ARTICLE IN PRESS

TagedAPRFiur TagedAPRFiur

TagedAPREnUrologic Oncology: Seminars and Original Investigations 000 (2023) 1−9

Clinical-Prostate cancer
agedAPTRH1Attainment of early, deep prostate-specific antigen response in metastatic
castration-sensitive prostate cancer: A comparison of patients initiated on
apalutamide or enzalutamideTagedAPTREn
agedAPTRBenjamin Lowentritt, M.D.a, Dominic Pilon, MAb,*, Ibrahim Khilfeh, Pharm.D.c,
Carmine Rossi, Ph.D.b, Erik Muser, Pharm.D.c, Frederic Kinkead, MAb, Dexter Waters, MPHc,
Lorie Ellis, Ph.D.c, Patrick Lefebvre, MAb, Gordon Brown, D.O.dTagedAPREn
a
Chesapeake Urology, Towson, MD
b
Analysis Group, Inc., Montr eal, QC, Canada
c
Janssen Scientific Affairs, LLC, Horsham, PA
d
New Jersey Urology, Cherry Hill, NJ
Received 28 September 2022; received in revised form 13 February 2023; accepted 10 March 2023

TagedAPRAbstract
Background: Deep prostate-specific antigen (PSA) response, defined as a ≥90% decline in PSA (PSA90), is an important early response
indicator for achieving radiographic progression-free and overall survival in patients with metastatic castration-sensitive prostate cancer
(mCSPC) treated with a next-generation androgen signaling inhibitor (ASI), such as apalutamide or enzalutamide. The objective of this
study was to compare deep PSA response among patients with mCSPC newly initiated on apalutamide or enzalutamide.
Methods: Clinical data from 69 community urology practices in the United States were evaluated. Patients with mCSPC were classified
into cohorts based on their first dispensation (index date) for apalutamide or enzalutamide and were followed until the earliest of treatment
discontinuation, initiation of a new next-generation androgen receptor signaling inhibitor, end of clinical activity (including death), or end
of data availability (03/05/2021). Inverse probability of treatment weights (IPTW) were used to reduce baseline confounding. PSA90 was
defined as the earliest ≥90% PSA decline relative to baseline PSA. The proportion of patients achieving PSA90 and time to PSA90 were
reported using weighted Kaplan-Meier analysis and weighted Cox proportional hazards models, respectively.
Results: The apalutamide and enzalutamide cohorts comprised 186 and 165 patients, respectively. Patient characteristics were generally
well balanced after IPTW. By 6 months, patients initiated on apalutamide had a 56% greater likelihood of attaining PSA90 than those initi-
ated on enzalutamide (P = 0.014). This result remained significant through the end of the observation period. The median time to achieving
PSA90 was 3.1 months with apalutamide and 5.2 months with enzalutamide.
Conclusions: This real-world study demonstrated that apalutamide initiation is associated with a significantly higher likelihood of
achieving ≥90% reduction in PSA as compared to initiation of enzalutamide. Moreover, this deep PSA response was observed to occur ear-
lier with apalutamide treatment than with enzalutamide. Ó 2023 The Author(s). Published by Elsevier Inc. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

TagedAPREnTagedAPRKeywords: Androgen receptor inhibitor; Hormone sensitive; Kaplan-Meier; Real-world evidence; Treatment effectivenessTagedAPTREn

TagedAPRH11. IntroductionTagedAPTREn combination with first generation androgen deprivation

TagedAPRCurrent guidelines support the use of next-generation therapy (ADT) for the care of early advanced prostate can-
androgen receptor signaling inhibitors (ARSIs) in cer (PC), that is non-metastatic castration resistant prostate

TagedAPREnFinancial support for this research was provided by Janssen Scientific Affairs, LLC.
TagedAPREn*Corresponding author. Tel.: +514-394-4450; fax: +514-394-4461.
E-mail address: dominic.pilon@analysisgroup.com (D. Pilon).

