- Email: [email protected]
The Effect of Treatment Sequence on Overall Survival for Men With Metastatic Castration-resistant Prostate Cancer: A Multicenter Retrospective Study
Journal Pre-proof The effect of treatment sequence on overall survival for men with metastatic castration-resistant prostate cancer: A multicenter retrospective study Kazutaka Okita, Shingo Hatakeyama, Shintaro Narita, Masahiro Takahashi, Toshihiko Sakurai, Sadafumi Kawamura, Senji Hoshi, Masanori Ishida, Toshiaki Kawaguchi, Shigeto Ishidoya, Jiro Shimoda, Hiromi Sato, Koji Mitsuzuka, Akihiro Ito, Norihiko Tsuchiya, Yoichi Arai, Tomonori Habuchi, Chikara Ohyama PII:
S1558-7673(19)30275-7
DOI:
https://doi.org/10.1016/j.clgc.2019.09.006
Reference:
CLGC 1347
To appear in:
Clinical Genitourinary Cancer
Received Date: 17 July 2019 Revised Date:
29 August 2019
Accepted Date: 10 September 2019
Please cite this article as: Okita K, Hatakeyama S, Narita S, Takahashi M, Sakurai T, Kawamura S, Hoshi S, Ishida M, Kawaguchi T, Ishidoya S, Shimoda J, Sato H, Mitsuzuka K, Ito A, Tsuchiya N, Arai Y, Habuchi T, Ohyama C, The effect of treatment sequence on overall survival for men with metastatic castration-resistant prostate cancer: A multicenter retrospective study, Clinical Genitourinary Cancer (2019), doi: https://doi.org/10.1016/j.clgc.2019.09.006. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Graphical Abstract OS (Unadjusted n=146) ART → ART → DTX → DTX →
Percent survival
100 80 60
ART n=35 DTX n=33 ART n=68 CBZ n=10
40 20 0 0
12 24 36 48 60 72 84 96 108 120
Months
P=0.057 P=0.365
1
The effect of treatment sequence on overall survival for men with metastatic
2
castration-resistant prostate cancer: A multicenter retrospective study
3
4
Kazutaka Okita1, Shingo Hatakeyama1*, Shintaro Narita2, Masahiro Takahashi3, Toshihiko Sakurai4, Sadafumi
5
Kawamura5, Senji Hoshi6, Masanori Ishida7, Toshiaki Kawaguchi8, Shigeto Ishidoya9, Jiro Shimoda7, Hiromi
6
Sato2, Koji Mitsuzuka3, Akihiro Ito3, Norihiko Tsuchiya4, Yoichi Arai5, Tomonori Habuchi2, Chikara Ohyama1
7
1
Department of Urology, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.
8
2
Department of Urology, Akita University School of Medicine, 1-1-1, Hondo, Akita, 010-8543, Japan.
9
3
Department of Urology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi,
10
980-8575, Japan.
11
4
12
Japan.
13
5
Department of Urology, Miyagi Cancer Center, 47-1, Nodayama, Shiote, Aijima, Natori, Miyagi, 981-1293, Japan.
14
6
Department of Urology, Yamagata Prefectural Central Hospital, 1800, Aoyanagi, Yamagata, 990-2292, Japan.
15
7
Department of Urology, Iwate Prefectural Isawa Hospital, 61, Ryugabaab, Mizusawa-ku, Oshu, Iwate, 023-0864,
16
Japan.
17
8
18
030-8553, Japan.
Department of Urology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, Yamagata, 990-9585,
Department of Urology, Aomori Prefectural Central Hospital, 2-1-1, Higashi-tsukurimichi, Aomori, Aomori,
1
19
9
20
Japan.
21
E-mail addresses: Kazutaka Okita: [email protected], Shingo Hatakeyama: [email protected], Shintaro
22
Narita: [email protected], Masahiro Takahashi: [email protected], Toshihiko Sakurai:
23
[email protected], Sadafumi Kawamura: [email protected], Senji Hoshi:
24
[email protected], Masanori Ishida: [email protected], Toshiaki Kawaguchi:
25
[email protected], Shigeto Ishidoya: [email protected], Jiro Shimoda:
26
[email protected], Hiromi Sato: [email protected], Koji Mitsuzuka:
27
[email protected], Akihito Ito: [email protected], Norihiko Tsuchiya:
28
[email protected], Yoichi Arai: [email protected], Tomonori Habuchi:
29
[email protected], Chikara Ohyama: [email protected]
30
*, Corresponding author: Shingo Hatakeyama, M.D. (ORCID: 0000-0002-0026-4079), Department of Urology,
31
Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562,
32
Japan. E-mail address: [email protected], Tel. no.: 81-172-39-5091, Fax no.: 881-172-39-5092
33
Short title: Treatment sequence in mCRPC patients
34
Word count: abstract: 247; main text: 2653
Department of Urology, Sendai City Hospital, 1-1-1, Nagamachi, Asuto, Taihaku-ku, Sendai, Miyagi, 982-8502,
35
36
Abstract 2
37
Purpose: We aimed to evaluate the treatment sequence for patients with metastatic castration-resistant prostate
38
cancer (mCRPC) in real-world practice and compare overall survival in each sequential therapy.
39
Patients and Methods: We retrospectively evaluated 146 patients with mCRPC who were initially treated with
40
androgen deprivation therapy as metastatic hormone-naïve prostate cancer in 14 hospitals between January 2010
41
and March 2019. The agents for the sequential therapy included new androgen receptor-targeted agents (ART:
42
abiraterone acetate or enzalutamide), docetaxel, and/or cabazitaxel. We evaluated the treatment sequence for
43
mCRPC and the effect of sequence patterns on overall survival.
44
Results: The median age was 71 years. A total of 35 patients received ART-ART, 33 received ART-docetaxel, 68
45
received docetaxel-ART, and 10 received docetaxel-cabazitaxel sequences. The most prescribed treatment
46
sequence was docetaxel-ART (47%), followed by ART-ART (24%). Overall survival calculated from the initial
47
diagnosis reached 83, 57, 79, 37 months in the ART-ART, ART-docetaxel, docetaxel-ART, and
48
docetaxel-cabazitaxel, respectively. Multivariate Cox regression analyses showed no significant difference in
49
overall survival between the first-line ART (n = 68) and first-line docetaxel (n = 78) therapies (hazard ratio: HR
50
0.84, P = 0.530), between the ART-ART (n = 35) and docetaxel-mixed (n = 111) sequences (HR 0.82, P = 0.650),
51
and between the first-line abiraterone (n = 32) and first-line enzalutamide (n = 36) sequences (HR 1.58, P =
52
0.384).
53
Conclusion; The most prescribed treatment sequence was docetaxel followed by ART. No significant difference
54
was observed in overall survival among the treatment sequences in real-world practice. 3
55
Key words: castration-resistant prostate cancer; metastasis; patterns; sequence; survival
56
57
Introduction Prostate cancer (PC) is one of the common malignancies worldwide.
58
2-8
1-4
Approximately 10% of patients
59
with PC have distant metastases in Japan.
60
androgen deprivation therapy (ADT),
61
castration-resistant prostate cancer (mCRPC), resulting in poor prognosis.
