 5, 
E 1 2. 7, E 1 3. 2 – E 1 3. 5, E 1 3 .7, 
E 1 4. 2 – E 1 4. 5, E 1 4. 7
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 4 3 of 4 7
A p pe n di x 1 T a ble 3. A d mi nistr ati ve c o des f or c o m or bi dities
C o n diti o ns a n d c o m or bi dities
I C D- 9-C M 
I C D- 1 0-C M 
Dia betes wit h o ut c hr o nic 
c o m plicati o n
2 5 0. 0 – 2 5 0. 3, 2 5 0. 8, 2 5 0. 9
E 1 0. 0, E 1 0. 1, E 1 0. 6, E 1 0. 8, 
E 1 0. 9, E 1 1. 0, E 1 1. 1, E 1 1. 6, 
E 1 1. 8, E 1 1. 9, E 1 2. 0, E 1 2. 1, 
E 1 2. 6, E 1 2. 8, E 1 2. 9, E 1 3. 0, 
E 1 3. 1, E 1 3. 6, E 1 3. 8, E 1 3. 9, 
E 1 4. 0, E 1 4. 1, E 1 4. 6, E 1 4. 8, 
E 1 4. 9
He mi ple gia or para ple gia
3 3 4. 1, 3 4 2, 3 4 3, 3 4 4. 0 –
3 4 4. 6, 3 4 4. 9
G 0 4. 1, G 1 1. 4, G 8 0. 1, 
G 8 0. 2, G 8 1, G 8 2, G 8 3. 0 –
G 8 3. 4, G 8 3. 9
Mil d li ver disease
0 7 0. 2 2, 0 7 0. 2 3, 0 7 0. 3 2, 
0 7 0. 3 3, 0 7 0. 4 4, 0 7 0. 5 4, 
0 7 0. 6, 0 7 0. 9, 5 7 0, 5 7 1, 
5 7 3. 3, 5 7 3. 4, 5 7 3. 8, 5 7 3. 9, 
V 4 2. 7
B 1 8, K 7 0. 0 – K 7 0. 3, K 7 0. 9, 
K 7 1. 3 – K 7 1. 5, K 7 1. 7, K 7 3, 
K 7 4, K 7 6. 0, K 7 6. 2 – K 7 6. 4, 
K 7 6. 8, K 7 6. 9, Z 9 4. 4
M o derate or se vere li ver disease
4 5 6. 0 – 4 5 6. 2, 5 7 2. 2 – 5 7 2. 8
I 8 5. 0, I 8 5. 9, I 8 6. 4, I 9 8. 2, 
K 7 0. 4, K 7 1. 1, K 7 2. 1, 
K 7 2. 9, K 7 6. 5, K 7 6. 6, K 7 6. 7
Peri p heral vasc ular disease
0 9 3 . 0, 4 3 7. 3, 4 4 0, 4 4 1, 
4 4 3. 1 – 4 4 3. 9, 4 4 7. 1, 5 5 7. 1, 
5 5 7. 9, V 4 3. 4
I 7 0, I 7 1, I 7 3. 1, I 7 3. 8, I 7 3. 9, 
I 7 7. 1, I 7 9. 0, I 7 9. 2, K 5 5. 1, 
K 5 5. 8, K 5 5. 9, Z 9 5. 8, Z 9 5. 9
Re nal disease
4 0 3. 0 1, 4 0 3. 1 1, 4 0 3. 9 1, 
4 0 4. 0 2, 4 0 4. 0 3, 4 0 4. 1 2, 
4 0 4. 1 3, 4 0 4. 9 2, 4 0 4. 9 3, 5 8 2, 
5 8 3. 0 – 5 8 3. 7, 5 8 5 , 5 8 6, 
5 8 8. 0, V 4 2. 0, V 4 5. 1, V 5 6
I 1 2. 0, I 1 3. 1, N 0 3. 2– N 0 3. 7, 
N 0 5. 2 – N 0 5. 7, N 1 8, N 1 9, 
N 2 5. 0, Z 4 9. 0 – Z 4 9. 2, Z 9 4. 0, 
Z 9 9. 2
I n di vi d u al c o n diti o ns
H y perte nsi o n
3 6 2. 1 1, 4 0 1. x x - 4 0 5. x x, 
4 3 7. 2
H 3 5. 0 3 9, I 1 0 – I 1 3, I 1 5– I 1 6, 
I 6 7. 4
Str o ke
4 3 0- 4 3 4, 4 3 6, 3 6 2. 3 1- 3 6 2. 3 4
I 6 0, I 6 1, I 6 2, I 6 4, I 6 5, I 6 7, 
H 3 4. 1, H 3 4. 2 3, H 3 4. 2 1, 
H 3 4. 0
Ac ute C or o nar y S y n dr o me
4 1 1. x, 4 1 0. x x
I 2 4, I 2 1
A n gi na Pect oris
4 1 3
I 2 0
Arr h yt h mia
4 2 7. 1, 4 2 7. 4, 4 2 7. 4 1, 
4 2 7. 4 2, 4 2 7. 5, 4 2 7. 6 9, 
4 2 7. 2, 4 2 7. 6 0, 4 2 7. 8, 
4 2 7. 8 9, 4 2 7. 9
I 4 7. 0, I 4 7. 2, I 4 9. 0, I 4 6, 
I4 9. 3, I 4 9. 4 9, I 4 7. 9, I 4 9. 4 0, 
I 4 9. 5, I 4 9. 8, I 4 9. 9
M y ocar dial I nfarcti o n
4 1 0, 4 1 2
I 2 1, I 2 2, I 2 5. 2
C o n gesti ve Heart Fail ure
4 2 8. x x
I 0 9. 9, I 1 1. 0, I 1 3. 0, I 1 3. 2, 
I 2 5. 5, I 4 2. 0, I 4 2. 5-I 4 2. 9, 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 4 4 of 4 7