https://doi.org/10.1016/j.urolonc.2023.03.003
1078-1439/Ó 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
 ARTICLE IN PRESS
2 B. Lowentritt et al. / Urologic Oncology: Seminars and Original Investigations 00 (2023) 1−9
cancer (nmCRPC) and metastatic castration sensitive pros-
tate cancer (mCSPC) [1−3]. These recommendations are
based on clinical trial evidence demonstrating superiority in
delaying progression and prolonging survival of patients
with advanced PC when treated with one of these agents
+ADT compared to ADT alone [4−9]. In mCSPC, apaluta-
mide+ADT produced significant improvements in radio-
graphic progression-free survival (rPFS) and overall
survival (OS) vs. placebo+ADT in the TITAN trial [6,7].
Similarly, enzalutamide+ADT has been associated with sig-
nificant rPFS and OS improvement vs. placebo+ADT in the
ARCHES trial [4,5].TagedAPTREn
TagedAPRAdditionally, post-hoc analyses from the Phase 3 trials
of ARSIs + ADT have demonstrated that deep prostate-spe-
cific antigen (PSA) reduction (i.e., decline ≥90%) is an
important early prognostic indicator of successful longer-
term outcomes, such as rFPS, metastasis-free survival
(mFS), or OS. Specifically, that deeper reductions in PSA
after initiating an ARSI + ADT were associated with a
greater probability of delayed disease progression and
improved survival compared with those without a deep
response or with no response [10−14].TagedAPTREn
TagedAPREarly response indicators of therapeutic success can be
an important consideration for patients, physicians, and
decision makers as they consider the merits of various ther-
apeutics, particularly when the goal of therapy is to mean-
ingfully delay progression or extend life. Currently, no
studies have directly compared attainment of PSA
responses in men treated with various ARSIs in the real-
world setting. This study used data from community-based
urology practices in the United States (US) to compare
deep PSA reduction among patients with mCSPC who initi-
ated apalutamide or enzalutamide.TagedAPTREn
TagedAPRH12. MethodsTagedAPTREn
TagedAPRH22.1. Data sourceTagedAPTREn
TagedAPRClinical data from an integrated electronic medical
record (EMR) database were obtained from Precision Point
Specialty (PPS) Analytics (1 February 2017 to 5 March
2021). The clinical data was collected during routine care
from 69 community-based urology practices providing in-
office dispensation information located throughout the US.
The data included information on patient demographics and
clinical variables, including dates of metastasis and castra-
tion resistance assessment, ARSI dispensations, ADT use,
and laboratory assessments (e.g., PSA testing, testosterone
measurements). All data are de-identified and comply with
the requirements of the Health Insurance Portability and
Accountability Act of 1996. Approval from an institutional
review board was not required to conduct this study.TagedAPTREn
TagedAPRH22.2. Study designTagedAPTREn
TagedAPRA retrospective longitudinal design was used
(Supplementary Fig. 1). Patients were assigned to mutually
exclusive treatment cohorts based on their first observed
use of either apalutamide or enzalutamide. The index date
was defined as the date of initiation of either apalutamide or
enzalutamide occurring on or after the US Food and Drug
Administration (FDA) approval date for the most recently
approved mCSPC therapy (i.e., enzalutamide FDA approval
date 16 December 2019 [15]). The 12-month period preced-
ing the index date was defined as the baseline period. The
observation period spanned from the index date until the
earliest of i) index treatment discontinuation (i.e., ≥90-day
gap in treatment supply), ii) initiation of a new next-genera-
tion ARSI (i.e., apalutamide, enzalutamide, darolutamide,
or abiraterone acetate) or a radiopharmaceutical, iii) last
indicator of clinical activity (including death), or iv) end of
data availability (i.e., 5 March 2021).TagedAPTREn
TagedAPRH22.3. Patient selection criteriaTagedAPTREn
TagedAPRAdult patients (age ≥18 years) were required to have
evidence of metastatic disease prior to or on the index date
in the absence of castration resistance (see Supplementary
Appendix 1). Metastatic disease was identified using a PPS-
provided flag for the presence of bone, nodal, or visceral
metastasis based on secondary neoplasm diagnosis codes or
manual data entry by a clinical EMR user. Patients also had
≥1 in-office medication dispensation for apalutamide or
enzalutamide to be included in this analysis. Patients were
excluded if they initiated ≥2 next-generation ARSIs on the
index date, had been previously prescribed a next-genera-
tion ARSI other than the index medication prior to the index
date (i.e., using all available clinical data), initiated apaluta-
mide or enzalutamide prior to 16 December 2019, had <12
months since beginning clinical activity in the EMR prior
to the index date, had no PSA testing in the 13-week period
prior to (and including) the index date, and were previously
treated with radiopharmaceuticals during the baseline
period (Fig. 1). Concomitant ADT use was not required for
inclusion in the analysis. A sensitivity analysis restricting
to patients who had no prior ADT use or who initiated ADT
≤8 months prior to initiating apalutamide or enzalutamide
was also performed.TagedAPTREn
TagedAPRH22.4. Study measuresTagedAPTREn
TagedAPRThe following demographic and clinical characteristics
were described during the 12-month baseline period: age,
race, year of index treatment initiation, time between
metastasis and index treatment initiation, prior use of ADT,
prior use of first-generation androgen receptor inhibitor,
most recent PSA level, most recent testosterone level, and
most recent Gleason score. Post-index PSA measurement
patterns were also described in the observation period. For
the primary analysis, the time to which patients first
achieved ≥90% relative decline in PSA (i.e., PSA90) from
the most recent baseline value observed within 13 weeks of
the index date was assessed during the first 6 months of the
 ARTICLE IN PRESS
B. Lowentritt et al. / Urologic Oncology: Seminars and Original Investigations 00 (2023) 1−9
TagedAPRFiur 3

