Fichier PDF

Partagez, hébergez et archivez facilement vos documents au format PDF

Partager un fichier Mes fichiers Boite à outils PDF Recherche Aide Contact



pros23141 .pdf



Nom original: pros23141.pdf
Titre: Prognostic factors for clinical outcomes in patients with metastatic castration resistant prostate cancer treated with sequential novel androgen receptor-directed therapies

Ce document au format PDF 1.4 a été généré par Arbortext Advanced Print Publisher 11.0.2924/W Unicode / Acrobat Distiller 9.0.0 (Windows); modified using iTextSharp 5.2.1 (c) 1T3XT BVBA, et a été envoyé sur fichier-pdf.fr le 05/12/2016 à 16:57, depuis l'adresse IP 160.176.x.x. La présente page de téléchargement du fichier a été vue 2506 fois.
Taille du document: 237 Ko (9 pages).
Confidentialité: fichier public




Télécharger le fichier (PDF)









Aperçu du document


The Prostate 76:512–520 (2016)

Prognostic Factors for Clinical Outcomes in Patients
With Metastatic Castration Resistant Prostate
Cancer Treated With Sequential Novel Androgen
Receptor-Directed Therapies
Rosa Nadal, Hua-Ling Tsai, Victoria J. Sinibaldi, Channing J. Paller,
Emmanuel S. Antonarakis, Sammuel R. Denmeade, Michael A. Carducci,
and Mario A. Eisenberger*
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland

BACKGROUND. Prognostic factors associated with clinical outcomes in patients with
metastatic castration-resistant prostate cancer (mCRPC) treated with a novel androgen
receptor-directed therapies (ARDT) in the second line setting has not been formally
evaluated.
PATIENTS AND METHODS. We retrospectively reviewed and analyzed medical records of
all patients with mCRPC who received sequential treatment with ARDT. We analyzed
potential clinical factors associated with post treatment endpoints including 50% decline in
prostatic-specific antigen (PSA), PSA-progression-free survival (PFS), clinical or radiographic
PFS and overall survival (OS). Prognostic univariate and multivariate Cox proportional
hazard models were developed and assessed.
RESULTS. One hundred twenty-six patients with mCRPC treated with a second-line novel
ARDT were included. Overall, 50% decline in PSA was observed in 22% of patients and a
median PSA-PFS of 2.9 months and a PFS of 3.6 months. After adjusting for potential
confounders including prior exposure to docetaxel and number of prior antiandrogen agents,
time to development of CRPC was an independent factor associated with PSA-PFS (hazard
ratio [HR]: 0.99; 95% confidence interval [CI]: 0.99–1; P ¼ 0.02) and PFS (HR: 0.99; CI: 0.98–1;
P¼ 0.01). PSA response (50% decline) to first-line novel ARDT correlated negatively with
PSA-PFS with second-line novel ARDT (HR: 1.7; 95% CI: 1.14–2.53; P ¼ 0.009) and lower pretreatment levels of albumin were associated with shorter PFS (HR: 0.56; 95% CI: 0.32-0.97;
P ¼ 0.03). Performance status, pre-treatment levels of albumin, extent of disease and time to
development CRPC were associated with OS.
CONCLUSIONS. Second-line ARDT is associated with modest outcomes in patients with
mCRPC. Time to development of CRPC is the strongest predictor of PSA response, PSA-PFS
and OS which suggest that intrinsic resistance to AR directed treatment is the major
treatment outcome factor in these patients. Future studies in patients receiving long term

Grant sponsor: Janssen, Johnson & Johnson, Sanofi, Dendreon, Exelixis, Genentech, Novartis, and Tokai; Grant sponsor: Lilly.
Conflict of Interest: Dr. Antonarakis has served as a paid consultant/advisor for Janssen, Astellas, Sanofi, Dendreon, Essa, and Medivation
and is a co-inventor of a technology that has been licensed to Tokai. Dr. Paller has served as a paid consultant for Dendreon. Other authors
have declared no conflicts of interest.


Correspondence to: Prof. Mario A. Eisenberger, MD, Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore,
MD. E-mail: eisenma@jhmi.edu
Received 8 November 2015; Accepted 3 December 2015
DOI 10.1002/pros.23141
Published online 22 December 2015 in Wiley Online Library
(wileyonlinelibrary.com).

ß 2015 Wiley Periodicals, Inc.