62
agents (ART), such as abiraterone acetate (ABI) and enzalutamide (ENZ), improved survival in real-world
63
practices
64
mCRPC who develop resistance to a first-line ART are also resistant to subsequent ART therapy 19-26 as well as
65
taxane-based chemotherapy (docetaxel: DTX and/or cabazitaxel: CBZ) . Despite the cross-resistance, sequential
66
treatment with ART, DTX, and CBZ remains a therapeutic option. However, no randomized trial has directly
67
compared the various systemic therapies for CRPC. In addition, limited evidence is available for the direct
68
comparison of OS between the ABI and ENZ for mCRPC patients. Therefore, we conducted a retrospective study
69
to evaluate the treatment sequence for patients with mCRPC in real-world practice and effect of sequence therapy
70
on prognosis in with mCRPC.
71
Patients and Methods
72
Study population and patient selection
11-16
1-8
Although PC is highly androgen-dependent and sensitive to initial
men with metastatic hormone-naïve PC eventually develop metastatic
and large randomized phase III trials.
17, 18
4
1-14
New androgen receptor-targeted
However, clinical data suggested that patients with
73
The present multicenter retrospective study was performed in accordance with the ethical standards of the
74
Declaration of Helsinki, and it was approved by the ethics review board of the Hirosaki University School of
75
Medicine (authorization number: 2018–062) and all hospitals.
76
We evaluated 837 patients with metastatic hormone-naïve PC (mHNPC) who were initially treated with ADT
77
in the Michinoku Japan Urological Cancer Study Group database (n = 667) and Hirosaki University related
78
hospitals (n = 170) between January 2001 and March 2019.
79
proven prostate cancer, 2) patients with mCRPC after primary ADT, 3) patients who were treated sequential
80
life-extending therapy greater than or equal to two lines including DTX, ABI, ENZ, and CBZ, and 4) minimum
81
follow-up of 3 months after the second life-extending therapy. Exclusion criteria were 1) patients who did not
82
develop mCRPC, 2) patients who had vintage agents alone (flutamide, estramustine phosphate, and/or
83
ethinylestradiol) for mCRPC, and 3) insufficient data of baseline clinical information. Patients were classified into
84
four groups: ART followed by another ART (ART-ART), ART followed by DTX (ART-DTX), DTX followed by
85
ART (DTX-ART), and DTX followed by CBZ (DTX-CBZ).
86
Indication of life-extending therapy for CRPC in Japan
5, 6, 8, 27-29
Inclusion criteria were 1) histologically
87
Therapeutic agents of DTX, ENZ, ABI, and CBZ were approved for all patients with CRPC in February
88
2007, June 2014, September 2014, and September 2014, respectively. We can select either ART or DTX as
89
first-line therapy for mCRPC after June 2014. No limitation is available for ART-ART, ART-DTX, DTX-ART, and
90
DTX-CBZ sequences. Cabazitaxel is approved to use the post-docetaxel setting. 5
91
Evaluation of variables
92
The following variables were analyzed at diagnosis: age, year of diagnosis, Eastern Cooperative
93
Oncology Group (ECOG), Gleason score, serum prostate-specific antigen (PSA), metastatic tumor burden,
94
treatment era (ART era: after June 2014), time to CRPC, and PSA nadir. Tumor stage and grade were assigned
95
based on the 2009 TNM classification of the Union of International Cancer Control. Metastatic status was
96
evaluated via chest and body computed tomography and bone scintigraphy before initiating ADT. Bone metastatic
97
volume was evaluated by the extent of disease on bone scintigraphy. High-volume disease was defined as the
98
presence of visceral metastases and/or four more bone metastases with at least one outside of the vertebral column
99
and pelvis according to the risk criteria of Chemohormonal Therapy Versus Androgen Ablation Randomized Trial 7, 30, 31
100
for Extensive Disease in Prostate Cancer (CHAARTED) trial in PC.
Radium-223 and vintage agents were
101
not included in the mCRPC treatment sequence in this study. Progression-free survival was not evaluated because
102
there was no information in the database. Treatment sequences were evaluated from first-line to fourth-line
103
therapies.
104
Treatment protocol
105
All patients were initially treated with ADT (medical or surgical castration with or without bicalutamide).
106
Some patients received bone-modifying agents, such as bisphosphonate or denosumab, for bone pain or
107
prophylactic use against skeletal-related events based on the decision of attending physicians. The CRPC
108
definition was according to the recommendations of the Cancer Clinical Trials Working Group 2 6
32
. After the
109
diagnosis of CRPC, some patients received subsequent treatments, such as vintage anti-androgen therapy
110
(flutamide or estramustine), anti-androgen withdrawal therapy, and/or low-dose oral steroid therapy. Thereafter,
111
patients underwent chemotherapy (DTX and/or CBZ) and/or ART therapy (ABI and/or ENZ) based on their
112
attending physicians’ recommendations. We did not include radium-233 as an agent of sequential therapy in the
113
analysis. We allowed administration of any bone protective agents, radium-233 and radiation therapy for pain
114
control. The general impetus for changing CRPC therapeutic agents was disease progression including PSA
115
increase and/or radiologic progression. Imaging tests (bone scan and CT) were performed when patients
116
experienced PSA progression and/or any symptoms.
117
Outcome evaluation
118
We evaluated the treatment sequence for mCRPC in real-world practice. Treatment sequences were
119
evaluated using a Sankey diagram and classified into four groups including the combination of first- and
120
second-line therapies for mCRPC such as ART-ART, ART-DTX, DTX-ART, and DTX-CBZ groups. In addition,
121
the effect of sequence patterns on OS between the first-line ART (ART-1st) vs first-line DTX (DTX-1st), between
122
the, ART-ART sequences vs DTX-mixed sequences, and first-line ABI (ABI-1st) vs first-line ENZ (ENZ-1st)
123
were compared.
124
Statistical analysis
125
Statistical analyses were performed using GraphPad Prism 5.03 (GraphPad Software, San Diego, CA,
126
USA), BellCurve for Excel (Social Survey Research Information Co., Ltd., Tokyo, Japan), and R 3.3.2 (The R 7
127
Foundation for Statistical Computing, Vienna, Austria). Quantitative variables were expressed as mean with
128
standard deviation or median with interquartile range (IQR). Fisher’s exact test, χ2 test, Student’s t-test, or Mann–
129
Whitney U-test were used to analyze the intergroup difference. The Kruskal–Wallis test is used to compare
130
medians among four comparison groups. OS rates from initial treatment until any death were estimated using the
131
Kaplan–Meier method and compared with the log-rank test. Background adjusted inverse probability of treatment
132
weighting (IPTW) Cox regression analysis was performed to evaluate the effect of treatment patterns on OS and
133
OS after diagnosis of CRPC. Hazard ratios (HR) with 95% confidence interval (95%CI) were calculated after
134
controlling for potential confounders, including patient age, ECOG PS, initial PSA at diagnosis, Gleason score,
135
CHAARTED high-volume disease, visceral metastasis, time to mCRPC, and treatment era after the approval of
136
enzalutamide in Japan (ART era: after June 2014). Values of P < 0.05 were considered statistically significant.