Fig. 1. Patient identification flowchart, ARSI= androgen receptor signaling inhibitor; mCSPC= metastatic castration-sensitive prostate cancer; PSA = pros-
tate-specific antigen.
Notes:
a. Agent identified at index date was based on medication dispensation only.
b. To confirm that patients were newly initiated on a next-generation ARSI as identified through dispensations, prescription information was examined to
exclude patients with prescriptions for next-generation ARSIs prior to the index date.
c. The Food and Drug Administration (FDA) approved enzalutamide as treatment for mCSPC on 16 December 2019.
d. Continuous clinical activity was defined as the period from the first to last record in the clinical database. Patients with no observation period after the
TagedAPREn index date were excluded.
 ARTICLE IN PRESS
TagedAPREn4 B. Lowentritt et al. / Urologic Oncology: Seminars and Original Investigations 00 (2023) 1−9
observation period. As an exploratory objective, PSA90
was also assessed during the entire observation period.TagedAPTREn
TagedAPRH22.5. Statistical analysisTagedAPTREn
TagedAPRBaseline characteristics and post-index PSA measure-
ment patterns were reported using means, standard devia-
tions (SDs), and medians for continuous variables, and
counts and proportions for categorical variables. To account
for potential differences in baseline characteristics between
patients in the apalutamide or enzalutamide cohorts,
patients in each treatment cohort were weighted based on
inverse probability of treatment weighting (IPTW; Supple-
mentary Appendix 2).TagedAPTREn
TagedAPRDifferences in baseline characteristics between the apa-
lutamide and enzalutamide cohorts were evaluated using
standardized differences, both prior to and after IPTW.
Characteristics with a standardized difference <10% were
considered well balanced [16]. Weighted Cox proportional
hazards models were used to generate hazard ratios (HRs)
and 95% confidence intervals (CIs) comparing index treat-
ments and the time to PSA90 by 6 months (primary objec-
tive) and over the entire observation period (exploratory
objective). The proportion of patients achieving PSA90
over the entire observation period was also compared
between the weighted apalutamide and enzalutamide
cohorts using Kaplan-Meier curves by 3-, 6-, 9-, and 12-
months post-index.TagedAPTREn
TagedAPRH13. ResultsTagedAPTREn
TagedAPRH23.1. Baseline characteristicsTagedAPTREn
TagedAPRBefore applying IPTW, 186 mCSPC patients initiating
apalutamide and 165 mCSPC patients initiating enzaluta-
mide were included in the analysis (Fig. 1). After applying
IPTW, the weighted sample sizes were 174 patients in the
apalutamide cohort and 177 patients in the enzalutamide
cohort (Table 1). Baseline patient characteristics were gen-
erally well-balanced between the weighted apalutamide
and enzalutamide cohorts, with standardized differences
<10%. The mean (median) age was 76.1 (76.0) years
(SD = 7.8) in the apalutamide cohort and 76.3 (75.0) years
(SD = 8.0) in the enzalutamide cohort. Black patients rep-
resented 17.6% of the apalutamide cohort and 18.0% of
enzalutamide cohort. The mean (median) most recent base-
line PSA level was 18.4 (3.3) ng/ml (SD = 45.2) for the
apalutamide cohort and 18.3 (2.6) ng/ml (SD = 42.1) for
the enzalutamide cohort. The mean (median) time between
diagnosis of metastasis and treatment initiation was 7.4
(1.6) months (SD = 14.0) for the apalutamide cohort and
7.6 (1.9) months (SD = 13.9) for the enzalutamide cohort
(Table 1). Concomitant ADT use was observed in 95.9%
of the apalutamide cohort and 95.8% of the enzalutamide
cohort.TagedAPTREn
TagedAPRH23.2. PSA testing in the observation periodTagedAPTREn
TagedAPRThe mean (median) observation period was 169 (120)
days (SD = 141) for the weighted apalutamide cohort and
141 (93) days (SD = 122) for the weighted enzalutamide
cohort. PSA testing frequency appeared similar between the
weighted apalutamide and enzalutamide cohorts. Overall,
73.6% of apalutamide patients and 70.5% of enzalutamide
patients had ≥1 PSA test during the observation period,
with nearly all these patients (apalutamide: 100%; enzaluta-
mide: 98.7%) having their first PSA test within 6 months
following treatment initiation (Table 2). The mean (median)
number of PSA tests observed per year was 4.4 (3.8;
SD = 4.4) for the apalutamide cohort and 4.5 (3.3; SD = 6.1)
for the enzalutamide cohort.TagedAPTREn
TagedAPRH23.3. PSA outcomesTagedAPTREn
TagedAPRPatients with mCSPC who initiated apalutamide had a
greater likelihood of attaining an early PSA90 response
compared to similar patients initiated on enzalutamide (HR
1.56, 95% CI: 1.09, 2.22; P = 0.014), with 69.3% of patients
in the apalutamide cohort and 55.6% of patients in the enza-
lutamide cohort achieving PSA90 by 6 months (Fig. 2).
Additionally, patients in the apalutamide cohort had a
greater likelihood of attaining PSA90 response by the end
of the entire observation period (HR 1.49, 95% CI: 1.05,
2.11; P = 0.024), with 70.4% of apalutamide and 62.5% of
enzalutamide patients achieving PSA90. The median time
to PSA90 response over the entire observation period (i.e.,
the time by which 50% of the population had the response)
was 3.1 months for the apalutamide cohort and 5.2 months
for the enzalutamide cohort.TagedAPTREn
TagedAPRH23.4. Sensitivity analysisTagedAPTREn
TagedAPRAfter applying IPTW to the 125 apalutamide patients
and 88 enzalutamide patients selected for the sensitivity
analysis of patients who had no prior ADT use or who initi-
ated ADT ≤8 months prior to initiating their index medica-
tion, patient characteristics remained generally well-
balanced (Supplementary Table 1). Further, a similar trend
of greater likelihood of PSA90 response was observed for
patients in the apalutamide cohort relative to the enzaluta-
mide cohort (Supplementary Fig. 2).TagedAPTREn
TagedAPRH14. DiscussionTagedAPTREn
TagedAPRTo the best of our knowledge, this study was the first to
compare PSA90 responses among patients with mCSPC
treated with apalutamide or enzalutamide in a real-world
setting. Using a large urology EMR database and applying
IPTW to generate well-balanced cohorts, patients with
mCSPC initiated on apalutamide were found to be 56%
more likely to attain an early PSA90 response by 6 months
post-treatment than those initiated on enzalutamide.
Table 1
TagedAPRCptionBaseline characteristics TagedAPREn