Prognostic Factors for Patients With mCRPC Treated With Sequential Novel ARDT

513

ARTD should include the identification of predictive biomarkers to facilitate treatment
selection. Prostate 76:512–520, 2016. # 2015 Wiley Periodicals, Inc.
KEY WORDS:
castration-resistant prostate cancer; androgen receptor; prognostic
factors; enzalutamide and abiraterone

INTRODUCTION
The androgen receptor (AR) remains a key driver
of tumor growth in castration-resistant prostate cancer. Based on this rationale, a new generation of ARdirected therapies has been successfully developed:
abiraterone acetate, a CYP17 inhibitor which prevents
testicular, adrenal and intratumoral androgen synthesis and enzalutamide, a second generation AR antagonist with a higher affinity for the AR compared with
first generation antiandrogens. Both agents have
yielded an improvement in OS when compared to
placebo in patients with mCRPC [1–4].
The four pivotal phase III studies with abiraterone
and enzalutamide were restricted to patients previously untreated with novel AR-targeted therapies.
Treatment with second-line novel ARDT has not been
prospectively evaluated to date. However, small
retrospective series have demonstrated that the effectiveness of second-line ARDT is low in patients pretreated with abiraterone/enzalutamide, docetaxel, or
both [5–8]. Collectively, these series have reported
PSA decline ( 50%) in 5–38% of patients and a
median PFS/time to PSA progression ranging from
2.5 to 4 months. Despite these modest results and the
lack of prospective evaluation of sequential ARtargeted therapies, second-line therapy with abiraterone and enzalutamide is commonly used in clinical
practice. Various mechanism of resistance to novel
second-line ARDT including AR splice variant AR-V7,
AR point mutations, AR phosphorylation or posttranslational modifications to the AR among others
have been to focus of major studies and are currently
being evaluated [9] as potential molecular biomarkers
in tumor cells of patients with mCRPC that may
facilitate treatment selection. In the meantime, the
identification of prognostic clinical factors and risk
groups to accurately assess the clinical benefit of
sequential AR targeted treatment and potentially
guide clinical management is of paramount importance.
We explored the effect of pre-treatment clinical
factors and their relationship with outcomes in
patients with metastatic CRPC treated with secondline ARDT. The ultimate aim of this analysis is to
define potential prognostic factors associated with
PSA-PFS, PFS and OS in patients with metastatic
CRPC using a novel ARDT in the second line setting.

This study specifically includes mCRPC patients
treated with sequential novel AR targeted treatments
(abiraterone and enzalutamide).
PATIENTS AND TREATMENTS
This was a retrospective, single-institution analysis
that included all consecutive patients with mCRPC
who were treated with sequential novel ARDT. The
population comprised patients with histologically
confirmed prostate adenocarcinoma, progressive disease despite “castration levels” of serum testosterone
(<50 ng per deciliter [dl]) with continuous LHRH
agonist/antagonist therapy, and documented metastatic lesions. For this study, baseline demographic
characteristics, as well as, clinical and analytic factors
prior to second-line ARDT irrespective of the agent
administered were recorded.
Abiraterone was administered orally at a starting
dose of 1,000 mg once a day with prednisone 5 mg
twice a day and enzalutamide was also administered
continuously at a starting dose of 160 mg daily.
Treatment continued until disease progression, lack of
clinical benefit or unacceptable toxicity.
While this is a retrospective analysis, all follow-up
assessments were prospectively defined as follows:
PSA measurements were obtained every 1–2 months,
and CT of the chest, abdomen, and pelvis and
technetium-99m bone scanning were performed every
2–4 months. Therapy with enzalutamide or abiraterone was continued until disease progression, lack of
clinical benefit, or the occurrence of drug-related
unacceptable toxicity. Institutional review board approval was obtained prior to data collection.

DATA COLLECTED
Electronic medical records were reviewed to record
patient age, race, Gleason score, extent of disease,
details of the prior treatments including initial treatment, number of prior first-generation androgenreceptor antagonist (bicalutamide, flutamide, and/or
nilutamide), ketoconazole and docetaxel regimens
administered. Disease status at androgen deprivation
therapy (ADT)-initiation, absolute PSA value at the
end of a 7-month ADT period, time to development of
castration-resistant disease, disease status at time of
The Prostate

514

Nadal et al.