137
Results
138
Baseline characteristics of participants
139
Of the 837 patients, 546 (65%) developed mCRPC. Of those, 400 patients were excluded because they
140
had vintage agents alone (flutamide, estramustine phosphate, and/or ethinylestradiol) (n = 193), non-sequential (=
141
single) life-extending therapy (n = 207). Finally, 146 patients who received sequential life-extending therapies for
142
mCRPC were included (Fig. 1). There was no significant difference between the patients with non-sequential and
143
sequential therapies in age (Fig. S1A; 70 versus 71, respectively: P = 0.620), initial PSA (Fig. S1B; 383 versus
144
324 ng/mL, respectively: P = 0.996), GS (Fig. S1C; 9 versus 9, P = 0.070), CHAARTED-high volume (Fig. S1D; 8
145
75% versus 73%, respectively: P = 0.621), PSA nadir (Fig. S1E; 0.783 versus 0.975 ng/mL, respectively: P =
146
0.193), and time to CRPC (Fig. S1F; 14 versus 14 months, respectively: P = 0.720), except for ECOG PS >1 (Fig.
147
S1G; 12% versus 2.1%, respectively: P < 0.001), and EOD (Fig. S1H; 2 versus 1, respectively: P < 0.001). Table
148
1 shows the characteristics of the study participants at the initial diagnosis of metastatic hormone-naïve PC. The
149
median age, PSA, and a follow-up period of all patients were 71 (IQR: 65–75) years, 324 (IQR: 80–1045) ng/mL,
150
and 47 (IQR:30–66) months, respectively.
151
Treatment sequence analysis
152
A total of 35 patients received ART-ART, 33 received ART-DTX, 68 received DTX-ART, and 10 received
153
DTX-CBZ sequences. There were significant difference in the median age (P = 0.037), high-volume disease (P =
154
0.003), treatment era (P = 0.002), and use of DTX and CBZ (P <0.001) The median time to CRPC and PSA nadir
155
were not significantly different among the groups (P = 0.052 and 0.475, respectively). A Sankey diagram showed
156
treatment patterns of 146 patients in our medical area (Fig. 2A). Of the 146, 68 (47%) and 78 (53%) patients
157
received first-line ART (ADT-1st) and first-line DTX (DTX-1st) therapies, respectively (Fig. 2B). The most
158
prescribed treatment sequence was DTX-ART (47%), followed by ART-ART (24%), ART-DTX (23%), and
159
DTX-CBZ (6.9%) (Fig. 2C). The use of ABI or ENZ for first-line ART therapy (n = 68) was 46 (47%) and 57
160
(53%), respectively.
161
Overall survival among the treatment patterns
162
OS calculated from the initial diagnosis reached 83, 57, 79, 37 months in the ART-ART, ART-DTX, 9
163
DTX-ART, and DTX-CBZ groups, respectively (Fig. 3A). The unadjusted OS was not significantly different
164
between the ART-ART vs ART-DTX (P = 0.057), and between the ART-ART vs DTX-ART (P = 0.365). Among
165
the sequences, no significant difference was observed in unadjusted OS between the ART-1st vs DTX-1st (Fig.
166
3B; P = 0.461), between the ART-ART (n = 35) vs DTX-mixed (n = 111) sequences (Fig. 3C; P = 0.163), and
167
between the first-line abiraterone (ABI-1st, n = 32) vs first-line enzalutamide (ENZ-1st, n=36) (Fig. 3D; P =
168
0.246).
169
The background (age, ECOG PS, initial PSA at diagnosis, Gleason score, CHAARTED high-volume
170
disease, visceral metastasis, time to mCRPC, and treatment era) adjusted IPTW Cox regression analyses showed
171
no significant difference was observed in OS between the ART-1st and DTX-1st therapies (P = 0.530, HR 0.84),
172
between the ART-ART and DTX-mixed sequences (P = 0.650, HR 0.82), and between the ABI-1st and ENZ-1st
173
therapies (P = 0.384, HR 1.58) (Fig. 4A, Table 2). Similarly, no significant difference was observed in OS after
174
diagnosis of mCRPC between the ART-1st and DTX-1st therapies (P = 0.636, HR 0.88), between the ART-ART
175
and DTX-mixed sequences (P = 0.866, HR 1.07), and between the ABI-1st and ENZ-1st therapies (P = 0.392, HR
176
1.58) (Fig. 4B, Table 2).
177
Discussion
178
In this study, we evaluated the treatment sequence for patients with mCRPC in real-world practice and
179
assessed the effect of treatment sequences on OS in patients with mCRPC. Our results showed the DTX-ART
180
sequence was the most prescribed treatment sequence. This might be due to the difficulty in continuous 10
181
administration of toxic chemotherapy for mCRPC patients even the patients receiving the first-line DTX were
182
significantly younger than that of first-line ART (68 vs 73, respectively). As the median cycle of first-line DTX
183
therapy for mCRPC was 6 (IQR: 4-11), less than 10 cycles of DTX might be optimal in the balance of effects and
184
harms. The use of ABI or ENZ for first-line CRPC therapy was similar (47 vs 53%, respectively) in our cohort. In
185
the second-line therapy, we found ART therapies (ABI: n = 46, ENZ: n = 57) was the most popular therapy for
186
mCRPC. The administration of CBZ was increased in the third- or fourth-line therapies. In this cohort, the number
187
of patients who treated third- or fourth-line therapy was 54 (36%) and 11 (7.5%), respectively. In addition, the
188
number of patients who had the opportunity to use CBZ as one of the life-extending agents was 41 (28%) patients.
189
These results suggested that it is not easy to receive all the treatable option in those patients.
190
We found the association between treatment sequence and OS was not significant in our clinical practice
191
regardless of the sequences. The first-line DTX may be more beneficial in patients with CRPC and poor
192
prognostic features such as an early progression from the initial ADT.
193
significant difference in OS and OS after CRPC diagnosis between the ART-1st vs DTX-1st groups. It was not
194
significant even we adjusted tumor volume and time to CRPC in IPTW-adjusted analysis. Despite the existence of
195
selection biases among these groups, no significant difference in OS may suggest a saturated efficacy of these
196
sequence therapies. Our observations were supported by previous studies that OS after CRPC was not prolonged
197
significantly despite the short-term efficacy in progression-free survival.
198
PROREPAIR-B cohort study evaluating treatment patterns and outcomes in 406 mCRPC patients suggested that 11
16, 19, 23, 24
19-24
However, our results showed no
More recently, the prospective
199
the choice of the first-line agent was associated with progression-free survival after the next line therapy (PFS2),
200
but not associated with OS. They found a significant difference in PFS2 between patients treated with initial
201
ABI/ENZ vs DTX (20.6 vs 16.6m; HR:0.78; P = 0.006), but not OS (31.3 vs 29.9 m; HR:1.05; P = 0.725).
202
Therefore, the OS might be similar despite treatment sequences for mCRPC. However, recent evidence suggested
203
that early administration of new agents for non-metastatic CRPC (nmCRPC) have a significant benefit on
204
prognosis.
205
antigen (PSMA) ligand has remarkable diagnostic value for staging and detecting recurrence in many studies. 36-38
206
Therefore, the new agents for nmCRPC and next-generation PET imaging make passible the treatment strategy
207
shift from mCRPC to nmCRPC.