Non-weighted population IPTW population TagedAPREn a

ApalutamideTagedAPTREn EnzalutamideTagedAPTREn ApalutamideTagedAPTREn EnzalutamideTagedAPTREn TagedAPREn

Standardized Standardized
N = 186TagedAPTREn N = 165TagedAPTREn difference bTagedAPREn Weighted N = 174TagedAPTREn Weighted N = 177TagedAPTREn difference bTagedAPREnboy

Age, mean § SD [Q1, median, Q3]TagedAPTREn 76.2 § 8.0 [70.0, 76.0, 82.0]TagedAPTREn 76.1 § 7.7 [71.0, 75.0, 81.0]TagedAPTREn 1.4TagedAPTREn 76.1 § 7.8 [70.0, 76.0, 82.0]TagedAPTREn 76.3 § 8.0 [70.0, 75.0, 82.0]TagedAPTREn 2.5TagedAPTREn
Age group, n (%)TagedAPTREn TagedAPREn
≤60TagedAPTREn 3TagedAPTREn (1.6)TagedAPTREn 2TagedAPTREn (1.2)TagedAPTREn 3.4TagedAPTREn 3TagedAPTREn (1.5)TagedAPTREn 2TagedAPTREn (1.3)TagedAPTREn 1.3TagedAPTREn

TagedAPREnB. Lowentritt et al. / Urologic Oncology: Seminars and Original Investigations 00 (2023) 1−9
61−70TagedAPTREn 49TagedAPTREn (26.3)TagedAPTREn 38TagedAPTREn (23.0)TagedAPTREn 7.7TagedAPTREn 44TagedAPTREn (25.1)TagedAPTREn 43TagedAPTREn (24.2)TagedAPTREn 2.0TagedAPTREn
71−80TagedAPTREn 78TagedAPTREn (41.9)TagedAPTREn 83TagedAPTREn (50.3)TagedAPTREn 16.9TagedAPTREn 79TagedAPTREn (45.5)TagedAPTREn 82TagedAPTREn (46.4)TagedAPTREn 1.8TagedAPTREn
≥81TagedAPTREn 56TagedAPTREn (30.1)TagedAPTREn 42TagedAPTREn (25.5)TagedAPTREn 10.4TagedAPTREn 49TagedAPTREn (28.0)TagedAPTREn 50TagedAPTREn (28.1)TagedAPTREn 0.2TagedAPTREn
Race, n (%)TagedAPTREn TagedAPREn
WhiteTagedAPTREn 135TagedAPTREn (72.6)TagedAPTREn 106TagedAPTREn (64.2)TagedAPTREn 18.0TagedAPTREn 123TagedAPTREn (71.0)TagedAPTREn 125TagedAPTREn (70.5)TagedAPTREn 1.1TagedAPTREn
BlackTagedAPTREn 32TagedAPTREn (17.2)TagedAPTREn 35TagedAPTREn (21.2)TagedAPTREn 10.2TagedAPTREn 31TagedAPTREn (17.6)TagedAPTREn 32TagedAPTREn (18.0)TagedAPTREn 1.0TagedAPTREn
OtherTagedAPTREn 3TagedAPTREn (1.6)TagedAPTREn 1TagedAPTREn (0.6)TagedAPTREn 9.6TagedAPTREn 2TagedAPTREn (1.0)TagedAPTREn 1TagedAPTREn (0.5)TagedAPTREn 5.9TagedAPTREn
UnknownTagedAPTREn 16TagedAPTREn (8.6)TagedAPTREn 23TagedAPTREn (13.9)TagedAPTREn 16.9TagedAPTREn 18TagedAPTREn (10.3)TagedAPTREn 19TagedAPTREn (11.0)TagedAPTREn 2.1TagedAPTREn