development of CRPC and sites of metastasis at time
to ADT progression was collected. Castrationresistant disease was defined as two increases in the
PSA level at least 1 month apart or evidence of new
clinical disease while the patient was receiving ADT
and the testosterone was at castrate levels.
Eastern Cooperative Oncology Group performance
status (ECOG-PS), baseline hemoglobin (g/dl), alkaline phosphate (UI/l), albumin (g/dl), PSA (ng/ml)
levels, presence of pain-related symptoms ( 3 on the
visual analogue pain scale) and the extent of the
disease (minimal disease vs. extensive disease) as
previously defined in the CHAARTED study [10].
ENDPOINTS
Clinical outcomes of interest included PSA response rates, PSA-PFS, clinical/radiographic PFS
and OS. PSA response was defined as a reduction
in the PSA level from baseline by 50%. PSA-PFS
was defined as a rising PSA level while on
abiraterone or enzalutamide that was 25%, with
the last value being 2.0 ng per milliliter or higher
(Prostate Cancer Working Group 2 [PCWG2] definition) [11]. Those that remained alive without PSA
progression were censored at the time of last PSA
assessment. For PSA-related outcomes, PSA level
was confirmed at a subsequent date in most
instances; however, confirmation was not consistently performed on all patients. PFS was defined
as the time interval from second-line ARDT initiation until radiographic or clinical progression or
death, whichever came first [11]. Soft tissue progression was evaluated per Response Evaluation Criteria in Solid Tumors criteria (RECIST, version 1.1)
and bone scan progression was assessed per
PCWG2 criteria. Confirmatory scans were not generally performed since patients were treated per
regular clinical practice [11,12]. PSA elevations
alone were not considered in the definition of PFS.
Subjects were censored upon initiating a new
therapy subsequent to second-line novel ARDT if
they did not display evidence of clinical/radiographic progression by that time. Patients with
insufficient imaging data available for evaluation of
PFS were still evaluated for PSA response. OS with
second-line novel ARDT was also measured, and
was defined as the interval from the initiation of
second-line novel ARDT to death from any cause.
For outcomes with first-line novel ARDT treatment
period, PSA response, PSA-PFS and PFS were also
assessed and were defined from the initial date of
first-line novel ARDT to the corresponding event
occurrence, or censored on the initial date of next
therapy.
The Prostate

STATISTICAL ANALYSIS
Patient’s demographics are summarized descriptively. Median PSA-PFS, PFS, and OS with secondline novel ARDT were reported for each category and
probabilities of PSA-PFS, PFS, and OS were estimated
based on Kaplan–Meier method. An analysis was
performed investigating the impact of a pre-specified
set of clinical and analytic factors on PSA-response,
PSA-PFS, and PFS. Univariate and multivariate Cox
proportional hazard models were accessed for evaluating the risks of interested outcomes. Multivariate
models for the interested outcomes were performed
including variables with P-value 0.15 in univariate
analysis, then backward procedures selected based on
AIC. The threshold of significant level was set up as
0.05 without considering multiplicity.
Age at diagnosis, PSA level at diagnostic, time to
development of CRPC, PSA, hemoglobin, alkaline
phosphatase, and albumin levels prior to second-line
novel ARDT, were considered continuous variables.
Time to first-line novel ARDT PSA-progressed and
PFS were also included in the list of risk factors to
assess the effect on PSA-PFS and PFS with second-line
novel ARDT. Continuous factors were investigated
assuming a linear effect and investigating for a
potential nonlinear effect.
Race (Caucasian vs. non-Caucasian), disease status
at diagnosis (M0 vs. M1), Gleason sum (<8 vs. 8),
initial treatment (radical prostatectomy vs. radiation
therapy vs. initial ADT), neoadjuvant/adjuvant ADT
(yes vs. no), disease status at ADT initiation (M0 vs.
M1), PSA-response to ADT ( 4 vs. >4 ng/ml), disease
status at the time of CRPC development (M0 vs. M1),
sites of metastasis at time to ADT progression (bones
vs. lymph nodes vs. visceral involvement), # of prior
first-generation androgen-receptor antagonist (0, 1 vs.
2), prior ketoconazole (yes vs. no), prior docetaxel
(yes vs. no), ECOG-PS (0 vs. 1), presence of bone
pain (yes vs. no), extension of disease (minimal vs.
extensive) and PSA response to first-line novel ARDT
(yes vs. no) were considered categorical variables.
Comparisons between patient subgroup and PSAresponse were performed using x2 test for categorical
data, Wilcoxon rank test for continuous data, or logic
regression models in the multivariable analysis.
RESULTS
Patient’s Characteristics
We identified 126 patients with mCRPC who
received a second-line novel ARDT, either abiraterone
(13%) or enzalutamide (87%), between March 13, 2012
and March 13, 2015. At the data cutoff for this
analysis, the median duration of follow-up after

Prognostic Factors for Patients With mCRPC Treated With Sequential Novel ARDT
initiation of second-line novel ARDT was 1.6 years
(range 0.08–2.9 years). Patient’s baseline demographic
and pretreatment clinical and laboratory characteristics are summarized in Table I. One third of the
patients were newly-diagnosed metastatic prostate
cancer patients. Sites of metastasis at time to ADT
progression included bone in 96 patients (76.2%),
lymph nodes in 27 patients (21.4%), and lung
(visceral) in three patients (2.4%).
Abiraterone was the most common choice for first
ARDT (n ¼ 109; 87%) and only 13% (n ¼ 17) had initial
enzalutamide. Clinical outcomes according to the
type of novel ARDT are summarized in Table II. This
difference likely reflects historical trends, as the
majority of patients receiving abiraterone as their first
AR-targeted therapy started therapy after the Food
and Drug Administration (FDA) approval and became available in 2011. Fifty-three percent of patients
also had prior docetaxel. Other prior regimens included first-generation androgen-receptor antagonists
in about 90% and ketoconazole in 34% of the patients.
The median PSA level at the time of second-line
ARDT initiation was 50.6 ng/ml (range 1–3204 ng/ml).
The majority of these patients had extensive disease
(84%) at the time of Second-AR initiation.