34, 35
33
Also, next-generation positron emission tomography (PET) using prostate-specific membrane
208
There is not enough evidence to guide the decision for the appropriate use of these agents. Our finding
209
of no significant difference in OS among the treatment patterns might be one of the best results of individualized
210
sequences therapy in each patient based on general status, tolerability, economic condition, and disease
211
aggressiveness. Although several studies suggested that consecutive use of ART may be not beneficial to patients
212
with mCRPC,
213
option in selected patients such as slow progression disease. As the outcomes of the first-line therapy itself are one
214
of the biomarkers for efficacy, clinicians can modify the second-line sequence based on the outcomes of first-line
215
therapy. The other potential reason for no significant difference in OS among the treatment patterns might be a
216
cross-resistance among those agents. 39-41 Although we could not prove this hypothesis in our study, a clinical and
16, 19-24
not all patients were feasible for toxic chemotherapy and ART-ART sequences might be an
12
217
molecular marker for the aggressiveness and response to therapies might guide the decision for the appropriate
218
selection of these agents in the future. The novel therapeutic strategy is needed to improve outcomes.
219
This study had several limitations. First, our results should be interpreted with caution considering the
220
retrospective design, limited sample size, and possible selection bias. ECOG PS at the time of CRPC diagnosis
221
was not available in this study. Also, Information on local therapy for the oligometastatic disease was not
222
available in this study. Second, very few men in this cohort (n = 8, 5.5%) received the current standard of care
223
(upfront DTX or ABI) when they had hormone-naïve PCa because of long-term periods of this study. Third, the
224
exclusion of more half of men with mCRPC who received vintage agents alone or non-sequence life-extending
225
therapy (alive or dead after single therapy of ABI, ENZ or DTX) is strong selection bias in this study. However,
226
we observed no statistical difference in CRPC-free survival between the included and excluded patients and
227
confirmed the feasibility of patient selection. Fourth, we could not address the response rate and progression-free
228
survival after life-extending therapy in this study due to the lack of information in the database as the response to
229
first-line therapy for mCRPC may have a significant association with overall survival. Fifth, our results cannot be
230
generalized to non-Asian populations because of racial difference. Furthermore, limitation existed in quality of
231
life measures and side effects. Finally, we could not obtain information regarding baseline clinical data such as
232
comorbidities, and the influence of metastatic organs and PSA doubling time at the CRPC diagnosis, which are
233
significantly associated with mortality. Despite these limitations, our study revealed no significant difference in
234
OS in patients with mCRPC among the treatment sequences in real-world practice. 13
235
Conclusions
236
The most prescribed treatment sequence was DTX followed by ART. No significant difference was
237
observed in OS among the treatment sequences in real-world practice. Further study is needed to validate our
238
observation.
239
240
241
Acknowledgments We would like to thank Takuma Narita, Hirotake Kodama, Toshikazu Tanaka, Itsuto Hamano, Naoki
242
Fujita, Hiromichi Iwamura, Teppei Okamoto, Yuki Fujita, Yukie Nishizawa, and the entire staff of the Department
243
of Urology in Hirosaki University for their invaluable help with the data collection. The authors would also like to
244
thank Enago (www.enago.jp) for the English language review.
245
Funding: This work was supported by a Grant-in-Aid for Scientific Research (Grant Nos. 17K11119, 18K16681,
246
and 18K09157) from the Japan Society for the Promotion of Science.
247
Conflict of Interest: The authors declare that they have no conflict of interest.
248
Ethics statement
249
The present retrospective, multicenter study was performed in accordance with the ethical standards of the
250
Declaration of Helsinki, and it was approved by the ethics review board of the Hirosaki University School of
251
Medicine (authorization number: 2018–062) and all hospitals. Pursuant to the provisions of the ethics committee
14
252
and the ethics guidelines in Japan, written informed consent is not required for public disclosure of study
253
information in the case of a retrospective and/or observational study using materials, such as existing documents
254
(opt-out approach).
255
Authors’ Contribution
256
Kazutaka Okita: Manuscript writing, data analysis, data collection
257
S Hatakeyama: Manuscript editing, data analysis, data collection
258
S Narita, M Takahashi, T Sakurai, S Kawamura, S Hoshi, M Ishida, T Kawaguchi, S Ishidoya, J Shimoda, H Sato,
259
K Mitsuzuka: Project development, data collection
260
A Ito, N Tsuchiya, Y Arai, T Habuchi, and C Ohyama: Project development, critical review and supervision
261
15
262
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383
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384
385
Figure legends
386
Figure 1. Patient selection
387
Of the 837 patients, 546 (65%) developed mCRPC. Of those, 400 patients were excluded because they 22
388
had vintage agents alone (flutamide, estramustine phosphate, and/or ethinylestradiol) (n = 193), non-sequential (=
389
single) life-extending therapy (n = 207). Finally, 146 patients who received sequential life-extending therapies for
390
mCRPC were included.
391
Figure 2. Treatment sequences in real-world patients
392
A sankey diagram showed treatment patterns of 146 patients in real-world setting (A). Treatment
393
patterns in the first-, second-, third-, and fourth-line therapy was evaluated (B). The number of patients who
394
received sequential therapy such as DTX followed by ART (DTX–ART), ART followed by another ART (ART –
395
ART), ART followed by DTX (ART–DTX), and DTX followed by CBZ (DTX–CBZ) was 68 (47%), 35 (24%),
396
33 (23%), and 10 (6.9%), respectively (C).
397
Figure 3. Overall survival (OS)
398
Unadjusted OS among the treatment sequences was evaluated using Kaplan–Meier method and
399
compared with the log-rank test (A). Unadjusted OS between the ART-1st vs DTX-1st (B), between the ART-ART
400
sequence vs DTX-mixed sequence (C), and between the first-line abiraterone acetate (ABI-1st) and enzalutamide
401
(ENZ-1st) (D) was evaluated using Kaplan–Meier method and compared with the log-rank test.
402
Figure 4. IPTW-adjusted Cox regression analysis for OS and OS after mCRPC diagnosis
403
An IPTW-adjusted multivariate Cox proportional hazards regression analyses on OS (A) and OS after
404
mCRPC diagnosis (B) was performed. No significant difference was observed among the treatment sequences.
405
Variables included in the IPTW model were age, initial PSA at diagnosis, Gleason score, CHAARTED 23
406
high-volume disease, time to CRPC, and treatment era (ART era: after June 2014).
407
Figure S1. Background comparison between the non-sequential (excluded from the analysis) and sequential
408
therapies
409
As the patients with vintage agents alone were not targeted patients in this study, we evaluated baseline
410
data between the patients with non-sequential and sequential therapies. We observed no significant difference
411
between the patients with non-sequential and sequential therapies in age (A: 70 versus 71, respectively: P =
412
0.620), initial PSA (B: 383 versus 324 ng/mL, respectively: P = 0.996), GS (C: 9 versus 9, P = 0.070),
413
CHAARTED-high volume (D: 75% versus 73%, respectively: P = 0.621), PSA nadir (E: 0.783 versus 0.975
414
ng/mL, respectively: P = 0.193), and time to CRPC (F: 14 versus 14 months, respectively: P = 0.720), except for
415
ECOG PS >1 (G: 12% versus 2.1%, respectively: P < 0.001), and EOD (H: 2 versus 1, respectively: P < 0.001).