ARTICLE IN PRESS
Year of treatment initiation (index date), n (%)TagedAPTREn TagedAPREn
2019−2020TagedAPTREn 140TagedAPTREn (75.3)TagedAPTREn 135TagedAPTREn (81.8)TagedAPTREn 16.0TagedAPTREn 134TagedAPTREn (77.2)TagedAPTREn 137TagedAPTREn (77.1)TagedAPTREn 0.1TagedAPTREn
2021TagedAPTREn 46TagedAPTREn (24.7)TagedAPTREn 30TagedAPTREn (18.2)TagedAPTREn 16.0TagedAPTREn 40TagedAPTREn (22.8)TagedAPTREn 41TagedAPTREn (22.9)TagedAPTREn 0.1TagedAPTREn
Time between metastasis and treatment initiation, 6.3 § 12.7 [0.5, 1.6, 5.8]TagedAPTREn 8.4 § 14.7 [0.6, 2.2, 9.7]TagedAPTREn 15.5TagedAPTREn 7.4 § 14.0 [0.6, 1.6, 7.6]TagedAPTREn 7.6 § 13.9 [0.6, 1.9, 8.6]TagedAPTREn 1.5TagedAPTREn
months, mean § SD [Q1, median, Q3]TagedAPTREn
<6 months, n (%)TagedAPTREn 141TagedAPTREn (75.8)TagedAPTREn 107TagedAPTREn (64.8)TagedAPTREn 24.2TagedAPTREn 125TagedAPTREn (71.6)TagedAPTREn 123TagedAPTREn (69.6)TagedAPTREn 4.4TagedAPTREn
Visceral metastasisc, n (%)TagedAPTREn 7TagedAPTREn (3.8)TagedAPTREn 5TagedAPTREn (3.0)TagedAPTREn 4.1TagedAPTREn 7TagedAPTREn (3.9)TagedAPTREn 5TagedAPTREn (2.8)TagedAPTREn 6.5TagedAPTREn
Bone metastasisc, n (%)TagedAPTREn 139TagedAPTREn (74.7)TagedAPTREn 118TagedAPTREn (71.5)TagedAPTREn 7.3TagedAPTREn 126TagedAPTREn (72.6)TagedAPTREn 123TagedAPTREn (69.4)TagedAPTREn 7.2TagedAPTREn
Nodal metastasisc, n (%)TagedAPTREn 81TagedAPTREn (43.5)TagedAPTREn 63TagedAPTREn (38.2)TagedAPTREn 10.9TagedAPTREn 80TagedAPTREn (46.1)TagedAPTREn 72TagedAPTREn (40.8)TagedAPTREn 10.7TagedAPTREn
Prior use of ADTd, n (%)TagedAPTREn 172TagedAPTREn (92.5)TagedAPTREn 147TagedAPTREn (89.1)TagedAPTREn 11.7TagedAPTREn 159TagedAPTREn (91.4)TagedAPTREn 162TagedAPTREn (91.2)TagedAPTREn 0.7TagedAPTREn
Time between ADT initiation and index date, 16.1 § 24.6 [1.1, 2.9, 21.6]TagedAPTREn 21.4 § 30.5 [1.6, 8.5, 29.2]TagedAPTREn 19.4TagedAPTREn 18.9 § 25.9 [1.4, 4.2 29.4]TagedAPTREn 19.3 § 30.4 [1.6, 5.1, 24.5]TagedAPTREn 1.4TagedAPTREn
months, mean § SD [Q1, median, Q3]TagedAPTREn
≥6 months, n (%)TagedAPTREn 66TagedAPTREn (38.4)TagedAPTREn 84TagedAPTREn (57.1)TagedAPTREn 38.3TagedAPTREn 73TagedAPTREn (45.9)TagedAPTREn 77TagedAPTREn (47.6)TagedAPTREn 3.6TagedAPTREn
Concomitant ADT usee, n (%)TagedAPTREn 179TagedAPTREn (96.2)TagedAPTREn 158TagedAPTREn (95.8)TagedAPTREn 2.4TagedAPTREn 167TagedAPTREn (95.9)TagedAPTREn 170TagedAPTREn (95.8)TagedAPTREn 0.7TagedAPTREn
Prior use of first-generation ARIf, n (%)TagedAPTREn 23TagedAPTREn (12.4)TagedAPTREn 26TagedAPTREn (15.8)TagedAPTREn 9.8TagedAPTREn 23TagedAPTREn (13.3)TagedAPTREn 25TagedAPTREn (14.2)TagedAPTREn 2.5TagedAPTREn
Baseline PSA levelg, ng/ml, mean § SD [Q1, median, Q3]TagedAPTREn 19.0 § 45.1 [0.4, 3.4, 13.1]TagedAPTREn 18.9 § 44.7 [0.3, 2.0, 13.4]TagedAPTREn 0.2TagedAPTREn 18.4 § 45.2 [0.3, 3.3, 11.5]TagedAPTREn 18.3 § 42.1 [0.3, 2.6, 16.2]TagedAPTREn 0.3TagedAPTREn
Reported baseline testosterone testsh, n (%)TagedAPTREn 120TagedAPTREn (64.5)TagedAPTREn 91TagedAPTREn (55.2)TagedAPTREn 19.2TagedAPTREn 107TagedAPTREn (61.3)TagedAPTREn 106TagedAPTREn (60.0)TagedAPTREn 2.7TagedAPTREn
Testosterone <50 ng/dlTagedAPTREn 86TagedAPTREn (71.7)TagedAPTREn 75TagedAPTREn (82.4)TagedAPTREn 25.8TagedAPTREn 81TagedAPTREn (75.9)TagedAPTREn 82TagedAPTREn (77.5)TagedAPTREn 3.7TagedAPTREn
Baseline Gleason scorei, n (%)TagedAPTREn TagedAPREn
≤6TagedAPTREn 19TagedAPTREn (10.2)TagedAPTREn 10TagedAPTREn (6.1)TagedAPTREn 15.2TagedAPTREn 14TagedAPTREn (8.0)TagedAPTREn 13TagedAPTREn (7.1)TagedAPTREn 3.5TagedAPTREn
7TagedAPTREn 49TagedAPTREn (26.3)TagedAPTREn 35TagedAPTREn (21.2)TagedAPTREn 12.1TagedAPTREn 44TagedAPTREn (25.3)TagedAPTREn 45TagedAPTREn (25.4)TagedAPTREn 0.1TagedAPTREn
8TagedAPTREn 18TagedAPTREn (9.7)TagedAPTREn 22TagedAPTREn (13.3)TagedAPTREn 11.5TagedAPTREn 20TagedAPTREn (11.7)TagedAPTREn 22TagedAPTREn (12.5)TagedAPTREn 2.4TagedAPTREn
9TagedAPTREn 47TagedAPTREn (25.3)TagedAPTREn 32TagedAPTREn (19.4)TagedAPTREn 14.1TagedAPTREn 40TagedAPTREn (22.7)TagedAPTREn 37TagedAPTREn (21.1)TagedAPTREn 3.9TagedAPTREn
10TagedAPTREn 4TagedAPTREn (2.2)TagedAPTREn 9TagedAPTREn (5.5)TagedAPTREn 17.3TagedAPTREn 6TagedAPTREn (3.3)TagedAPTREn 7TagedAPTREn (3.9)TagedAPTREn 3.2TagedAPTREn
Not availableTagedAPTREn 49TagedAPTREn (26.3)TagedAPTREn 57TagedAPTREn (34.5)TagedAPTREn 17.9TagedAPTREn 50TagedAPTREn (28.9)TagedAPTREn 53TagedAPTREn (30.1)TagedAPTREn 2.5TagedAPTREn

