Novel Hormonal Therapy (NHT) for Treating Patients With Metastatic Castration-Sensitive Prostate Cancer (mCSPC): An Analysis of National Veterans Affairs Health Care Network Data
Conditions: Prostatic Neoplasms
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study Information
Title
Novel Hormonal Therapy (NHT) for Treating Patients with 
Metastatic Castration-Sensitive Prostate Cancer (mCSPC): An 
Analysis of National Veterans Affairs Health Care Network 
Data
Protocol number
C3431052
Protocol version identifier
1.0
Date
06 November 2023
Active substance
Enzalutamide
Medicinal product
Xtandi
Research question and 
objectives
The main research question is to identify men with mCSPC 
from the Veterans Affairs Health Care Network Data who 
were treated with NHT, including abiraterone (ABI), 
apalutamide (APA), or enzalutamide (ENZ), in the first line 
(1L) setting and describe clinical outcomes of interest. 
 
 
 
 
 
More specifically, the study objectives include:

Primary objective: Describe duration of therapy (DOT) 
among patients with mCSPC who initiated NHT in 1L

Secondary objective: Describe time to next therapy 
(TTNT) among patients with mCSPC who initiated NHT
in 1L

Exploratory objectives:
1. Describe patient baseline characteristics overall
 
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4. Describe time to deep prostate-specific antigen (PSA)
response and time to undetectable PSA overall 
 
5. Describe time to progression overall
 
6. Describe the distribution of next therapy regimens
overall 
Author
, MA
Pfizer Inc.
This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................3
2. LIST OF ABBREVIATIONS................................................................................................5
3. RESPONSIBLE PARTIES....................................................................................................7
4. ABSTRACT...........................................................................................................................8
5. AMENDMENTS AND UPDATES.....................................................................................11
6. MILESTONES.....................................................................................................................12
7. RATIONALE AND BACKGROUND................................................................................13
8. RESEARCH QUESTION AND OBJECTIVES .................................................................13
9. RESEARCH METHODS ....................................................................................................14
9.1. Study Design ...........................................................................................................14
9.2. Setting......................................................................................................................14
9.2.1. Inclusion Criteria ........................................................................................15
9.2.2. Exclusion Criteria.......................................................................................17
9.3. Variables..................................................................................................................17
9.4. Data Sources............................................................................................................22
9.5. Study Size................................................................................................................22
9.6. Data Management ...................................................................................................22
9.7. Data Analysis ..........................................................................................................22
9.7.1. Data Analysis for Primary Objective: Describe TTNT among 
patients with mCSPC who initiated NHT in 1L ..............................................22
9.7.2. Data Analysis for Secondary Objective: Describe TTNT among 
patients with mCSPC who initiated NHT in 1L ..............................................23
9.7.3. Data Analysis for Exploratory Objectives..................................................23
9.7.3.1. Data Analysis for Exploratory Objective 1: Describe 
patient baseline characteristics overall 
 
 
......................................................................................23
 
...........................................23
9.7.3.3. Data Analysis for Exploratory Objective 4: Describe time 
to deep prostate-specific antigen (PSA) response and time to 
undetectable PSA overall 
 
.............24
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9.7.3.4. Data Analysis for Exploratory Objective 5: Describe time 
to progression overall
 
................................24
9.7.3.5. Data Analysis for Exploratory Objective 6: Describe the 
distribution of next therapy regimens overall 
 
....................................................................................................24
9.8. Quality Control........................................................................................................25
9.9. Limitations of the Research Methods......................................................................25
9.10. Other Aspects ........................................................................................................25
10. PROTECTION OF HUMAN PARTICIPANTS ...............................................................26
10.1. Patient Information................................................................................................26
10.2. Patient Consent......................................................................................................26
10.3. Institutional Review Board (IRB)/ Ethics Committee (EC)..................................26
10.4. Ethical Conduct of the Study ................................................................................26
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................26
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........26
13. REFERENCES ..................................................................................................................27
14. LIST OF TABLES.............................................................................................................29
15. LIST OF FIGURES ...........................................................................................................29
ANNEX 1. LIST OF STANDALONE DOCUMENTS ..........................................................29
ANNEX 2. ADDITIONAL INFORMATION.........................................................................30
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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
ABI
abiraterone acetate
ADT
Androgen Deprivation Therapy
AE
adverse event
APA
apalutamide
CCI
Charlson Comorbidity Index
CDW
Corporate Data Warehouse
CI
confidence interval
CRPC
castration-resistant prostate cancer
CSPC
castration-sensitive prostate cancer
DOT
duration of treatment
EC
Ethics Committee
ENZ
enzalutamide
FDA
United States Food and Drug Administration
ICD-10-CM
International Classification of Diseases, 10th 
Revision, Clinical Modification
IPTW
Inverse probability treatment weighting
IRB
Institutional Review Board
KM
Kaplan-Meier
mCRPC
metastatic CRPC
mCSPC
metastatic CSPC
NCI
National Cancer Institute
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Abbreviation
Definition
NHT
Novel Hormonal Therapy
NSAA
non-steroidal anti-androgen
PC
prostate cancer
PH
proportional hazards
PSA
prostate-specific antigen
PFS
progression-free survival
SAS
Statistical Analysis System
SLVHCS
Southeast Louisiana Veterans Health Care System
SMD
Standardized Mean Difference
TTNT
time to next therapy
VA
Veterans’ Affairs
VHA
Veterans’ Health Administration
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3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, Degree(s)
Job Title
Affiliation
Address
Jasmina Ivanova, MA
Senior Director, Value & 
Evidence – Xtandi
Patient & Health Impact
Pfizer Inc.
66 Hudson Blvd.
New York New York 10001
Dave Russell, MD
Senior Director, Global 
Medical Affairs, Xtandi 
Lead
Pfizer Inc.
66 Hudson Blvd.
New York New York 10001
Maelys Touya, PharmD, MSc
Director, HEOR 
Oncology
Astellas Pharma 
US, Inc.
2375 Waterview Drive
Northbrook, IL 60062
Hongbo Yang, PhD, MS
Vice President
Analysis Group
111 Huntington Ave
14th Floor
Boston, MA 02199
Wei Gao, PhD, MS
Vice President
Analysis Group
111 Huntington Ave
14th Floor
Boston, MA 02199
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4. ABSTRACT
Title: Novel Hormonal Therapy (NHT) for Treating Patients with Metastatic Castration-
Sensitive Prostate Cancer (mCSPC): An Analysis of National Veterans Affairs Health Care 
Network Data
Version: 1.0
Date of Protocol: 06 November 2023
Author: 
Rationale and Background: Prostate cancer is the most common cancer and the second 
leading cause of cancer death among men in the United States. While the long-term outlook 
is positive for early-stage prostate cancer, survival rates drastically decrease once the disease 
has spread beyond the prostate gland. Metastatic castration-sensitive prostate cancer 
(mCSPC) is form of metastatic prostate cancer among men who have never received or are 
sensitive to androgen deprivation therapy (ADT). Conventional therapy for mCSPC has been 
ADT, however, mCSPC treated with ADT might eventually transition to castration-resistant 
prostate cancer (CRPC) stage with a median survival of approximately 3 years. Upfront 
intensified treatment with NHTs, including abiraterone acetate (ABI), apalutamide (APA), 
and enzalutamide (ENZ), added to a backbone of ADT, has substantially improved survival
in clinical trials. Due to relatively recent approval of NHTs in mCSPC there is limited 
information on real-world duration of treatment and time to next treatment with these 
therapies. The current study proposes to use the Veterans Health Administration (VHA) 
database to describe outcomes of patients with NHT use in mCSPC.
Objectives: The study objectives include:

Primary objective: Describe duration of therapy (DOT) among patients with 
mCSPC who initiated NHT in the first line (1L)

Secondary objective: Describe time to next therapy (TTNT) among patients with 
mCSPC who initiated NHT in 1L

Exploratory objectives:
1. Describe patient baseline characteristics overall
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4. Describe time to deep prostate-specific antigen (PSA) response and time to 
undetectable PSA overall
 
5. Describe time to progression overall
 
6. Describe the distribution of next therapy regimens overall 
Study Design: This is a retrospective, observational study using the VHA data. Patients with 
mCSPC who initiated NHT in 1L during January 2020 – December 2022 will be selected 
based on diagnosis history, treatment history, PSA measurements, age, and continuous 
enrollment.
. Patients will be required to have 
365 days of continuous enrollment in the National Veterans’ Affairs (VA) Health Care 
Network prior to their index date, during which baseline characteristics will be assessed. The 
follow-up period will be defined as the time from the index date to the end of continuous 
enrollment, the end of the data availability, or death, whichever comes first. During the 
follow-up period, the outcome measures (ie, DOT, TTNT, time to deep PSA response, time 
to undetectable PSA, time to progression, and the distribution of next treatment) will be 
assessed. 
Population: The population for the primary and secondary objectives will consist of patients 
with mCSPC who initiated NHT in 1L and who meet all the sample selection criteria.
 
 
Variables: Baseline demographic and clinical characteristics will include age, race,
geographic regions, index year, treatment history, diagnosis history, prognostic variables, 
Charlson Comorbidity Index score, and individual comorbidities. Outcomes will include
DOT, TTNT, time to deep PSA response, time to undetectable PSA, and time to progression.
Data Sources: VHA Medical Statistical Analysis System datasets.  
Study Size: All eligible patients available for the analysis will be included.
Data Analysis: In the primary and secondary analyses, DOT and TTNT will be described in 
the overall sample of patients with mCSPC who initiated 1L NHT using Kaplan-Meier (KM) 
analysis. The number at risk table and the median time to event and its 95% confidence 
interval will be reported. In the exploratory analyses, patient baseline characteristics will be 
described in the overall sample
. Means, standard deviations, medians, 
and interquartile range will be e
ous variables; counts and percentages 
will be estimated for categorical variables.
 
 
 KM analysis will be conducted to describe time to deep PSA response, time to 
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undetectable PSA, and time to progression in the overall sample 
 
 
 
 
 
 Data analysis will be executed using statistical software SAS version 9.4 (Cary, 
NC).
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5. AMENDMENTS AND UPDATES
None.
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6. MILESTONES
Milestone
Planned Date
Start of data collection
21 November 2023
End of data collection
31 October 2024
Final study report
31 December 2024
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7. RATIONALE AND BACKGROUND
Prostate cancer is the most common cancer and the second leading cause of cancer death 
among men in the United States. The National Cancer Institute estimates that in 2022 there 
will be 268,490 new cases of prostate cancer (PC) and 34,500 deaths due to PC.8 While the 
long-term outlook is positive for early-stage prostate cancer, survival rates drastically 
decrease once the disease has spread beyond the prostate gland.9
Metastatic castration-sensitive prostate cancer (mCSPC) is form of metastatic prostate cancer 
among men who have never received or are sensitive to ADT.5 Conventional therapy for 
mCSPC has been ADT, however, mCSPC treated with ADT might eventually transition to
CRPC stage with a median survival of approximately 3 years.11
Several NHTs have been approved for treatment in mCSPC together with ADT. ABI and 
ENZ were initially approved by the United States Food and Drug Administration (FDA) for 
metastatic CRPC patients with prior chemotherapy in April 2011 and August 2012, 
respectively, and for chemotherapy-naïve patients in December 2012 and September 2014, 
respectively. ABI was later approved in February 2018, followed by ENZ in December 2019, 
for the treatment of mCSPC.1,2 One of the most recent NHTs, apalutamide (APA) was 
approved by the FDA in September 2019 for patients with mCSPC.3
Upfront intensified treatment with NHTs in mCSPC, including ABI, APA, and ENZ, added 
to a backbone of ADT, has substantially improved survival.4,6,10 With the rapidly expanding 
treatment landscape, there have been limited studies describing clinical outcomes with NHTs
in mCSPC. 
The current study proposes to use the VHA database to describe outcomes of patients with 
NHT use in in mCSPC. 
8. RESEARCH QUESTION AND OBJECTIVES
The main research question is to identify men with mCSPC from the VHA database who 
were treated with NHT, including ABI, APA, and ENZ, in the 1L setting and describe 
clinical outcomes of interest.
 