Efficacy of Second-Line Novel AR-Targeted
Therapy
PSA-related outcomes. A total of 126 patients were
evaluable for PSA-response. PSA-response with second-line novel ARDT was observed in 28 of 126
(22.4%) patients. Waterfall plots depicting maximum
PSA changes with second-line novel ARDT are presented in Figure 1. PSA-response to second-line novel
ARDT was more likely observed in patients with
ECOG-PS of 0 or absence of bone pain (P ¼ 0.08 and
P ¼ 0.03, respectively). Patients who achieve PSAresponse had also higher baseline hemoglobin and
albumin levels (P ¼ 0.03 and P ¼ 0.05, respectively).
There was no significant association noted between
PSA-response and extent of the disease, PSA level
prior to second-line novel ARDT or the type of
second-line novel ARDT administered (abiraterone vs.
enzalutamide). PSA-response with first-line novel
ARDT was not significantly associated with PSA
response to second-line novel ARDT. Only, 20%
percent (n ¼ 12/61) of patient who responded by PSA
to first-line novel ARDT were also PSA responders to
second-line novel ARDT, whereas 25% (n ¼ 16/64) of
non-PSA responders to first-line novel ARDT
achieved a PSA response with second-line novel
ARDT. In the multivariate analysis, hemoglobin levels
(OR 0.89; 95%CI: 0.78-0.99; P ¼ 0.04) and PSA-PFS to

515

first-line ARDT (OR 0.89; 95%CI: 0.78-0.99; P ¼ 0.04)
were weakly associated to PSA response to secondline ARDT.
The median PSA-PFS for second-line novel ARDT
was 2.9 months (95% CI, 2.3–3.3 months) (Fig. 2). A
multivariable proportional hazard Cox regression
model was constructed to control for potential confounding factors. In this analysis, longer time to
development of CRPC was associated with improved
PSA-PFS (HR 0.99; 95%CI: 0.99–1; P ¼ 0.02) and PSA
response to first-line novel ARDT was associated to
shorter PSA-PFS (HR 1.7; 95%CI: 1.14–2.53; P ¼ 0.009).
Detailed results and the hazard ratios of the multivariable analysis are listed in Table III.
Progression-Free Survival to Second-Line Novel
AR-Directed Therapy
Median PFS for second-line novel ARDT therapy
was 3.6 month (95%CI, 3.1–5.0 months) which was
shorter than the median PFS for first-line novel ARDT
therapy (8.5 months; 95%CI: 6.2–9.7 months) (Fig. 2).
Overall, the probability of PFS at 6 and 12 months
after initiation of second-line novel ARDT was 35%
(95% CI: 0.27–0.45) and 17% (95% CI: 0.11–0.28),
respectively. Longer time to CRPC development (HR
0.99; 95%CI 0.98–1; P ¼ 0.01) and higher levels of
albumin at the initiation of second-line novel ARDT
(HR ¼ 0.56; 95%CI 0.32–0.97; P ¼ 0.04) were correlated
with improved PFS to second-line novel ARDT. No
other clinical characteristics included in our multivariable model were found to be statistically associated
with differences in PFS. Detailed results and the
hazard ratios of the multivariable analysis are listed
in Table III.
Overall Survival to Second-Line Novel ARDirected Therapy
Median OS was 1 year (95% CI: 0.9–1.2 years) after
second-line novel ARDT. At 18 months after secondline therapy, the survival probability was 30% (95%
CI: 0.22–0.41). The significant prognostic factors in the
univariate analysis (defined as P < 0.15) were considered in the proportional hazards Cox regression
model. Number of prior first-generation androgenreceptor antagonist, Gleason sum score, ECOG-PS,
extent of disease, albumin levels prior to second-line
novel ARDT and time to development of CRPC were
included in the final model. After adjusting for
potential confounding factors, patients with longer
time to develop CRPC (HR ¼ 0.98; 95% CI: 0.97–0.99;
P ¼ 0.0028) and higher levels of albumin (HR 0.35;
95% CI 0.19–0.63; P ¼ 0.00054) had lower risk of death.
Those patients who had an ECOG-PS score greater or
The Prostate

516

Nadal et al.