ADT = androgen deprivation therapy; ARI = androgen receptor inhibitor; IPTW = inverse probability of treatment weighting; PSA = prostate-specific antigen; Q1 = first quartile; Q3 = third quartile; SD = standard deviation.TagedAPTREn
Notes:TagedAPTREn
a
Propensity scores were generated using probability estimates from a logistic regression model using the following predictors: age group, race, index year, previous ADT use, baseline duration of ADT ≥6 months, baseline first-generation ARI, baseline PSA level (continuous),
baseline testosterone level (categorized as <50 ng/dl, ≥50 ng/dl and missing), categorized Gleason score, and time between metastasis and the index date. Each patient was attributed an inverse probability of treatment weight that was defined as follows: 1/(propensity score)
for the apalutamide cohort and 1/(1-propensity score) for the enzalutamide cohort.
b
Standardized differences <10% indicate that the variable was balanced between the apalutamide and enzalutamide cohorts.
c
Visceral, bone, and nodal metastasis was assessed any time prior to and including the index date.
d
Prior use of ADT medication was defined as any ADT at any time prior to (and excluding) the index date.
e
Concomitant use of ADT medication was defined as any ADT administration observed 180 days prior to or 180 days following the index date.
f
Prior use of first-generation ARI was defined at any time prior to (and excluding) the index date.
g
Baseline PSA was evaluated as the most recent value from 13 weeks preindex up to, and including, the index date.
h

5
Testosterone testing was evaluated during the 12-month baseline period and included the index date.
i
Gleason score was evaluated at any time prior to and including the index date.