416
These results may suggest that clinical response might be similar between the groups while baseline data of
417
ECOG PS and EOD were significantly worse in the non-sequential patients.
24
Table 1 Background of patients at the diagnosis of metastatic hormone-naïve prostate cancer Treatment sequences ART-ART
ART-DTX
DTX-ART
DTX-CBZ
35
33
68
10
73 (67-77)
72 (66-77)
68 (63-75)
68 (66-73)
0.037*
ECOG PS 0/1/>1
33 / 1 / 1
30 / 2 / 1
66 / 1 / 1
9/1/0
0.400
Initial PSA (IQR)
181 (53-2828)
127 (43-478)
493 (119-1368)
256 (10-937)
0.087*
9 (8-9)
9 (8-10)
9 (9-9)
9 (9-9)
0.575*
32 (91%)
18 (55%)
47 (69%)
9 (90%)
0.003
5 (14%)
3 (9.1%)
8 (12%)
3 (30%)
0.346
1.2 (0.17-10)
0.96 (0.15-4.1)
0.97 (0.15-4.5)
0.94 (0.15-3.4)
0.475*
Number
P value
of
patients Age,
median
(IQR)
Gleason
score
(IQR) High-volume disease, n (%) Visceral metastasis PSA kinetics PSA nadir,
ng/dL Time to CRPC, median
21 (9-40)
11 (8-16)
15 (9-25)
10 (6-20)
0.052*
8 (23%)
7 (21%)
36 (53%)
2 (20%)
0.002
2 (2-3)
2 (2-3)
2 (2-3)
2 (2-2)
0.194
6 (17%)
26 (79%)
68 (100%)
10 (100%)
<0.001
4 (11%)
10 (30%)
17 (25%)
10 (100%)
<0.001
56 (37-77)
38 (26-56)
46 (33-79)
33 (25-59)
13 (37%)
12 (36%)
30 (44%)
7 (70%)
(IQR) CRPC diagnosis in ART era Number of sequence therapy Use of DTX, n (%) Use of CBZ, n (%) Median follow-up, months (IQR) Deceased, n (%) *, Kruskal–Wallis test ART, androgen receptor-targeted agents; CBZ, cabazitaxel; CRPC, castration-resistant prostate cancer;
DTX, docetaxel; CBZ, cabazitaxel; IQR, interquartile range; PSA, prostate-specific antigen
Table 2
IPTW-adjusted Cox regression analysis for OS and OS after mCRPC diagnosis
OS
HR
DTX-1st
1 (ref)
ART-1st
0.84
DXT-mixed sequences ART-ART sequences
95%CI
P value
0.475-1.44
0.530
0.35-1.94
0.650
1 (ref) 0.82
ABI-1st
1 (ref)
ENZ-1st
1.58
0.56-4.41
0.384
OS after mCRPC diagnosis
HR
95%CI
P value
0.52-1.50
0.636
0.51-2.25
0.866
DTX-1st
1 (ref)
ART-1st
0.88
DXT-mixed sequences ART-ART sequences
1 (ref) 1.07
ABI-1st
1 (ref)
ENZ-1st
1.58
0,56-4.46
0.392
IPTW, inverse probability of treatment weighting; ART, androgen receptor-targeted agents; CBZ, cabazitaxel; DTX, docetaxel; CBZ, cabazitaxel; ABI, abiraterone acetate; ENZ, enzalutamide
Fig. 1
mHNPC n=837 CRPC n=546
Vintage agents alone n=193
Non-sequential therapy n=207 (excluded from this study)
DTX, ABI, or ENZ n=353
Sequential therapy n=146 (included in this study)
Fig. 2
B
Treatment paterns
A
7%
100
2nd line
3rd line
4th line
% of patients
1st line
n=78 (53%)
ART DTX CBZ
35%
23%
53%
100%
18%
50
47%
70%
47%
0 1st line
2nd line
3rd line
4th line
Treatment line
C
Treatment sequence n=146 50
(1st → 2nd-line)
40
47%
30
24%
23%
20
6.9%
10
C B Z → TX D
R T→ D TX A
A R T R T→ A
→
A R T
0
TX
n=68 (47%)
% of patients
CRPC
D
mCRPC n=146
ART → ART → DTX → DTX →
100
Percent survival
B
OS (Unadjusted n=146)
80 60
ART n=35 DTX n=33 ART n=68 CBZ n=10
40 20
100
P=0.057 P=0.365
OS (Unadjusted n=146)
Percent survival
A
0
ART-1st n=68 DTX-1st n=78
80
P=0.461 60 40 20 0
0
12 24 36 48 60 72 84 96 108 120
0
Months
C
D OS (Unadjusted n=68)
ART-ART seq. n=35 DTX-mixed seq. n=111 P=0.163
60 40 20 0 0
12 24 36 48 60 72 84 96 108 120
Months
100
Percent survival
80
12 24 36 48 60 72 84 96 108 120
Months
OS (Unadjusted n=146) 100
Percent survival
Fig. 3
ABI-1st n=32 ENZ-1st n=36 P=0.246
80 60 40 20 0 0
12 24 36 48 60 72 84 96 108 120
Months
Fig. 4
A
IPTW-adjusted Cox regression model for OS DTX-1st
B
IPTW-adjusted Cox regression model for OS after CRPC diagnosis DTX-1st
ref.
ref.
0.84
0.88
ART-1st
ART-1st
ref.
DTX-mixed
ref.
DTX-mixed
0.82
1.07
ART-ART
ART-ART
ref.
ABI-1st
ref.
ABI-1st
1.58
1.58
ENZ-1st
ENZ-1st 0.3
1.0
HR
3.2
10.0
0.3
1.0
HR
3.2
10.0
Fig. S1
11
P=0.996
10000
years
ng/mL
80
1000 100
60 10 1
40 n=207
E
F
PSA nadir
100
P=0.193 Percent survival
ng/mL
1 0.1 0.01
0.001 non-sequencing Sequencing n=207
n=146
9 8 7
non-sequencing n=207 Sequencing n=146 Median: 14 vs 14 mo HR 0.96 (95%CI 0.78-1.19) P=0.720
40
40
0 non-sequencing Sequencing n=207
n=146
ECOG PS >1 15
60
60
20
n=207
G
P=0.621
80
6
n=146
CRPC-free survival
80
100
non-sequencing Sequencing
100
10
CHAARTED-high vol.