TABLE I. Summary Table of Patient’s Characteristics: Overall Population and Stratified by PSA Response to SecondLine Novel ARDT
Overall population
(n ¼ 126)

<50% decline PSA
(n ¼ 98)

>50% decline PSA
(n ¼ 28)

Baseline characteristics
Age, years, mean (SD)
62.03 (8.4)
62.21 (8.3)
61.39 (8.7)
Race
No-Caucasian
20 (15.9)
17 (17.4)
3 (10.7)
Caucasian
106(84.1)
81 (82.6)
25 (89.3)
Gleason score
6, 7
45 (35.7)
37 (37.8)
8 (28.6)
8
76 (60.3)
59 (60.2)
17 (60.7)
Missing
5 (4)
2 (2.1)
3 (10.7)
PSA level at diagnostic, ng/ml, median (range)
11.4 (1.4–3514)
10.8 (1.4–3514)
14.85 (1.7–1874)
Disease status at diagnostic
M0
90 (71.4)
72 (73.5)
18 (64.3)
M1
36 (28.6)
26 (26.5)
10 (35.7)
Initial treatment
Radical prostatectomy
59 (46.8)
49(50)
10 (35.7)
Radiation therapy
31 (24.6)
22 (22.5)
9 (32.2)
Primary ADT
36 (28.6)
27 (27.5)
9 (32.1)
Neo-/Adjuvant therapy
No
87 (69)
68 (69.4)
19 (67.9)
Yes
39 (31)
30 (30.6)
9 (32.1)
Disease status at initiation of ADT
M0
56 (44.4)
42 (42.9)
14 (50)
M1
70 (55.6)
55 (57.1)
14 (50)
PSA response to initial ADT
4 ng/ml
102 (80.9)
79 (80.6)
23 (82.2)
>4 ng/ml
19 (15.1)
16 (16.3)
3 (10.7)
Missing
5 (4)
3 (3.1)
2 (7.1)
Disease status at time of development of CRPC
M0
29 (23)
20 (20.4)
9 (32.1)
M1
97 (77)
78 (79.6)
19 (67.9)
Disease sites at the time of progression to ADT
Bone metastasis þ bone and nodal metastasis
96 (76.2)
79 (80.6)
17 (60.7)
Nodal metastasis
27 (21.4)
18 (18.4)
9 (32.2)
Visceral metastasis (lung)
3 (2.4)
1 (1.0)
2 (7.1)
Number of prior first generation antiandrogen
therapy ; n (%)
0
11 (8.7)
8 (8.2)
3 (10.7)
1
84 (66.7)
68 (69.4)
16 (57.1)
2
31 (24.6)
22 (22.4)
9 (32.2)
Ketoconazole; n (%)
No
83 (65.87)
64 (65.31)
19 (67.86)
Yes
43 (34.13)
34 (34.69)
34 (34.69)
Prior docetaxel therapy; n (%)
No
56 (46.8)
45 (45.9)
14 (5)
Yes
67 (53.2)
53 (54.1)
14 (5)
Patient’s characteristics at the time of novel second AR-targeted therapy
Performance status; n (%)
0
67 (53.2)
48 (49)
19 (67.9)
1
59 (46.8)
50 (51)
9 (32.1)
Presence of bone pain; n (%)
No
75 (59.5)
54 (55.1)
21 (75)
Yes
51 (40.5)
44 (44.9)
7 (25)
Extent of disease; n (%)
Minimal
20 (15.9)
14(14.3)
6 (21.4)
Extensive
106 (83.1)
84 (85.7)
22 (78.6)
PSA level, ng/ml, mean (SD)
156.11 (373.01)
145.32 (279.24)
193.47 (599.88)
Alkaline phosphatase level, IU/l, mean (SD)
150.7 (145.51)
161.16 (152.95)
115.21 (111.98)

P-value
0.65
0.56

0.65

0.28
0.35

0.40

1

0.52

0.76

0.20

0.04

0.43

1

0.83

0.89

0.08

0.38
0.68
0.086

(Continued)
The Prostate

Prognostic Factors for Patients With mCRPC Treated With Sequential Novel ARDT

517

TABLE I. Continued.
Overall population
(n ¼ 126)

<50% decline PSA
(n ¼ 98)

Hemoglobin level, g/dl, mean (SD)
11.89 (1.63)
11.71 (1.58)
Albumin level, g/dl, mean (SD)
4.02 (0.38)
3.99 (0.38)
Type of novel second AR-targeted therapy; n (%)
Abiraterone
17 (13.49)
14 (14.29)
Enzalutamide
109 (86.51)
84 (85.71)
Time to development CRPC, mean (SD)
26.65 (29.34)
24.27 (21.99)
Correlation with outcomes with first novel AR-targeted therapy
PSA Response novel 1AR; n (%)
No
64 (50.79)
48 (48.98)
Yes
61 (48.41)
49 (50)
No evaluable
1 (0.79)
1 (1.02)
PSA-PFS, median (range)
5.61 (0.46, 23.61)
6.31 (0.82, 23.61)
Rx-PFS, median (range)
7.26 (0.82, 27.51)
7.79 (0.82, 27.51)