 
More specifically, the study objectives include:

Primary objective: Describe DOT among patients with mCSPC who initiated NHT 
in 1L

Secondary objective: Describe TTNT among patients with mCSPC who initiated 
NHT in 1L
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
Exploratory objectives:
1. Describe patient baseline characteristics overall
4. Describe time to deep PSA response and time to undetectable PSA overall
 
 
5. Describe time to progression overall and
 
6. Describe the distribution of next therapy regimens overall 
 
9. RESEARCH METHODS 
9.1. Study Design
This is a retrospective, observational study using the VHA data. Patients with mCSPC who 
initiated NHT in 1L during January 2020 – December 2022 will be selected based on 
diagnosis history, treatment history, PSA measurements, age, and continuous enrollment.
 
 
. Patients will be required to have one year of continuous 
enrollment in the National VA Health Care Network prior to their index date, during which 
patient baseline characteristics will be assessed. The time period (January 2020 – December 
2022) to identify NHT initiation reflects the recency of NHT approvals, and the baseline 
period allows us to capture any potential comorbidities and characteristics that may be 
confounders to the outcomes. The follow-up period will be defined as the time from the 
index date to the end of continuous enrollment, the end of the data availability, or death, 
whichever comes first. During the follow-up period, the outcome measures (ie, DOT, TTNT, 
time to deep PSA response, time to undetectable PSA, time to progression, and the 
distribution of next treatment) will be assessed. The follow-up period is chosen to maximally 
capture any potential outcomes among patients with mCSPC who initiated NHT in 1L. 
9.2. Setting
The study population will include patients with mCSPC who initiated NHT in 1L in the VHA 
database. Inclusion and exclusion criteria are specified below.
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9.2.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:

Males.

Have at least one claim with a diagnosis code of PC (PC; ICD-10-CM code C61).

Have documented secondary metastasis codes on or after the initial PC diagnosis 
(ICD-10 codes C77, C78, C79, C7B).

Have initiated ABI, APA, or ENZ (1) during the index window of January 2020 –
December 2022, and (2) within 90 days prior to or any time after the first claim for 
metastatic disease. The initiation of date of ABI, APA, or ENZ will be defined as the 
index date.

Index window of January 2020 – December 2022 is selected, as during this period 
all NHTs were approved for mCSPC, which will help remove early initiator bias 
(eg, when a product/class of products became available, patients with severe 
diseases tend to try first). Table 1 lists the approval dates for when each NHT was 
approved for treating mCSPC. 
Table 1.
FDA Approval Dates for NHTs in mCSPC
ABI
07 February 2018
APA
17 September 2019
ENZ
16 December 2019

At least 18 years old at the index date.

Have continuous enrollment for at least 365 days before the index date.

Have evidence to be castration sensitive AND have no evidence to be castration 
resistant. This is tentatively defined as:
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Evidence to be castration sensitive:

No prior surgical castration (ie, bilateral orchiectomy, Appendix Table 1) any 
time prior to the index date or no medical castration (ie, degarelix, relugolix, 
goserelin, histrelin, leuprolide, and triptorelin; ≥8 weeks of continuous use; 
Appendix Table 1) within -90 to -365 days prior to the index date, OR

Presence of ICD-10-CM diagnosis code indicating hormone sensitive 
malignancy status (ie, Z19.1, which was introduced on 01 October 2016) 
within 90 days before the index date 
No evidence to be castration resistant:

No evidence of castration resistance any time prior to the index date. Evidence 
of castration resistance is defined by the following:

ICD-10-CM diagnosis code indicating hormone resistance (Z19.2), OR

A rise in PSA from the nadir by ≥2 ng/mL after castration (nadir is defined 
as the lowest PSA since surgical or medical castration and before the 
index date) 

Patients with other PC treatment including NHT, non-steroidal anti-
androgen (NSAA), chemotherapy, immunotherapy, radium 223, lutetium 
Lu 177 vipivotide tetraxetan, ketoconazole, niraparib, olaparib, rucaparib, 
or talazoparib at any time prior to the index date 
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Figure 1. Study Schema
9.2.2. Exclusion Criteria
Patients meeting any of the following criteria will not be included in the study:

Patients with any other primary cancer (excluding non-melanoma skin cancer) prior 
to the index date 

Participation in clinical trial during the 30 days prior to the index date 
 
9.3. Variables
Table 2.
Baseline Demographics and Clinical Characteristics
Variable
Operational Definition
Baseline period
The baseline period will be defined as 365 days prior to the 
index date.
Age
Age will be defined as of the index date and retained in the 
dataset as a continuous variable and a categorical variable: 
18-49, 50-59, 60-69, 70-79, and ≥80 years old.
Race
Proportion of patients that were Hispanic, non-Hispanic 
white, black, other, and unknown races will be evaluated.
Follow-up period 
From the index date to the end of continuous 
eligibility, the end of data availability, or death,
whichever happens first