TagedAPREn6 B. Lowentritt et al. / Urologic Oncology: Seminars and Original Investigations 00 (2023) 1−9
Table 2
TagedAPRCptionPSA testing during the observation period
IPTW PopulationaTagedAPREn
ApalutamideTagedAPTREn
Weighted N = 174TagedAPTREn
Patients with ≥1 PSA test, 128 (73.6)TagedAPTREn
n (%)TagedAPTREn
Within 3 months of 120 (93.6)TagedAPTREn
observationTagedAPTREn
Within 6 months of 128 (100.0)TagedAPTREn
observationTagedAPTREn
Number of PSA tests per 4.4 § 4.4 [0.0, 3.8,
year, mean § SD [Q1, 6.1]TagedAPTREn
median, Q3]TagedAPTREn
Patients with PSA test 81 (46.6)TagedAPTREn
on average every 3
months, n (%)TagedAPTREn
Patients with PSA test 124 (71.2)TagedAPTREn
on average every 6
months, n (%)TagedAPTREn
IPTW = inverse probability of treatment weighting; PSA = prostate-
specific antigen; Q1 = first quartile; Q3 = third quartile; SD = standard
deviation.TagedAPTREn
Note:TagedAPTREn
a
Propensity scores were generated using probability estimates from a
logistic regression model using the following predictors: age group,
race, index year, baseline ADT use, baseline duration of ADT ≥6
months, baseline first-generation antiandrogen use, baseline PSA level
(continuous), baseline testosterone level (categorized as <50 ng/dl,
≥50 ng/dl and missing), categorized Gleason score, and time between
metastasis and the index date. Each patient was attributed an inverse
probability of treatment weight that was defined as follows: 1/(propen-
sity score) for the apalutamide cohort and 1/(1-propensity score) for
the enzalutamide cohort.
Additionally, the median time to PSA90 was numerically
shorter with apalutamide (3.1 months) than with enzaluta-
mide (5.2 months). In the absence of head-to-head trials
comparing the efficacy of apalutamide and enzalutamide in
patients with mCSPC, real-world evidence on the effective-
ness of the two medications, such as those regarding PSA90
responses observed in this study, may provide useful
insights to inform initial treatment decisions for mCSPC.TagedAPTREn
TagedAPRThese findings complement PSA kinetics results
reported from the post-hoc analysis of the TITAN trial
among 525 patients with mCSPC treated with apaluta-
mide + ADT [5,17]. The TITAN post-hoc analysis found
that PSA90 response was evident as early as 3 months post-
treatment, and the proportion of patients with a confirmed
PSA90 response continued to increase over time (6 months:
67%; 12 months: 71%; any time after apalutamide treat-
ment: 72%).[5,17] These results are consistent with the
PSA90 responses observed in the current real-world apalu-
tamide cohort (69.3% by 6 months and 70.4% by 12
months). In the TITAN post-hoc analysis, the median time
to PSA90 response was 1.9 months (range: 0.3−20.3
months) [5], which was slightly shorter than the 3.1 months
observed in the current study. However, PSA screening
ARTICLE IN PRESS
TagedAPREn
EnzalutamideTagedAPTREn
Weighted N = 177TagedAPTREnboy
125 (70.5)TagedAPTREn
103 (82.8)TagedAPTREn
123 (98.7)TagedAPTREn
4.5 § 6.1 [0.0, 3.3,
5.7]TagedAPTREn
74 (41.5)TagedAPTREn
120 (67.8)TagedAPTREn
occurred more frequently in TITAN (once per 28-day treat-
ment cycle [18]) than in real-world practice (4.4 tests per
year as suggested in this study), which may account for this
difference. Nonetheless, it is recognized that clinical trials,
as gold standards for evaluating treatment efficacy for
advanced PC, impose strict eligibility criteria, are strin-
gently monitored, and included strict timing of PSA meas-
urements; therefore, outcomes from trials may not always
reflect those observed in clinical practice [19]. As such, the
highly consistent results in PSA90 responses and relatively
fast time to response among patients with mCSPC who
received apalutamide in TITAN and this real-world study
demonstrate the promising effectiveness of apalutamide
in inducing a rapid, deep PSA response. Though PSA kinet-
ics were not reported for the ARCHES trial on enzaluta-
mide, an understanding of how they compare with the
current real-world findings is warranted as data become
available.TagedAPTREn
TagedAPRA rapid, deep PSA response in patients with mCSPC
may serve as an early indicator of treatment effectiveness;
furthermore, the depth and velocity of PSA response may
also have prognostic value [13,17,20−22]. To date, at least
five ARSI trials have reported a beneficial association
between attainment of a rapid, deep PSA response and lon-
ger-term outcomes relating to disease progression and sur-
vival in advanced PC [5,11−14]. In the TITAN post-hoc
analysis, apalutamide-treated patients who attained a PSA
response (including PSA50, PSA90, and undetectable PSA
[≤0.2 ng/ml]) had prolonged rPFS and OS compared with
those who did not achieve these PSA responses [5]. Addi-
tionally, when comparing patients with PSA50, PSA90, and
undetectable PSA vs. no response, a deeper PSA response
was associated with significantly better long-term progres-
sion-free and survival outcomes [17]. Similar associations
of PSA responses with improved metastasis-free survival
(MFS) and OS have also been demonstrated in the post-hoc
analyses of the abiraterone acetate trial LATITUDE in
mCSPC, as well as in the apalutamide trial SPARTAN
[14], the enzalutamide trial PROSPER [12], and the darolu-
tamide trial ARAMIS [11,23] among patients with
nmCRPC.TagedAPTREn
TagedAPRThe prognostic impact of PSA response in mCSPC has
also been reported in real-world studies, although studies
that specifically evaluated patients treated with ARSIs or
measured PSA90 are scarce [20−22,24]. Among studies in
patients with mCSPC treated with ADT, a faster time to
attaining PSA50 has been associated with significantly pro-
longed OS and PFS [20] and reduced risk of overall mortal-
ity [22]. It is worth noting that a PSA90 response
encompasses PSA50, suggesting that a PSA90 response
could be associated with even greater impact on halting dis-
ease progression and prolonging survival in mCSPC
[14,17]. Together with the ample evidence on the prognos-
tic impact of a rapid, deep PSA from clinical trials men-
tioned above, these studies highlight the potential
prognostic implications of the current findings on the
 ARTICLE IN PRESS
TagedAPREnB. Lowentritt et al. / Urologic Oncology: Seminars and Original Investigations 00 (2023) 1−9
TagedAPRFiur 7

Fig. 2. Comparison of time to PSA90 response among patients with mCSPCa.

CI = confidence interval; HR = hazard ratio; mCSPC = metastatic castration-sensitive prostate cancer; PSA = prostate-specific antigen.
* Significant at the 5% level.
Notes:
a. PSA response was defined as the first decline for a follow-up PSA value of 90% or more from the most recent PSA value within 13 weeks of the index
date.
b. Propensity scores were generated using probability estimates from a logistic regression model using the following predictors: age group, race, index
year, baseline ADT use, baseline duration of ADT ≥6 months, baseline first-generation antiandrogen use, baseline PSA level (continuous), baseline tes-
tosterone level (categorized as <50 ng/dl, ≥50 ng/dl and missing), categorized Gleason score, and time between metastasis and the index date. Each
patient was attributed an inverse probability of treatment weight that was defined as follows: 1/(propensity score) for the apalutamide cohort and 1/(1-
propensity score) for the enzalutamide cohort.
TagedAPREn c. A hazard ratio >1 indicates that the apalutamide cohort had a higher rate of PSA response ≥90% compared to the enzalutamide cohort.