A p pe n di x 1 T a ble 3. A d mi nistr ati ve c o des f or c o m or bi dities
C o n diti o ns a n d c o m or bi dities
I C D- 9-C M 
I C D- 1 0-C M 
I 4 3. x, I 5 0. x, P 2 9. 0
H y perli pi de mia
2 7 2. 0- 2 7 2. 4
E 7 8. 0 0, E 7 8. 0 1, E 7 8. 1,
E 7 8. 2, E 7 8. 3, E 7 8. 4 1, 
E 7 8. 4 9, E 7 8. 5
L o w -e xtre mit y Arterial Occl usi ve 
Disease
4 4 4. 2 2
I 7 4. 3, I 7 4. 4
T y pe II Dia betes
2 5 0. 0- 2 5 0. 3, 2 5 0. 7
E 1 0. 0, E 1 0. 1, E 1 0. 6, E 1 0. 8, 
E 1 0. 9, E 1 1. 0, E 1 1. 1, E 1 1. 6, 
E 1 1. 8, E 1 1. 9, E 1 2. 0, E 1 2. 1, 
E 1 2. 6, E 1 2. 8, E 1 2. 9, E 1 3. 0, 
E 1 3. 1, E 1 3. 6, E 1 3. 8, E 1 3. 9, 
E 1 4. 0, E 1 4. 1, E 1 4. 6, E 1 4. 8, 
E 1 4. 9
C hr o nic O bstr ucti ve P ul m o nar y 
Disease
4 9 0- 4 9 2, 4 9 4, 4 9 6
J 40 , J 4 1, J 4 2, J 4 3, J 4 7, 
J 44. 9
I nfla m mat or y b o wel disease
     Cr o h n’s disease
5 5 5
K 5 0
     Ulcerati ve C olitis
5 5 6
K 5 1
Ot her ca ncers
1 4 0- 1 7 2, 1 7 4- 1 8 4, 1 8 6- 1 9 5, 
1 9 9- 2 0 9
C 0 0 -C 4 3, C 4 5 -C 6 0, C 6 2 -
C 7 6, C 8 0 -C 9 6, C 7 A, C 7 B
A ne mia
2 8 0- 2 8 5
D 5 0 -D 5 3, D 5 5 -D 5 9, D 6 0 -
D 6 4
A b bre vi ati o ns : I C D- 9-C M, I nter nati o nal Classificati o n of Diseases, Ni nt h Re visi o n, Cli nical M o dificati o n; 
I C D-1 0 -C M, I nter nati o nal Classi ficati o n of Diseases, Te nt h Re visi o n, Cli nical M o dificati o n
N otes:
[ 1] S o urce: Q ua n, H u de, et al. C o di n g al g orit h ms f or defi ni n g c o m or bi dities i n I C D - 9-C M a n d I C D -1 0 
a d mi nistrati ve data. Me dical care ( 2 0 0 5): 1 1 3 0 -1 1 3 9. A da pte d usi n g c o des f o u n d i n N CI C o m o r bi dit y I n de x 
O ver vie w: htt ps:// healt hcare deli ver y.ca ncer. g o v/seer me dicare/c o nsi derati o ns/c o m or bi d it y. ht ml
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 4 5 of 4 7
A p pe n di x 2 T a ble 1. S u m m ar y of preli mi n ar y list of pr o g n ostic f act ors f or O S i n 
m C R P C f or a dj ust me nt i n m ulti v ari a ble a n al ysis
I de ntifie d fr o m t he 
t ar gete d liter at ure 
re vie w b y at le ast 2 
st u dies
F act ors a d de d b ase d o n 
cli nic al i n p ut 
C o ns oli d ate d list fr o m 
liter at ure re vie w a n d 
cli nic al i n p ut
A dj ust a ble i n Fl atir o n 
E H R
D e m o gr a p hics
A ge
A ge
Yes
Race /et h nicit y
Race /et h nicit y
Yes
Ge o gra p hic re gi o ns 
Ge o gra p hic re gi o ns 
Yes
S oci oec o n o mic stat us 
S oci oec o n o mic stat us 
Yes
B MI
B MI
Yes (s u bject t o 
c o m plete ness )
Site a n d e xte nt of m et ast ases
Li ver metastasis
Li ver metastasis
Yes
Visceral metastasis
Visceral metastasis
Yes
L y m p h n o de metastasis 
al o ne
L y m p h n o de metastasis 
al o ne
Yes
B o ne metastases/ N o. of 
b o ne metastases
B o ne metastases/ N o. of 
b o ne metastases
Yes, f or prese nce of b o ne 