>50% decline PSA
(n ¼ 28)
12.5 (1.67)
4.14 (0.35)

0.031
4.14 (0.35)

3 (10.71)
25 (89.29)
35.19 (46.82)

16
12
0
3.72
5.2

P-value

0.76
0.24

(57.14)
(42.86)
(0)
(0.46, 13.87)
(1.25, 15.61)

0.52

0.10
0.15

ARDT, Androgen receptor-directed therapy; ADT, androgen deprivation therapy; CRPC, castration-resistant prostate cancer; AR,
androgen receptor; PSA, prostatic specific antigen; PFS, progression free survival; Rx, radiographic.

Bicalutamide, nilutamide, flutamide.

TABLE II. Clinical Outcomes by Type of Novel ARDT
Second-line ARDT
Abiraterone
Enzalutamide
Overall

50% PSA decline

Median PSA-PFS (months)

Median PFS (months)

17.6% (3/17)
22.9% (25/109)
22.5% (28/124)

2.6 (2.1–NA)
2.9 (2.3–3.4)
2.9 (2.3–3.3)

4.8 (3.1–NA)
3.4 (3.0–5.2)
3.6 (3.1–5.0)

ARDT, androgen receptor directed therapy; PSA, prostatic specific antigen; PFS, progression free survival.

equal to 1 (HR ¼ 1.67; 95% CI: 1.01–2.77; P ¼ 0.046)
and extensive disease (HR 3.23; 95% CI 1.16–9.04;
0.025) were associated with worse OS when compared
to patients with ECOG-PS of 0 and minimal disease at
the initiation of second-line novel ARDT, respectively.
Detailed results and the hazard ratios of the multivariable analysis are listed in Table IV.
DISCUSSION
Four pivotal trials have previously examined the
benefit of ARDT in the pre- and post-chemotherapy
setting. However, none of these trials allowed patients
previously treated with novel ADRTs and many
questions regarding the optimal sequencing of treatment remain unanswered. Recent small series suggest
poor anti-tumor activity with second-line ADRT in
unselected patients with mCRPC in the second-line
setting.
This analysis represents the largest evaluation in
patients treated with second-line ARDT in a standard prospective fashion in single institution with

Fig. 1. Waterfall plot of maximal PSA change (%) from baseline
of second-line novel androgen receptor therapies.
The Prostate

518

Nadal et al.

Fig. 2. Kaplan–Meier curves of overall survival, PFS, and
PSA-PFS with second-line androgen receptor-directed therapy
for the entire cohort.

data collected off study. Our study looked at all
consecutive patients who received prior ARDT or
chemotherapy with the focus defining potential
clinical parameters impacting on outcome. Results
either with second-line enzalutamide or abiraterone
were generally poor. It is important to note that the
22% PSA-response rate, a median PSA-PFS of 2.9
months and a PFS of 3.6 months found, is consistent with the published experience in other retrospective cohorts [5–8].
In our study, common prognostic factors such as
ECOG-PS, presence of bone pain, extent of disease or
alkaline phosphatase levels were not associated with
outcome endpoints such as PSA-PFS or PFS. However, time to development CRPC was associated both
with PSA-PFS and PFS. Recently, other investigators
reported that previous duration of response to ADT
was significantly associated with outcomes to a broad
spectrum of AR-axis targeted drugs, including antiandrogens, abiraterone, ketoconazole, oestrogens, and
enzalutamide [13]. We focused our study on only on

patients who received sequential abiraterone and
enzalutamide in view of the lack of prospective data
on sequencing these two agents. We also observed
significant improved PSA-PFS and PFS with secondline ARDT in those patients who benefited longer
from ADT. Our findings suggest that time to development CRPC may represent a surrogate of the degree
of AR-addicted biology of prostate cancer, even at a
later time of the disease when adaptive mechanisms
may have changed the sensitivity to AR manipulations.
Our group recently reported that AR-V7 detected in CTCs correlates with lack of response to
novel ARDTs [14] but not to chemotherapy [15].
Furthermore, “reversions” from AR-V7-positive to
AR-V7-negative status were only observed during
taxane therapies [16]. Extensive data with first-line
docetaxel in patients with mCRPC [17,18] indicate
a ( 50%) PSA response rate and a PFS significantly
longer than the same data with second-line ARDT
observed in this study and reported by others.
These data suggest that taxane-based chemotherapy
may be a better treatment option for patients with
mCRPC who failed first-line ARDT. Interestingly,
our data suggests that a PSA-response to first-line
novel ARDT correlated negatively with PSA-PFS
with second-line novel ARDT, suggesting that
contrary to what one would have intuitively predicted a response to first-line novel ARDT is not
necessarily associated with a benefit to subsequent
second-line novel ARDT.
Our study must be interpreted in the context of its
limitations, such as its retrospective design and its
single-institution patient cohort. The decision whether
to initiate second-line ADRT or chemotherapy and the
type of ARDT was made at the discretion of the
treating physician and not by randomization. Although adoption of these strategies was influenced by
emerging trends in patient care over the time period
of our review, individual patient characteristics may
have influenced the treatment decision and could