5 n=207
n=146
P=0.070
10
non-sequencing Sequencing
non-sequencing Sequencing
D
GS
% of patients
100000
P=0.620
H
EOD 5
P<0.001
n=146
P<0.001
4
% of patients
100
C
Initial PSA
score (0-4)
B
Age
Gleason score (6-10)
A
10
5
3 2 1
20
0
0
0 0
50
Months
100
non-sequencing Sequencing n=207
n=146
non-sequencing Sequencing n=207
n=146
S1558-7673(19)30275-7
DOI:
https://doi.org/10.1016/j.clgc.2019.09.006
Reference:
CLGC 1347
To appear in:
Clinical Genitourinary Cancer
Received Date: 17 July 2019 Revised Date:
29 August 2019
Accepted Date: 10 September 2019
Please cite this article as: Okita K, Hatakeyama S, Narita S, Takahashi M, Sakurai T, Kawamura S, Hoshi S, Ishida M, Kawaguchi T, Ishidoya S, Shimoda J, Sato H, Mitsuzuka K, Ito A, Tsuchiya N, Arai Y, Habuchi T, Ohyama C, The effect of treatment sequence on overall survival for men with metastatic castration-resistant prostate cancer: A multicenter retrospective study, Clinical Genitourinary Cancer (2019), doi: https://doi.org/10.1016/j.clgc.2019.09.006. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Graphical Abstract OS (Unadjusted n=146) ART → ART → DTX → DTX →
Percent survival
100 80 60
ART n=35 DTX n=33 ART n=68 CBZ n=10
40 20 0 0
12 24 36 48 60 72 84 96 108 120
Months
P=0.057 P=0.365
1
The effect of treatment sequence on overall survival for men with metastatic
2
castration-resistant prostate cancer: A multicenter retrospective study
3
4
Kazutaka Okita1, Shingo Hatakeyama1*, Shintaro Narita2, Masahiro Takahashi3, Toshihiko Sakurai4, Sadafumi
5
Kawamura5, Senji Hoshi6, Masanori Ishida7, Toshiaki Kawaguchi8, Shigeto Ishidoya9, Jiro Shimoda7, Hiromi
6
Sato2, Koji Mitsuzuka3, Akihiro Ito3, Norihiko Tsuchiya4, Yoichi Arai5, Tomonori Habuchi2, Chikara Ohyama1
7
1
Department of Urology, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.
8
2
Department of Urology, Akita University School of Medicine, 1-1-1, Hondo, Akita, 010-8543, Japan.
9
3
Department of Urology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi,
10
980-8575, Japan.
11
4
12
Japan.
13
5
Department of Urology, Miyagi Cancer Center, 47-1, Nodayama, Shiote, Aijima, Natori, Miyagi, 981-1293, Japan.
14
6
Department of Urology, Yamagata Prefectural Central Hospital, 1800, Aoyanagi, Yamagata, 990-2292, Japan.
15
7
Department of Urology, Iwate Prefectural Isawa Hospital, 61, Ryugabaab, Mizusawa-ku, Oshu, Iwate, 023-0864,
16
Japan.
17
8
18
030-8553, Japan.
Department of Urology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, Yamagata, 990-9585,
Department of Urology, Aomori Prefectural Central Hospital, 2-1-1, Higashi-tsukurimichi, Aomori, Aomori,
1
19
9
20
Japan.
21
E-mail addresses: Kazutaka Okita: [email protected], Shingo Hatakeyama: [email protected], Shintaro
22
Narita: [email protected], Masahiro Takahashi: [email protected], Toshihiko Sakurai:
23
[email protected], Sadafumi Kawamura: [email protected], Senji Hoshi:
24
[email protected], Masanori Ishida: [email protected], Toshiaki Kawaguchi:
25
[email protected], Shigeto Ishidoya: [email protected], Jiro Shimoda:
26
[email protected], Hiromi Sato: [email protected], Koji Mitsuzuka:
27
[email protected], Akihito Ito: [email protected], Norihiko Tsuchiya:
28
[email protected], Yoichi Arai: [email protected], Tomonori Habuchi:
29
[email protected], Chikara Ohyama: [email protected]
30
*, Corresponding author: Shingo Hatakeyama, M.D. (ORCID: 0000-0002-0026-4079), Department of Urology,
31
Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562,
32
Japan. E-mail address: [email protected], Tel. no.: 81-172-39-5091, Fax no.: 881-172-39-5092
33
Short title: Treatment sequence in mCRPC patients
34
Word count: abstract: 247; main text: 2653
Department of Urology, Sendai City Hospital, 1-1-1, Nagamachi, Asuto, Taihaku-ku, Sendai, Miyagi, 982-8502,
35
36
Abstract 2
37
Purpose: We aimed to evaluate the treatment sequence for patients with metastatic castration-resistant prostate
38
cancer (mCRPC) in real-world practice and compare overall survival in each sequential therapy.
39
Patients and Methods: We retrospectively evaluated 146 patients with mCRPC who were initially treated with
40
androgen deprivation therapy as metastatic hormone-naïve prostate cancer in 14 hospitals between January 2010
41
and March 2019. The agents for the sequential therapy included new androgen receptor-targeted agents (ART:
42
abiraterone acetate or enzalutamide), docetaxel, and/or cabazitaxel. We evaluated the treatment sequence for
43
mCRPC and the effect of sequence patterns on overall survival.
44
Results: The median age was 71 years. A total of 35 patients received ART-ART, 33 received ART-docetaxel, 68
45
received docetaxel-ART, and 10 received docetaxel-cabazitaxel sequences. The most prescribed treatment
46
sequence was docetaxel-ART (47%), followed by ART-ART (24%). Overall survival calculated from the initial
47
diagnosis reached 83, 57, 79, 37 months in the ART-ART, ART-docetaxel, docetaxel-ART, and
48
docetaxel-cabazitaxel, respectively. Multivariate Cox regression analyses showed no significant difference in
49
overall survival between the first-line ART (n = 68) and first-line docetaxel (n = 78) therapies (hazard ratio: HR
50
0.84, P = 0.530), between the ART-ART (n = 35) and docetaxel-mixed (n = 111) sequences (HR 0.82, P = 0.650),
51
and between the first-line abiraterone (n = 32) and first-line enzalutamide (n = 36) sequences (HR 1.58, P =
52
0.384).
53
Conclusion; The most prescribed treatment sequence was docetaxel followed by ART. No significant difference
54
was observed in overall survival among the treatment sequences in real-world practice. 3
55
Key words: castration-resistant prostate cancer; metastasis; patterns; sequence; survival
56
57
Introduction Prostate cancer (PC) is one of the common malignancies worldwide.
58
2-8
1-4
Approximately 10% of patients
59
with PC have distant metastases in Japan.
60
androgen deprivation therapy (ADT),
61
castration-resistant prostate cancer (mCRPC), resulting in poor prognosis.
62
agents (ART), such as abiraterone acetate (ABI) and enzalutamide (ENZ), improved survival in real-world
63
practices
64
mCRPC who develop resistance to a first-line ART are also resistant to subsequent ART therapy 19-26 as well as
65
taxane-based chemotherapy (docetaxel: DTX and/or cabazitaxel: CBZ) . Despite the cross-resistance, sequential
66
treatment with ART, DTX, and CBZ remains a therapeutic option. However, no randomized trial has directly
67
compared the various systemic therapies for CRPC. In addition, limited evidence is available for the direct
68
comparison of OS between the ABI and ENZ for mCRPC patients. Therefore, we conducted a retrospective study
69
to evaluate the treatment sequence for patients with mCRPC in real-world practice and effect of sequence therapy
70
on prognosis in with mCRPC.
71
Patients and Methods
72
Study population and patient selection
11-16
1-8
Although PC is highly androgen-dependent and sensitive to initial
men with metastatic hormone-naïve PC eventually develop metastatic
and large randomized phase III trials.
17, 18
4
1-14
New androgen receptor-targeted
However, clinical data suggested that patients with
73
The present multicenter retrospective study was performed in accordance with the ethical standards of the
74
Declaration of Helsinki, and it was approved by the ethics review board of the Hirosaki University School of
75
Medicine (authorization number: 2018–062) and all hospitals.