Diagnosis of mCSPC

Evidence to be castration 
sensitive AND No evidence to be 
castration resistant

No other primary cancer
Baseline period
365 days of continuous eligibility
Index date

Date of initiation of ABI, 
APA, or ENZ in 1L
between 01 January 2020 
and 31 December 2022
M l
18
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Variable
Operational Definition
Geographic regions
Proportion of patients that lived in Northeast, Midwest, 
South and West areas.
Index year
Variable will be created for the index calendar year (from 
2020 to 2022).
Treatment history
Proportion of patients who had radical prostatectomy, 
external radiotherapy, chronic corticosteroid use, hormone 
therapy, bone protective agents, and pain medication 
prescribed in the baseline period will be evaluated.
Time from Metastatic 
Diagnosis Date to Index 
Date
Time from the first observed metastatic date in the data to 
the index date will be evaluated.
Time from PC Diagnosis 
Date to Index Date
Time from the first observed PC date in the data to the 
index date will be evaluated.
Site of Metastasis 
Flags will be created for patients that had a metastatic 
diagnosis at the following sites: bone only, bone and node 
only, node only, viscera and other.
PSA Value
Baseline PSA value (if available) will be defined as the 
PSA value closest to the index date within 180 days prior 
to index date. 
Hemoglobin Value
Baseline hemoglobin value (if available) will be defined as 
the value closest to the index date within 180 days prior to 
index date.
Alkaline Phosphatase 
Value
Baseline alkaline phosphatase value (if available) will be 
defined as the value closest to the index date within 180 
days prior to index date.
Modified National Cancer 
Institute (NCI) Charlson 
Comorbidity Index (CCI) 
The NCI CCI score excluding cancer will be calculated
during the baseline period.
Acute Coronary Syndrome
A binary variable (yes/no) will be created for patients with 
claims for acute coronary syndrome during the baseline 
period.
Angina Pectoris
A binary variable (yes/no) will be created for patients with 
claims for angina pectoris during the baseline period.
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Variable
Operational Definition
Arrhythmia
A binary variable (yes/no) will be created for patients with 
claims for arrhythmia during the baseline period.
Chronic Obstructive 
Pulmonary Disease
A binary variable (yes/no) will be created for patients with 
claims for chronic obstructive pulmonary disease during 
the baseline period.
Congestive Heart Failure
A binary variable (yes/no) will be created for patients with 
claims for congestive heart failure during the baseline 
period.
Diabetes
A binary variable (yes/no) will be created for patients with 
claims for diabetes (types 1 and 2) during the baseline 
period.
Hyperlipidemia
A binary variable (yes/no) will be created for patients with 
claims for hyperlipidemia during the baseline period.
Hypertension
A binary variable (yes/no) will be created for patients with 
claims for hypertension during the baseline period.
Inflammatory Bowel 
Disease
A binary variable (yes/no) will be created for patients with 
claims for inflammatory bowel disease (ulcerative colitis, 
Crohn’s disease) during the baseline period.
Lower-extremity Arterial 
Occlusive Disease
A binary variable (yes/no) will be created for patients with 
claims for low-extremity arterial occlusive disease during 
the baseline period.
Myocardial Infarction
A binary variable (yes/no) will be created for patients with 
claims for myocardial infraction during the baseline period.
Stroke
A binary variable (yes/no) will be created for patients with 
claims for stroke during the baseline period.
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Table 3.
Outcomes During the Follow-up Period
Variable
Operational Definition
Follow-up period
The follow-up period will be defined as the time from the index 
date to the end of continuous enrollment, the end of the data 
availability, or death, whichever comes first.
DOT
Duration of therapy will be defined as the time from the index 
date to the date of NHT discontinuation for any reason.
Discontinuation of the current NHT will be defined as a 
treatment gap of at least 90 days (the last day with days supply 
before the gap as discontinuation date), the initiation of a new
therapy, or death, whichever comes first. Initiation of a new 
therapy will be defined by switching to a different NHT, 
switching to or augmentation with NSAA, chemotherapy, 
immunotherapy, radium 223, lutetium Lu 177 vipivotide 
tetraxetan, ketoconazole, niraparib, olaparib, rucaparib, or 
talazoparib. Patients who do not experience discontinuation will 
be censored at the end of data availability.
TTNT
Time to next therapy will be defined as the time from the index 
date to the initiation date of a new therapy (see the definition of 
a new therapy above). Patients who do not initiate a new therapy 
will be censored at the end of data availability or death, 
whichever comes first.
Next therapy regimen
The next therapy regimen will include all therapies noted below
initiated within 28 days of the start of the new therapy (different 
NHT, switching to or augmentation with NSAA, chemotherapy, 
immunotherapy, radium 223, lutetium Lu 177 vipivotide 
tetraxetan, ketoconazole, niraparib, olaparib, rucaparib, or 
talazoparib).
PSA assessment and PSA 
response description

The following will be described for patients with a 
baseline and at least one post baseline PSA value:

The distribution of the number of post baseline PSA 
assessments 

PSA nadir (lowest post-baseline value) 

Number and proportion of patients with deep PSA
response (≥ 90% decrease in a post-index PSA value 
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Variable
Operational Definition
from the baseline PSA value) any time during follow-up

Number and proportion of patients with undetectable 
PSA value post baseline (using different thresholds):