TABLE III. Multivariable Cox Proportional Hazard Model for PSA-PFS and PFS With Second-Line Novel ARDT
PSA-PFS
HR (95%CI)
Baseline albumin level prior Second-line novel ARDT
Prior docetaxel (yes vs. no)
Bone pain (yes vs. no)
Time to development CRPC (months)
Response to first-line novel ARDT (yes vs. no)

0.99 (0.99–1)
1.7 (1.14–2.53)

PFS
P-value

0.02
0.009

HR (95%CI)
0.56
1.47
1.53
0.99
1.37

(0.32–0.97)
(0.93–2.32)
(0.97–2.42)
(0.98–1)
(0.89–2.09)

P-value
0.03
0.1
0.06
0.01
0.14

PSA, prostatic-specific antigen; PFS, progression-free survival; ARDT, Androgen receptor directed therapies; HR, Hazard Ratio; CI,
Confidence Interval; CRPC, castration-resistant prostate cancer.
The Prostate

Prognostic Factors for Patients With mCRPC Treated With Sequential Novel ARDT

519

TABLE IV. Multivariable Cox Proportional Hazard Model for OS Mith Second-Mine Novel ARDT
OS
HR (95%CI)
Number of prior first generation antiandrogen therapy
Baseline alkaline phosphatase prior second-line novel ARDT
Performance status 0 versus 1
Baseline albumin level prior Second-line novel ARDT
Extent of disease (minimal vs. extensive)
Time to development CRPC (months)

0.65
1.00
1.91
0.37
2.53
0.99

(0.42–1.00)
(1.00–1.002)
(1.16–3.13)
(0.21–0.67)
(1.00–6.42)
(0.98–1.00)

P-value
0.049
0.08
0.01
0.0009
0.05
0.01

OS, Overall Survival; ARDT, Androgen receptor-directed therapies: HR, Hazard Ratio; CI, Confidence interval; CRPC, Castrationresistant prostate cancer.

have confounded the outcome. In order to evaluate
potential effects of prior treatment (prior to the second
line ARDT) we attempted to identify potential confounding effects of prior treatment with docetaxel and
use of enzalutamide versus abiraterone. We did not
observe significant associations between these parameters and the outcomes described herein.
The OS analysis has several limitations. First, half of
the patients had docetaxel-pre-treated; other patients
were unfit for chemotherapy and other preferred
another hormonal manipulation instead of chemotherapy. Second, the absence of adjustment for subsequent
life-prolonging treatments (cabazitaxel, radium-223 and
sipulleucel-T) may also have affected our OS analysis
although factors usually associated with outcomes in
(performance status, albumin, extent of disease and
prolonged response to ADT) in our current group were
comparable to those reported in the literature in
patients receiving docetaxel treatment [19].
CONCLUSION
In this report we describe the results of potential
associations of a variety of conventional prognostic
factors with PSA response, PSA-PFS, PFS, and OS.
Our data suggest that time to development CRPC is
associated with PSA-PFS and PFS, and OS. Prospective randomized trials should provide more definitive
data to assist in treatment selection for mCRPC
patients. Ongoing validation trials assessing the role
of molecular biomarkers in the selection of treatment
of patients with mCRPC is a critical step for further
therapeutic improvements in this disease.
REFERENCES
1. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de
Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J,
Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel
H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George
DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS,
Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE.