76
We evaluated 837 patients with metastatic hormone-naïve PC (mHNPC) who were initially treated with ADT
77
in the Michinoku Japan Urological Cancer Study Group database (n = 667) and Hirosaki University related
78
hospitals (n = 170) between January 2001 and March 2019.
79
proven prostate cancer, 2) patients with mCRPC after primary ADT, 3) patients who were treated sequential
80
life-extending therapy greater than or equal to two lines including DTX, ABI, ENZ, and CBZ, and 4) minimum
81
follow-up of 3 months after the second life-extending therapy. Exclusion criteria were 1) patients who did not
82
develop mCRPC, 2) patients who had vintage agents alone (flutamide, estramustine phosphate, and/or
83
ethinylestradiol) for mCRPC, and 3) insufficient data of baseline clinical information. Patients were classified into
84
four groups: ART followed by another ART (ART-ART), ART followed by DTX (ART-DTX), DTX followed by
85
ART (DTX-ART), and DTX followed by CBZ (DTX-CBZ).
86
Indication of life-extending therapy for CRPC in Japan
5, 6, 8, 27-29
Inclusion criteria were 1) histologically
87
Therapeutic agents of DTX, ENZ, ABI, and CBZ were approved for all patients with CRPC in February
88
2007, June 2014, September 2014, and September 2014, respectively. We can select either ART or DTX as
89
first-line therapy for mCRPC after June 2014. No limitation is available for ART-ART, ART-DTX, DTX-ART, and
90
DTX-CBZ sequences. Cabazitaxel is approved to use the post-docetaxel setting. 5
91
Evaluation of variables
92
The following variables were analyzed at diagnosis: age, year of diagnosis, Eastern Cooperative
93
Oncology Group (ECOG), Gleason score, serum prostate-specific antigen (PSA), metastatic tumor burden,
94
treatment era (ART era: after June 2014), time to CRPC, and PSA nadir. Tumor stage and grade were assigned
95
based on the 2009 TNM classification of the Union of International Cancer Control. Metastatic status was
96
evaluated via chest and body computed tomography and bone scintigraphy before initiating ADT. Bone metastatic
97
volume was evaluated by the extent of disease on bone scintigraphy. High-volume disease was defined as the
98
presence of visceral metastases and/or four more bone metastases with at least one outside of the vertebral column
99
and pelvis according to the risk criteria of Chemohormonal Therapy Versus Androgen Ablation Randomized Trial 7, 30, 31
100
for Extensive Disease in Prostate Cancer (CHAARTED) trial in PC.
Radium-223 and vintage agents were
101
not included in the mCRPC treatment sequence in this study. Progression-free survival was not evaluated because
102
there was no information in the database. Treatment sequences were evaluated from first-line to fourth-line
103
therapies.
104
Treatment protocol
105
All patients were initially treated with ADT (medical or surgical castration with or without bicalutamide).
106
Some patients received bone-modifying agents, such as bisphosphonate or denosumab, for bone pain or
107
prophylactic use against skeletal-related events based on the decision of attending physicians. The CRPC
108
definition was according to the recommendations of the Cancer Clinical Trials Working Group 2 6
32
. After the
109
diagnosis of CRPC, some patients received subsequent treatments, such as vintage anti-androgen therapy
110
(flutamide or estramustine), anti-androgen withdrawal therapy, and/or low-dose oral steroid therapy. Thereafter,
111
patients underwent chemotherapy (DTX and/or CBZ) and/or ART therapy (ABI and/or ENZ) based on their
112
attending physicians’ recommendations. We did not include radium-233 as an agent of sequential therapy in the
113
analysis. We allowed administration of any bone protective agents, radium-233 and radiation therapy for pain
114
control. The general impetus for changing CRPC therapeutic agents was disease progression including PSA
115
increase and/or radiologic progression. Imaging tests (bone scan and CT) were performed when patients
116
experienced PSA progression and/or any symptoms.
117
Outcome evaluation
118
We evaluated the treatment sequence for mCRPC in real-world practice. Treatment sequences were
119
evaluated using a Sankey diagram and classified into four groups including the combination of first- and
120
second-line therapies for mCRPC such as ART-ART, ART-DTX, DTX-ART, and DTX-CBZ groups. In addition,
121
the effect of sequence patterns on OS between the first-line ART (ART-1st) vs first-line DTX (DTX-1st), between
122
the, ART-ART sequences vs DTX-mixed sequences, and first-line ABI (ABI-1st) vs first-line ENZ (ENZ-1st)
123
were compared.
124
Statistical analysis
125
Statistical analyses were performed using GraphPad Prism 5.03 (GraphPad Software, San Diego, CA,
126
USA), BellCurve for Excel (Social Survey Research Information Co., Ltd., Tokyo, Japan), and R 3.3.2 (The R 7
127
Foundation for Statistical Computing, Vienna, Austria). Quantitative variables were expressed as mean with
128
standard deviation or median with interquartile range (IQR). Fisher’s exact test, χ2 test, Student’s t-test, or Mann–
129
Whitney U-test were used to analyze the intergroup difference. The Kruskal–Wallis test is used to compare
130
medians among four comparison groups. OS rates from initial treatment until any death were estimated using the
131
Kaplan–Meier method and compared with the log-rank test. Background adjusted inverse probability of treatment
132
weighting (IPTW) Cox regression analysis was performed to evaluate the effect of treatment patterns on OS and
133
OS after diagnosis of CRPC. Hazard ratios (HR) with 95% confidence interval (95%CI) were calculated after
134
controlling for potential confounders, including patient age, ECOG PS, initial PSA at diagnosis, Gleason score,
135
CHAARTED high-volume disease, visceral metastasis, time to mCRPC, and treatment era after the approval of
136
enzalutamide in Japan (ART era: after June 2014). Values of P < 0.05 were considered statistically significant.
137
Results
138
Baseline characteristics of participants
139
Of the 837 patients, 546 (65%) developed mCRPC. Of those, 400 patients were excluded because they
140
had vintage agents alone (flutamide, estramustine phosphate, and/or ethinylestradiol) (n = 193), non-sequential (=
141
single) life-extending therapy (n = 207). Finally, 146 patients who received sequential life-extending therapies for
142
mCRPC were included (Fig. 1). There was no significant difference between the patients with non-sequential and
143
sequential therapies in age (Fig. S1A; 70 versus 71, respectively: P = 0.620), initial PSA (Fig. S1B; 383 versus
144
324 ng/mL, respectively: P = 0.996), GS (Fig. S1C; 9 versus 9, P = 0.070), CHAARTED-high volume (Fig. S1D; 8
145
75% versus 73%, respectively: P = 0.621), PSA nadir (Fig. S1E; 0.783 versus 0.975 ng/mL, respectively: P =
146
0.193), and time to CRPC (Fig. S1F; 14 versus 14 months, respectively: P = 0.720), except for ECOG PS >1 (Fig.
147
S1G; 12% versus 2.1%, respectively: P < 0.001), and EOD (Fig. S1H; 2 versus 1, respectively: P < 0.001). Table
148
1 shows the characteristics of the study participants at the initial diagnosis of metastatic hormone-naïve PC. The
149
median age, PSA, and a follow-up period of all patients were 71 (IQR: 65–75) years, 324 (IQR: 80–1045) ng/mL,
150
and 47 (IQR:30–66) months, respectively.