differential PSA90 responses among patients receiving apa-
lutamide and enzalutamide in the real-world.TagedAPTREn
TagedAPRH24.1. LimitationsTagedAPTREn
TagedAPRFindings of this study should be considered with certain
limitations. The EMR database represents community urol-
ogy practices, a setting which may not be representative of
all patients with mCSPC in the US or other regions. Any
diagnoses, medical services, or prescription fills obtained
outside of the urology practices were not captured. Conse-
quently, patients whose follow-up on-treatment PSA testing
was performed outside the network may not have been
accurately identified in the study. All patients were included
in the study under the assumption that if no follow-up test-
ing was performed, the patient did not have a PSA response,
which may have underestimated the PSA response. As with
other EMR-based studies, analyses may be subject to data-
base limitations such as coding inaccuracies or omissions
(e.g., diagnosis dates, treatment start dates), which may
result in a misidentification of patients with mCSPC or PSA
response. More specifically, despite best efforts to exclude
castration resistant patients, some patients with castration
resistance may have been included by lack of information
to be able to classify them as such. However, results from a
sensitivity analysis excluding patients with longer ADT
exposure prior to initiating apalutamide or enzalutamide
demonstrated consistent findings, further reassuring that the
observed results from this study were not driven by such
potential misidentification. While this database allowed us
to confirm patients received PC medication including apalu-
tamide or enzalutamide in the clinic, it was not possible to
confirm if patients were taking their filled prescriptions as
prescribed. Heterogeneity may also exist in the timing of
PSA response due to variations in measurement as well as
when measurements were recorded. Moreover, this study is
subject to potential surveillance bias if more frequent PSA
testing is performed for one medication relative to the other.
Selection bias is also possible if new treatment is being pre-
scribed to patients with a more severe disease profile or
those who do not respond to existing treatments. In such
case, the next-generation ARSI cohorts may suffer from
confounding by indication by disease severity, although
this potential bias should similarly apply to both apaluta-
mide and enzalutamide cohorts due to the proximity of both
mCSPC approvals. Nevertheless, the use of IPTW helps
mitigate the underlying differences in baseline characteris-
tics and prognostic factors [25]. However, information on
some clinically relevant factors, such as the CHAARTED/
LATITUDE trials risk criteria [26,27], American Joint
Committee on Cancer (AJCC) staging criteria [28], alkaline
phosphatase levels, de novo PC diagnoses, and pelvic vs.
distant nodal metastasis, was limited or not available in the
PPS database, and thus could not be considered in the
IPTW. Though robust, the methodology applied in this
study is not intended to evaluate whether the differences
 ARTICLE IN PRESS
TagedAPREn8 B. Lowentritt et al. / Urologic Oncology: Seminars and Original Investigations 00 (2023) 1−9
observed are clinically meaningful or ascertain their impact
on longer-term survival outcomes. Finally, the study results
may be subject to residual confounding because of unmea-
sured factors (i.e., information not available in the clinical
data) and informative censoring due to treatment discontin-
uation/switches, which may potentially bias effect esti-
mates.TagedAPTREn
TagedAPRH15. ConclusionsTagedAPTREn
agedAPTRThis study demonstrated that patients initiated on apalu-
tamide had a significantly greater likelihood of attaining a
PSA90 response than those initiated on enzalutamide and
the median time to a PSA90 response was also shorter with
apalutamide. The clinical implications of these observations
warrant further consideration given the ample evidence on
the association between attainment of a rapid, deep, and
durable PSA response with survival-related endpoints in
patients with mCSPC treated with these therapies.TagedAPTREn
TagedAPRH1Authors’ ContributionsTagedAPTREn
TagedAPRD. Pilon, C. Rossi, F. Kinkead, and P. Lefebvre contrib-
uted to study conception and design, data analysis and inter-
pretation of the study results. B. Lowentritt, I. Khilfeh, E.
Muser, D. Waters, and L. Ellis contributed to study concep-
tion and design, and interpretation of the study results. G.
Brown contributed to the interpretation of the study results.
All authors reviewed and approved the final content of this
manuscript.TagedAPTREn
TagedAPRH1Previous presentationsTagedAPTREn
TagedAPRPart of the material in this manuscript was presented at
the ASCO 2022 Genitourinary Cancers Symposium from
February 17 to 19, 2022 as a poster presentation, the 32nd
Annual International Prostate Cancer Update (IPCU) from
March 6 to 9, 2022 as an encore poster podium presenta-
tion, and Academy of Managed Care Pharmacy (AMCP)
2022 Annual Meeting from March 29 to April 1, 2022, as
an encore poster presentation.TagedAPTREn
TagedAPRH1Declaration of Competing InterestTagedAPTREn
TagedAPRB. Lowentritt is an employee of Chesapeake Urology
Associates and has received consulting fees from Janssen
Scientific Affairs, LLC. D. Pilon, C. Rossi, F. Kinkead, and
P. Lefebvre are employees of Analysis Group, Inc., a con-
sulting company that has provided paid consulting services
to Janssen Scientific Affairs, LLC. I. Khilfeh, E. Muser, D.
Waters, and L. Ellis are employees of Janssen Scientific
Affairs, LLC. G. Brown is an employee of New Jersey
Urology and has received consulting fees from Janssen Sci-
entific Affairs, LLC.TagedAPTREn
TagedAPRH1AcknowledgmentsTagedAPTREn
TagedAPRMedical writing assistance was provided by Flora Chik,
PhD, and Loraine Georgy, PhD, employees of Analysis
Group, Inc., a consulting company that has provided paid
consulting services to Janssen Scientific Affairs, LLC,
which funded the development and conduct of this study
and manuscript.TagedAPTREn
TagedAPRH1Supplementary materialsTagedAPTREn
TagedAPRSupplementary material associated with this article can
be found in the online version at https://doi.org/10.1016/j.
urolonc.2023.03.003.TagedAPTREn
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