<0.2 ng/mL

<0.1 ng/mL

<0.01 ng/mL
Time to deep PSA response
Time to deep PSA response will be calculated among patients 
who have baseline PSA value and at least one PSA value after 
the index date. Time to deep PSA response will be defined as the 
time from the index date to the date of deep PSA response. Deep 
PSA response will be defined as ≥90% decrease in a post-index 
PSA value from the baseline PSA value. Patients who do not 
experience deep PSA response will be censored at the end of last 
available PSA assessment.
Time to undetectable PSA
Time to undetectable PSA will be calculated among patients 
who have baseline PSA value and at least one PSA value after 
the index date. Time to undetectable PSA will be defined as the 
time from the index date to the first evidence of undetectable 
PSA. Undetectable PSA may be defined using different 
thresholds (eg, <0.2 ng/mL). Patients who do not have 
undetectable PSA post index will be censored at the end of last 
available PSA assessment. 
Time to progression
Time to progression will be defined as the time from the index 
date to the first evidence of disease progression. Progression will 
be defined as PSA progression, initiation of a new therapy, or 
death, whichever comes first. PSA progression will be defined as
an increase of ≥25% and an absolute increase of ≥2ng/mL in 
PSA from the nadir value post-index. Patients who do not 
experience disease progression will be censored at the end of 
data availability.
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9.4. Data Sources
Data from the National VA Health Care Network will be used for this study. This network is 
the U.S.’s largest integrated health care system with over 1,700 sites of care, serving 
approximately 8.76 million veterans each year. The VA Health System Corporate Data 
Warehouse (CDW) includes all medical encounter information in the VA, comprised of 
medical centers, community-based outpatient clinics, community-living centers, veteran 
centers, and domiciliaries. The VA CDW stores data in separate databases, one for each type 
of clinical information - inpatient medication, inpatient laboratory, inpatient admission, 
outpatient medication, outpatient laboratory, outpatient visits, etc. The databases provide 
demographic information and contain comprehensive services, including primary care, 
specialty care, inpatient care, rehabilitation, long-term care, home care, and other services, to 
military veterans. The database also includes date of death. The date of death is extracted 
from the VA electronic health record systems and verified by official sources, including VA 
facilities, death certificates, and National Cemetery Administration. Information on CDW, 
including date of death, is updated on a daily base. Cause of death is not available on CDW.
9.5. Study Size
As no priori hypotheses are specified, sample size calculations are not applicable. The 
number of patients eligible for the study will be determined in accordance with the sample 
selection conducted per the criteria described in Section 9.2.
9.6. Data Management 
A clean, patient-level dataset will be generated for use throughout the study. This process 
will entail basic exploratory checks to ensure data integrity; cleaning and reformatting the 
raw data as needed; and creating variables for all key study measures, including patient 
characteristics, treatment start and end dates, and classification of treatments and medication. 
All data will be stored and maintained on National VA Health Care Network and accessed 
over Southeast Louisiana Veterans Health Care System (SLVHCS) at Tulane University. The 
data will be made accessible only to individuals working on the current study. No attempt 
will be made to identify individual patients, hospitals, or physicians. Analyses will be 
conducted using SAS 9.4 (SAS Institute, Cary NC).
9.7. Data Analysis
9.7.1. Data Analysis for Primary Objective: Describe TTNT among patients with 
mCSPC who initiated NHT in 1L
DOT, as defined in Table 3, will be summarized among the overall sample of patients with 
mCSPC who initiated NHT in 1L. Kaplan-Meier (KM) analysis will be used to describe 
DOT, and patients who do not experience treatment discontinuation will be censored at the 
end of data availability. The number of patients at risk and the number and proportion of 
individuals experiencing discontinuation during the follow-up period (eg, annually or every 6 
months) will be reported. The median DOT and corresponding 95% CI will be reported.
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9.7.2. Data Analysis for Secondary Objective: Describe TTNT among patients with 
mCSPC who initiated NHT in 1L
TTNT, as defined in Table 3, will be summarized among the overall sample of patients with 
mCSPC who initiated NHT in 1L. KM analysis will be used to describe TTNT, and patients 
who do not initiate a new therapy will be censored at the end of data availability. The number 
of patients at risk and the number and proportion of individuals initiating a new therapy
during the follow-up period (eg, annually or every 6 months) will be reported. The median 
TTNT and corresponding 95% CI will be reported.
9.7.3. Data Analysis for Exploratory Objectives
9.7.3.1. Data Analysis for Exploratory Objective 1: Describe patient baseline 
characteristics overall
 
Descriptive analysis will be conducted for baseline demographic and clinical characteristics, 
as defined in Table 2, in the overall sample of patients with mCSPC who initiated NHT in 1L 
Means, standard deviations, medians, and 
interquartile range will be estimated for continuous variables. Counts and percentages will be 
estimated for categorical variables. 
 
 
 
 
 
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9.7.3.3. Data Analysis for Exploratory Objective 4: Describe time to deep prostate-
specific antigen (PSA) response and time to undetectable PSA overall
 
Descriptive analysis will be conducted to describe the distribution of post-baseline PSA 
assessments, PSA nadir, deep PSA response, and undetectable PSA, as defined in Table 3, in 
the overall sample of patients with mCSPC who initiated NHT in 1L 
 
. Means, standard deviations, medians, and interquartile range 
will be estimated for continuous variables. Counts and percentages will be estimated for 
categorical variables.
 