metastasis
N o. of b o ne lesi o ns or 
b o ne lesi o n size
N o. of b o ne lesi o ns or 
b o ne lesi o n size
N o ( n ot a vaila ble)
B o ne sca n lesi o n area
B o ne sca n lesi o n area
N o ( n ot a vaila ble)
P S A
Baseli ne P S A
Baseli ne P S A
Yes (s u bject t o 
c o m plete ness )
Baseli ne P S A D T
Baseli ne P S A D T
N o ( n ot a vaila ble)
Perf or m a nce st at us
Kar n ofs k y
Kar n ofs k y
N o ( n ot a vai la ble)
E C O G
E C O G
Yes (s u bject 
c o m plete ness )
Dise ase c h ar acteristics
Ti m e fr o m dia g n osis t o 
t he i n de x date 
Ti m e fr o m dia g n osis t o 
t he i n de x date 
N o ( o verla p pi n g wit h 
ot her ti me varia bles 
bel o w )
Ti m e fr o m dia g n osis t o 
m C R P C
Ti m e fr o m dia g n osis t o
metastasis
Yes
Ti m e fr o m m C R P C t o t he 
i n de x date
Ti m e fr o m metastasis t o 
t he i n de x date
Yes
Ti m e fr o m A D T start t o 
t he i n de x date
Ti m e fr o m A D T start t o 
t he i n de x date
Yes
Pr o gressi o n t y pe: 
meas ura ble disease
Pr o gressi o n t y pe: 
meas ura ble disease
N o ( n ot a vaila ble)
Pr o gressi o n t y pe: b o ne 
sca n pr o gressi o n
Pr o gressi o n t y pe: b o ne 
sca n pr o gressi o n
N o ( n ot a vaila ble)
T u m or gra de ( Gleas o n)
T u m or gra de ( Gleas o n)
Yes
Pri or tre at me nts 
Ra dical pr ostatect o m y
Ra dical pr ostatect o m y
Yes
D urati o n o n p ri or 
h or m o ne t hera p y (e. g. ,
D urati o n o n pri or 
h or m o ne t hera p y ( e g,
Yes (a dj uste d as " Ti me 
fr o m A D T t o t he i n de x 
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 4 6 of 4 7
A p pe n di x 2 T a ble 1. S u m m ar y of preli mi n ar y list of pr o g n ostic f act ors f or O S i n 
m C R P C f or a dj ust me nt i n m ulti v ari a ble a n al ysis
I de ntifie d fr o m t he 
t ar gete d liter at ure 
re vie w b y at le ast 2 
st u dies
F act ors a d de d b ase d o n 
cli nic al i n p ut 
C o ns oli d ate d list fr o m 
liter at ure re vie w a n d 
cli nic al i n p ut
A dj ust a ble i n Fl atir o n 
E H R
A D T)
A D T)
date")
Pri or A D T 
Pri or A D T
N o (alrea d y i ncl u de d i n 
i ncl usi o n criteria) 
Pri or first -ge nerati o n 
a nti -a n dr o ge ns ( e g, > 9 0 
da ys)
Pri or first -ge nerati o n 
a nti -a n dr o ge ns ( e g, > 9 0 
da ys)
Yes
Pri or c he m ot hera p y
Pri or c he m ot hera p y
N o ( n ot rele va nt d ue t o 
e xcl usi o n criteria)
Pri or c hr o nic 
c ortic oster oi d use ( ie, > 9 0 
da ys)
Pri or c hr o nic 
c ortic oster oi d use ( ie, > 9 0 
da ys)
Yes
Pai n at ba seli ne
Pai n at baseli ne
N o ( b ut w ill a dj ust f or 
o pi oi d use)
O pi oi d a nal gesic use
O pi oi d a nal gesic use
O pi oi d a nal gesic use
Yes
L a b me as ures
Al b u mi n 
Al b u mi n 
Yes (s u bject t o 
c o m plete ness )
A L P 
A L P 
Yes (s u bject t o 
c o m plete ness )