COU-AA-302 Investigators Abiraterone in metastatic prostate
cancer without previous chemotherapy. N Engl J Med 2013;368:
138–148.
2. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN,
Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S,
Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS,
Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB,
Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM,
Tombal B; PREVAIL Investigators. Enzalutamide in metastatic
prostate cancer before chemotherapy. N Engl J Med 2014;371(5):424–433.
3. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L,
Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN,
Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T,
Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL,
Fl echon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini
D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995–2005.
4. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K,
de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig
TW, Fl echon A, Mainwaring P, Fleming M, Hainsworth JD,
Hirmand M, Selby B, Seely L, de Bono JS; AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer
after chemotherapy. N Engl J Med 2012;367:1187–1197.
5. Cheng HH, Gulati R, Azad A, Nadal R, Twardowski P,
Vaishampayan UN, Agarwal N, Heath EI, Pal SK, Rehman HT,
Leiter A, Batten JA, Montgomery RB, Galsky MD, Antonarakis
ES, Chi KN, Yu EY. Activity of enzalutamide in men with
metastatic castration-resistant prostate cancer is affected by
prior treatment with abiraterone and/or docetaxel. Prostate
Cancer Prostatic Dis 2015;18(2):122–127.
6. Loriot Y, Bianchini D, Ileana E, Sandhu S, Patrikidou A, Pezaro
C, Albiges L, Attard G, Fizazi K, De Bono JS, Massard C.
Antitumour activity of abiraterone acetate against metastatic
castration-resistant prostate cancer progressing after docetaxel
and enzalutamide (MDV3100). Ann Oncol 2013;24:1807–1812.
7. Schrader AJ, Boegemann M, Ohlmann CH, Schnoeller TJ,
Krabbe LM, Hajili T, Jentzmik F, Stoeckle M, Schrader M,
Herrmann E, Cronauer MV. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and
abiraterone. Eur Urol 2014;65:30–36.
8. Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi
KN. Clinical activity of abiraterone acetate in patients with
metastatic castration-resistant prostate cancer progressing after
enzalutamide. Ann Oncol 2013;24:1802–1807.

The Prostate

520

Nadal et al.

9. Maughan BL, Antonarakis ES. Androgen pathway resistance in
prostate cancer and therapeutic implications. Expert Opin
Pharmacother 2015;16(10):1521–1537.
10. Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF,
Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM,
Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia
JA, DiPaola RS. Chemohormonal therapy in metastatic hormonesensitive prostate cancer. N Engl J Med 2015;373(8):737–746.
11. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN,
Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer
R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ,
Beer TM, Wilding G, Martin A, M Hussain; Prostate Cancer
Clinical Trials Working Group. Design and end points of
clinical trials for patients with progressive prostate cancer and
castrate levels of testosterone: recommendations of the Prostate
Cancer Clinical Trials Working Group. J Clin Oncol 2008;
26:1148–1159.
12. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D,
Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein
L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New
response evaluation criteria in solid tumours: revised RECIST
guideline (version 1.1). Eur J Cancer 2009;45:228–247.
13. Loriot Y, Eymard JC, Patrikidou A, Ileana E, Massard C, Albiges
L, Di Palma M, Escudier B, Fizazi K. Prior long response to
androgen deprivation predicts response to next-generation
androgen receptor axis targeted drugs in castration resistant
prostate cancer. Eur J Cancer 2015;51(14):1946–1952.
14. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser
JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL,

The Prostate

Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller
CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J. ARV7 and resistance to enzalutamide and abiraterone in prostate
cancer. N Engl J Med 2014;371:1028–1038.
15. Antonarakis ES, Lu C, Luber B, Wang H, Chen Y, Nakazawa
M, Nadal R, Paller CJ, Denmeade SR, Carducci MA,
Eisenberger MA, Luo J. Androgen receptor splice variant 7
and efficacy of taxane chemotherapy in patients with
metastatic castration-resistant prostate cancer. JAMA Oncol
2015;1(5):582–591.
16. Nakazawa M, Lu C, Chen Y, Paller CJ, Carducci MA, Eisenberger MA, Luo J, Antonarakis ES. Serial blood-based analysis
of AR-V7 in men with advanced prostate cancer. Ann Oncol
2015;26(9):1859–1865.
17. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN,
Oudard S, Th eodore C, James ND, Turesson I, Rosenthal MA,
Eisenberger MA; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate
cancer. N Engl J Med 2004;351:1502–1512.
18. Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA,
Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson
MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and
estramustine compared with mitoxantrone and prednisone for
advanced refractory prostate cancer. N Engl J Med 2004;351:
1513–1520.
19. Armstrong AJ, Garrett-Mayer E, de Wit R, Tannock I, Eisenberger M. Prediction of survival following first-line chemotherapy in men with castration-resistant metastatic prostate cancer.
Clin Cancer Res 2010;16:203–211.


Documents similaires


Fichier PDF pros23141
Fichier PDF 1 s2 0 s156990561360487x main
Fichier PDF art 3a10 1007 2fs10147 011 0275 6
Fichier PDF fichier pdf sans nom
Fichier PDF screening and management
Fichier PDF carayol 2013 prevention tertiaire cancer


Sur le même sujet..





1 Pcs SSC1S311 SC1S311 1S311 SOP8 | Black Odyssey: the Ordeal of Slavery in America: Review | └ Specialty Services