Time to deep PSA response and time to undetectable PSA, as defined in Table 3, will be 
summarized in the overall sample of patients with mCSPC who initiated 1L NHT 
 
 
 
9.7.3.4. Data Analysis for Exploratory Objective 5: Describe time to progression overall 
Time to progression, as defined in Table 3, will be summarized in the overall sample of 
patients with mCSPC who initiated 1L NHT
 
 
9.7.3.5. Data Analysis for Exploratory Objective 6: Describe the distribution of next 
therapy regimens overall 
The number and proportion of patients who initiated a new therapy following the index NHT 
will be estimated in the overall sample
 
Among those who initiated a new therapy, the number and proportion of patients who 
received different type of regimen for first subsequent therapy will be described. A noted in 
Table 3, the next therapy regiment will include all therapies noted below initiated within 
28 days of the start of the new therapy (different NHT, switching to or augmentation with 
NSAA, chemotherapy, immunotherapy, radium 223, lutetium Lu 177 vipivotide tetraxetan,
ketoconazole, niraparib, olaparib, rucaparib, or talazoparib).
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9.8. Quality Control
Best practice guidelines will be followed to ensure project quality, including structured 
organization of project materials (eg, data extracts, statistical software programs, output 
tables) and standard internal audit process. The audit process both confirms the validity of 
the analytical approach and ensures that all programs and results are accurate.
9.9. Limitations of the Research Methods
The analyses conducted as part of this study are subject to the following limitations, which 
will be addressed in any write-up of the study:

As this study will be conducted among veterans, its findings may not be generalizable 
to other populations.

Also, as we are pulling VA only data, we are not able to capture care that occurs 
outside the VA which could lead to missing data and misclassification of disease 
states and treatment groups.

There are no specific diagnosis codes for CSPC. Assumptions will be made to select 
patients with CSPC based on clinical input.

Certain assumptions will be made in order to depict treatment patterns for 
determining TTNT. However, the definition of treatment patterns will nevertheless be 
subject to assumptions that may not match up to the prescribing physicians’ intent.

Data are subject to inaccuracies in coding of diagnoses. The presence of a diagnosis 
code in the data does not necessarily mean the presence of disease. The disease may 
be incorrectly coded or the code was included as a rule-out criterion. 

The presence of a prescription does not necessarily mean the medication was used as 
prescribed. In addition, prescriptions filled over the counter or provided as samples by 
the physician are not included in the data.