H e m o gl o bi n
He m o gl o bi n
Yes (s u bject t o 
c o m plete ness)
L D H
L D H
Yes (s u bject t o 
c o m plete ness)
Ne utr o p hil -t o-
l y m p h oc yte rati o
Ne utr o p hil -t o-
l y m p h oc yte rati o
N o ( n ot a vaila ble)
Platelet -t o-l y m p h oc yte 
rati o
Platelet -t o-l y m p h oc yte 
rati o
N o ( n ot a vaila ble)
Circ ulati n g T u m or cells
Circ ulati n g T u m or cells
N o ( n ot a vaila ble)
C -reacti ve pr otei n
C -reacti ve pr otei n
N o ( n ot a vaila ble)
C o m or bi dities
N CI a n d its c o m p o ne nts 
N CI a n d its c o m p o ne nts 
Yes
Dia betes
Dia betes
Yes
Car di o vasc ular disease
Car di o vasc ular dise ase
Yes
A ne mia
A ne mia
Yes
C o nc o mita nt ca ncer 
dia g n osis (e xce pt f or 
n o n- mela n o ma s ki n 
ca ncer)
C o nc o mita nt ca ncer 
dia g n osis (e xce pt f or 
n o n- mela n o ma s ki n 
ca ncer)
N o ( n ot rele va nt d ue t o 
e xcl usi o n criteria)
Pri or h os pit aliz ati o n a n d E R r o o m visits
P C -relate d h os pitalizati o n
P C -relate d h os pitalizati o n
N o ( n ot a vaila ble)
P C -relate d E R visit
P C -relate d E R visit
N o ( n ot a vaila ble)
All -ca use h os pitalizati o n
All -ca use h os pitalizati o n
N o ( n ot a vaila ble)
All -ca use E R visit
All -ca use E R visit
N o ( n ot a vaila ble)
N ote: T he c o m plete ness/ missi n g ness of partic ular varia bles is bei n g deter mi ne d.
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

E nzal uta mi de
C 3 4 3 1 0 4 7 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
Versi o n 1 . 0, 1 2 J u ne 2 0 2 3
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 4 . 0 N o n -I nterve nti o n al St u dy Pr ot oc ol F or Sec o n d ary D at a C ollecti o n St u dy
0 1 -J u n - 2 0 2 2
Pa ge 4 7 of 4 7
A p pe n di x 2 T a ble 1. S u m m ar y of preli mi n ar y list of pr o g n ostic f act ors f or O S i n 
m C R P C f or a dj ust me nt i n m ulti v ari a ble a n al ysis
I de ntifie d fr o m t he 
t ar gete d liter at ure 
re vie w b y at le ast 2 
st u dies
F act ors a d de d b ase d o n 
cli nic al i n p ut 
C o ns oli d ate d list fr o m 
liter at ure re vie w a n d 
cli nic al i n p ut
A dj ust a ble i n Fl atir o n 
E H R
A b bre viati o ns: A D T: a n dr o ge n de pri vati o n t hera p y; A L P: al kali ne p h os p hatase; B MI: b o d y mass i n de x; E C O G: 
Easter n C o o perati ve O nc ol o g y Gr o u p; E R: E mer ge nc y r o o m; L D H:  lactate de h y dr o ge nase; P C: pr ostate 
ca ncer; P S A: pr ostate -s pecific a nti ge n; P S A D T: pr ostate-s pecific a nti ge n d o u bli n g ti me.
0 9 0 1 7 7 e 1 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)

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 9 d e 7 8 d 0 2\ A p pr o v e d\ A p pr o v e d O n: 0 6- J ul- 2 0 2 3 1 5: 4 1 ( G M T)
P P D
P P D