Regression models cannot account for unmeasured factors.
9.10. Other Aspects
Not applicable.
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10. PROTECTION OF HUMAN PARTICIPANTS
10.1. Patient Information 
This study involves data that exist in deidentified/anonymized structured format and contain 
no patient personal information. 
10.2. Patient Consent
As this study involves deidentified/anonymized structured data, which according to 
applicable legal requirements do not contain data subject to privacy laws, obtaining informed 
consent from patients by Pfizer is not required.
10.3. Institutional Review Board (IRB)/ Ethics Committee (EC)
This protocol, and any subsequent modifications, will be reviewed and approved by the 
SLVHCS IRB prior to implementation. 
10.4. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value, and rigor and follow generally accepted research practices 
described in Guidelines for Good Pharmacoepidemiology Practices (GPP). Public Policy 
Committee, International Society of Pharmacoepidemiology. Pharmacoepidemiology and 
Drug Safety 2015; 25:2-10. https://onlinelibrary.wiley.com/doi/full/10.1002/pds.3891.
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This study involves data that exist as structured data by the time of study start. In these data 
sources, individual patient data are not retrieved or validated, and it is not possible to link 
(ie, identify a potential association between) a particular product and medical event for any 
individual. Thus, the minimum criteria for reporting an adverse event (AE) (ie, identifiable 
patient, identifiable reporter, a suspect product, and event) cannot be met.
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
Based on the analysis results and discussions with Pfizer, a study report summarizing the 
background, objectives, methods, results, and conclusion of the study will be prepared. The 
study report may be disseminated within Pfizer but is not expected to be externally 
communicated. 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
competent authority in any area of the world, or if the party responsible for collecting data 
from the participant is aware of any new information which might influence the evaluation of 
the benefits and risks of a Pfizer product, Pfizer should be informed immediately.
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13. REFERENCES
1.
US Food and Drug Administration. FDA approves abiraterone acetate in combination 
with prednisone for high-risk metastatic castration-sensitive prostate cancer 2018 
[Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-
approves-abiraterone-acetate-combination-prednisone-high-risk-metastatic-castration-
sensitive].
2.
US Food and Drug Administration. FDA approves enzalutamide for metastatic 
castration-sensitive prostate cancer 2019 [Available from: 
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-
enzalutamide-metastatic-castration-sensitive-prostate-cancer].
3.
US Food and Drug Administration. FDA approves apalutamide for metastatic 
castration-sensitive prostate cancer 2019 [Available from: 
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-
apalutamide-metastatic-castration-sensitive-prostate-cancer].
4.
Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, et 
al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 
2019;381(1):13-24.
5.
Damodaran S, Lang JM, Jarrard DF. Targeting Metastatic Hormone Sensitive Prostate 
Cancer: Chemohormonal Therapy and New Combinatorial Approaches. J Urol. 
2019;201(5):876-85.
6.
Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, et al. 
Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J 
Med. 2019;381(2):121-31.
7.
National Cancer Institute. Prostate Cancer 2022 [Available from: 
https://www.cancer.gov/types/prostate].
8.
National Cancer Institute. Cancer Stat Facts: Prostate Cancer 2022 [Available from: 
https://seer.cancer.gov/statfacts/html/prost.html].
9.
National Cancer Institute. Prostate Cancer Treatment – Health Professional Version 
2022 [Available from: https://www.cancer.gov/types/prostate/hp/prostate-treatment-
pdq].
10.
Rydzewska LHM, Burdett S, Vale CL, Clarke NW, Fizazi K, Kheoh T, et al. Adding 
abiraterone to androgen deprivation therapy in men with metastatic hormone-sensitive 
prostate cancer: A systematic review and meta-analysis. Eur J Cancer. 2017;84:88-101.
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11.
Tangen CM, Hussain MH, Higano CS, Eisenberger MA, Small EJ, Wilding G, et al. 
Improved overall survival trends of men with newly diagnosed M1 prostate cancer: a 
SWOG phase III trial experience (S8494, S8894 and S9346). J Urol. 2012;188(4):1164-
9.
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14. LIST OF TABLES 
Table 1.
FDA Approval Dates for NHTs in mCSPC
Table 2.
Baseline Demographics and Clinical Characteristics
Table 3.
Outcomes During the Follow-up Period
15. LIST OF FIGURES
Figure 1. Study Schema
ANNEX 1. LIST OF STANDALONE DOCUMENTS
None. 
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ANNEX 2. ADDITIONAL INFORMATION
Appendix Table 1. Codes for Treatments
Hormonal therapy
GPI
HCPCS/CPT
ICD
Androgen deprivation therapy
Bilateral orchiectomy
Identified by having at least one procedure code 
for bilateral orchiectomy, having unilateral 
procedure codes for both testicles (left and 
right), or having two unilateral orchiectomy 
procedures (location unspecified) on different 
dates  
CPT
54520, 54522, 54530, 54535, 54690
ICD-9-CM
V45.77
ICD-10-CM
Z90.79
ICD-9-PCS
623, 6241, 6242
ICD-10-PCS
0V590ZZ, 0V593ZZ, 0V594ZZ, 0V5B0ZZ, 
0V5B3ZZ, 0V5B4ZZ, 0V5C0ZZ, 0V5C3ZZ, 
0V5C4ZZ, 0VT90ZZ, 0VT94ZZ, 0VTB0ZZ, 
0VTB4ZZ, 0VTC0ZZ, 0VTC4ZZ
LHRH agonists/antagonists
Degarelix
2140552510
J9155
Relugolix
21405570000320
24993503800320
Goserelin
21405005
J9202
Histrelin
2140500710
J1675, J9225, J9226, S0133
Leuprolide
21405010
J1950, J9217, J9218, J9219, Q0057
Triptorelin
21405050
J3315
Novel hormonal therapy
Apalutamide
2140241000
Abiraterone
2140601020
Darolutamide
2140242500
Enzalutamide
2140243000
Non-steroidal anti-androgens
Bicalutamide
2140242000
Flutamide
2140244000
Nilutamide
2140246000
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Hormonal therapy
GPI
HCPCS/CPT
ICD
Definitive therapy
GPI
HCPCS
ICD
Radical prostatectomy
55831, 55840, 55842, 55845, 55866
ICD-9-PCS
6021, 6029, 603, 604, 605, 6061, 6062, 6069
ICD-10-PCS
0VT00ZZ, 0VT04ZZ, 0VT07ZZ, 0VT08ZZ, 
0VB00ZZ, 0VB03ZZ, 0VB04ZZ, 0VB07ZZ, 
0VB08ZZ, 0V500ZZ, 0V503ZZ, 0V504ZZ, 
0V507ZZ, 0V508ZZ
External beam radiation treatment
CPT
77401-77416
HCPCS
G6003-G6014
Brachytherapy
CPT
7761-77763, 77767-77768, 77770-
77772, 77778, 77789, 77750, 77790
HCPCS
0394T-0395T
Chemotherapy
GPI
HCPCS
ICD
Taxane Chemotherapy
Cabazitaxel
2150000300
C9276, J9043
Docetaxel
2150000500
J9170, J9171
Other Chemotherapy
Carboplatin
2110001500
J9045
Cisplatin
2110002000
J9060, J9062
Oxaliplatin
2110002800
J9263
Mitoxantrone 
2120005500
J9293
Immunotherapy
GPI
HCPCS
ICD
Pembrolizumab
21357953002
J9271, C9027
Sipuleucel-T
2165107000
Q2043, C9273
Radium
GPI
HCPCS
ICD
Radium-223
2160005500
A9606
Others
GPI
HCPCS
ICD
Lutetium Lu 177 vipivotide tetraxetan
21600045802020
A9607
Olaparib
21535560
Rucaparib
21535570
Niraparib
21535550200, 
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Hormonal therapy
GPI
HCPCS/CPT
ICD
21409902120
Talazoparib
215355804001
Ketoconazole
1140404000,
9630106400, 
9015404500
Radiation therapy
GPI
HCPCS
ICD
Brachytherapy
CPT
7761-77763, 77767-77768, 77770-
77772, 77778, 77789, 77750, 77790
HCPCS
0394T-0395T
External beam radiation treatment 
CPT
77401-77416
HCPCS
G6003-G6014
Intensity modulated radiation therapy
G6015-G6016 
CPT: 77385-77386
Proton beam therapy
CPT: 77520-77525
Stereotactic body radiation therapy
CPT: 77373
Bone protective agents
GPI
HCPCS
ICD
Denosumab
3004453000
J0897, C9272
Ibandronate
3004204810
J1740, C9229  
Zoledronic acid
3004209000
J3489, Q2051, J3487, J3488, 
Q4095
ICD-9-PCS
V58.68
ICD-10-PCS
Z79.83
Pamidronate disodium
3004206010
J2430
Corticosteroids
GPI
HCPCS
ICD
Corticosteroids
22, 8910, 8915
C9256, J0702, J0704, J1020, J1030, 
J1040, J1094, J1100, J1700, J1710, 
J1720, J2650, J2920, J2930, J3300, 
J3301, J3302, J3303, J7312, J7506, 
J7509, J7510, J7512, J8540
Pain medications (analgesics)
Non-narcotics
64
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Hormonal therapy
GPI
HCPCS/CPT
ICD
Opioids
65
Anti-inflammatory medications
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Appendix Table 2. Diagnosis Codes for Comorbidities
Conditions and comorbidities
ICD-9-CM 
ICD-10-CM 
Charlson comorbidity index 
(CCI)1
HIV/AIDS
042–044
B20–B22, B24
Cerebrovascular disease
362.34, 430–438
G45, G46, H34.0, I60–I69
Chronic pulmonary disease
416.8, 416.9, 490–505, 506.4, 
508.1, 508.8
I27.8, I27.9, J40–J47, J60–J67, J68.4, J70.1, 
J70.3
Congestive heart failure
398.91, 402.01, 402.11, 
402.91, 404.01, 404.03, 
404.11, 404.13, 404.91, 
404.93, 425.4–425.9, 428
I09.9, I11.0, I13.0, I13.2, I25.5, I42.0, 
I42.5–I42.9, I43, I50, P29.0
Dementia
290, 294.1, 331.2
F00–F03, F05.1, G30, G31.1
Diabetes with chronic 
complication
250.4–250.7
E10.2–E10.5, E10.7, E11.2–E11.5, E11.7, 
E12.2–E12.5, E12.7, E13.2–E13.5, E13.7, 
E14.2–E14.5, E14.7
Diabetes without chronic 
complication
250.0–250.3, 250.8, 250.9
E10.0, E10.1, E10.6, E10.8, E10.9, E11.0, 
E11.1, E11.6, E11.8, E11.9, E12.0, E12.1, 
E12.6, E12.8, E12.9, E13.0, E13.1, E13.6, 
E13.8, E13.9, E14.0, E14.1, E14.6, E14.8, 
E14.9
Hemiplegia or paraplegia
334.1, 342, 343, 344.0–344.6, 
344.9
G04.1, G11.4, G80.1, G80.2, G81, G82, 
G83.0–G83.4, G83.9
Mild liver disease
070.22, 070.23, 070.32, 
070.33, 070.44, 070.54, 
070.6, 070.9, 570, 571, 573.3, 
573.4, 573.8, 573.9, V42.7
B18, K70.0–K70.3, K70.9, K71.3–K71.5, 
K71.7, K73, K74, K76.0, K76.2–K76.4, 
K76.8, K76.9, Z94.4
Moderate or severe liver 
disease
456.0–456.2, 572.2–572.8
I85.0, I85.9, I86.4, I98.2, K70.4, K71.1, 
K72.1, K72.9, K76.5, K76.6, K76.7
Myocardial infarction
410, 412
I21, I22, I25.2
Peptic ulcer disease
531–534
K25–K28
Peripheral vascular disease
093.0, 437.3, 440, 441, 
443.1–443.9, 447.1, 557.1, 
557.9, V43.4
I70, I71, I73.1, I73.8, I73.9, I77.1, I79.0, 
I79.2, K55.1, K55.8, K55.9, Z95.8, Z95.9
Renal disease
403.01, 403.11, 403.91, 
404.02, 404.03, 404.12, 
404.13, 404.92, 404.93, 582, 
583.0–583.7, 585, 586, 588.0, 
V42.0, V45.1, V56
I12.0, I13.1, N03.2–N03.7, N05.2–N05.7, 
N18, N19, N25.0, Z49.0–Z49.2, Z94.0, 
Z99.2
Rheumatic disease
446.5, 710.0–710.4, 714.0–
714.2, 714.8, 725
M05, M06, M31.5, M32–M34, M35.1, 
M35.3, M36.0
Individual conditions
Hypertension
362.11, 401.xx-405.xx, 437.2
H35.039, I10–I13, I15–I16, I67.4
Stroke
430-434, 436, 362.31-362.34
I60, I61, I62, I64, I65, I67, H34.1, H34.23, 
H34.21, H34.0
Acute Coronary Syndrome
411.x, 410.xx
I24, I21
Angina Pectoris
413
I20
Arrhythmia
427.1, 427.4, 427.41, 427.42, 
427.5, 427.69, 427.2, 427.60, 
I47.0, I47.2, I49.0, I46, I49.3, I49.49, I47.9, 
I49.40, I49.5, I49.8, I49.9
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Conditions and comorbidities
ICD-9-CM 
ICD-10-CM 
427.8, 427.89, 427.9
Myocardial Infarction
410, 412
I21, I22, I25.2
Congestive Heart Failure
428.xx
I09.9, I11.0, I13.0, I13.2, I25.5, I42.0, 
I42.5-I42.9, I43.x, I50.x, P29.0
Hyperlipidemia
272.0-272.4
E78.00, E78.01, E78.1, E78.2, E78.3, 
E78.41, E78.49, E78.5
Low-extremity Arterial 
Occlusive Disease
444.22
I74.3, I74.4
Type II Diabetes
250.0-250.3, 250.7
E10.0, E10.1, E10.6, E10.8, E10.9, E11.0, 
E11.1, E11.6, E11.8, E11.9, E12.0, E12.1, 
E12.6, E12.8, E12.9, E13.0, E13.1, E13.6, 
E13.8, E13.9, E14.0, E14.1, E14.6, E14.8, 
E14.9
Chronic Obstructive 
Pulmonary Disease
490-492, 494, 496
J40, J41, J42, J43, J47, J44.9
Inflammatory bowel disease
    Crohn’s disease
555
K50
    Ulcerative Colitis
556
K51
Other cancers
140-172, 174-184, 186-195, 
199-209
C00-C43, C45-C60, C62, C63, C67-C76, 
C80-C96, C7A, C7B
Abbreviations: HIV: human immunodeficiency virus; ICD-9-CM, International Classification of Diseases, 
Ninth Revision, Clinical Modification; ICD-10-CM, International Classification of Diseases, Tenth Revision, 
Clinical Modification
[1] Source: Quan, Hude, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 
administrative data. Medical care (2005): 1130-1139.
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