151
Treatment sequence analysis
152
A total of 35 patients received ART-ART, 33 received ART-DTX, 68 received DTX-ART, and 10 received
153
DTX-CBZ sequences. There were significant difference in the median age (P = 0.037), high-volume disease (P =
154
0.003), treatment era (P = 0.002), and use of DTX and CBZ (P <0.001) The median time to CRPC and PSA nadir
155
were not significantly different among the groups (P = 0.052 and 0.475, respectively). A Sankey diagram showed
156
treatment patterns of 146 patients in our medical area (Fig. 2A). Of the 146, 68 (47%) and 78 (53%) patients
157
received first-line ART (ADT-1st) and first-line DTX (DTX-1st) therapies, respectively (Fig. 2B). The most
158
prescribed treatment sequence was DTX-ART (47%), followed by ART-ART (24%), ART-DTX (23%), and
159
DTX-CBZ (6.9%) (Fig. 2C). The use of ABI or ENZ for first-line ART therapy (n = 68) was 46 (47%) and 57
160
(53%), respectively.
161
Overall survival among the treatment patterns
162
OS calculated from the initial diagnosis reached 83, 57, 79, 37 months in the ART-ART, ART-DTX, 9
163
DTX-ART, and DTX-CBZ groups, respectively (Fig. 3A). The unadjusted OS was not significantly different
164
between the ART-ART vs ART-DTX (P = 0.057), and between the ART-ART vs DTX-ART (P = 0.365). Among
165
the sequences, no significant difference was observed in unadjusted OS between the ART-1st vs DTX-1st (Fig.
166
3B; P = 0.461), between the ART-ART (n = 35) vs DTX-mixed (n = 111) sequences (Fig. 3C; P = 0.163), and
167
between the first-line abiraterone (ABI-1st, n = 32) vs first-line enzalutamide (ENZ-1st, n=36) (Fig. 3D; P =
168
0.246).
169
The background (age, ECOG PS, initial PSA at diagnosis, Gleason score, CHAARTED high-volume
170
disease, visceral metastasis, time to mCRPC, and treatment era) adjusted IPTW Cox regression analyses showed
171
no significant difference was observed in OS between the ART-1st and DTX-1st therapies (P = 0.530, HR 0.84),
172
between the ART-ART and DTX-mixed sequences (P = 0.650, HR 0.82), and between the ABI-1st and ENZ-1st
173
therapies (P = 0.384, HR 1.58) (Fig. 4A, Table 2). Similarly, no significant difference was observed in OS after
174
diagnosis of mCRPC between the ART-1st and DTX-1st therapies (P = 0.636, HR 0.88), between the ART-ART
175
and DTX-mixed sequences (P = 0.866, HR 1.07), and between the ABI-1st and ENZ-1st therapies (P = 0.392, HR
176
1.58) (Fig. 4B, Table 2).
177
Discussion
178
In this study, we evaluated the treatment sequence for patients with mCRPC in real-world practice and
179
assessed the effect of treatment sequences on OS in patients with mCRPC. Our results showed the DTX-ART
180
sequence was the most prescribed treatment sequence. This might be due to the difficulty in continuous 10
181
administration of toxic chemotherapy for mCRPC patients even the patients receiving the first-line DTX were
182
significantly younger than that of first-line ART (68 vs 73, respectively). As the median cycle of first-line DTX
183
therapy for mCRPC was 6 (IQR: 4-11), less than 10 cycles of DTX might be optimal in the balance of effects and
184
harms. The use of ABI or ENZ for first-line CRPC therapy was similar (47 vs 53%, respectively) in our cohort. In
185
the second-line therapy, we found ART therapies (ABI: n = 46, ENZ: n = 57) was the most popular therapy for
186
mCRPC. The administration of CBZ was increased in the third- or fourth-line therapies. In this cohort, the number
187
of patients who treated third- or fourth-line therapy was 54 (36%) and 11 (7.5%), respectively. In addition, the
188
number of patients who had the opportunity to use CBZ as one of the life-extending agents was 41 (28%) patients.
189
These results suggested that it is not easy to receive all the treatable option in those patients.
190
We found the association between treatment sequence and OS was not significant in our clinical practice
191
regardless of the sequences. The first-line DTX may be more beneficial in patients with CRPC and poor
192
prognostic features such as an early progression from the initial ADT.
193
significant difference in OS and OS after CRPC diagnosis between the ART-1st vs DTX-1st groups. It was not
194
significant even we adjusted tumor volume and time to CRPC in IPTW-adjusted analysis. Despite the existence of
195
selection biases among these groups, no significant difference in OS may suggest a saturated efficacy of these
196
sequence therapies. Our observations were supported by previous studies that OS after CRPC was not prolonged
197
significantly despite the short-term efficacy in progression-free survival.
198
PROREPAIR-B cohort study evaluating treatment patterns and outcomes in 406 mCRPC patients suggested that 11
16, 19, 23, 24
19-24
However, our results showed no
More recently, the prospective
199
the choice of the first-line agent was associated with progression-free survival after the next line therapy (PFS2),
200
but not associated with OS. They found a significant difference in PFS2 between patients treated with initial
201
ABI/ENZ vs DTX (20.6 vs 16.6m; HR:0.78; P = 0.006), but not OS (31.3 vs 29.9 m; HR:1.05; P = 0.725).
202
Therefore, the OS might be similar despite treatment sequences for mCRPC. However, recent evidence suggested
203
that early administration of new agents for non-metastatic CRPC (nmCRPC) have a significant benefit on
204
prognosis.
205
antigen (PSMA) ligand has remarkable diagnostic value for staging and detecting recurrence in many studies. 36-38
206
Therefore, the new agents for nmCRPC and next-generation PET imaging make passible the treatment strategy
207
shift from mCRPC to nmCRPC.
34, 35
33
Also, next-generation positron emission tomography (PET) using prostate-specific membrane
208
There is not enough evidence to guide the decision for the appropriate use of these agents. Our finding
209
of no significant difference in OS among the treatment patterns might be one of the best results of individualized
210
sequences therapy in each patient based on general status, tolerability, economic condition, and disease
211
aggressiveness. Although several studies suggested that consecutive use of ART may be not beneficial to patients
212
with mCRPC,
213
option in selected patients such as slow progression disease. As the outcomes of the first-line therapy itself are one
214
of the biomarkers for efficacy, clinicians can modify the second-line sequence based on the outcomes of first-line
215
therapy. The other potential reason for no significant difference in OS among the treatment patterns might be a
216
cross-resistance among those agents. 39-41 Although we could not prove this hypothesis in our study, a clinical and
16, 19-24
not all patients were feasible for toxic chemotherapy and ART-ART sequences might be an
12
217
molecular marker for the aggressiveness and response to therapies might guide the decision for the appropriate
218
selection of these agents in the future. The novel therapeutic strategy is needed to improve outcomes.
219
This study had several limitations. First, our results should be interpreted with caution considering the
220
retrospective design, limited sample size, and possible selection bias. ECOG PS at the time of CRPC diagnosis
221
was not available in this study. Also, Information on local therapy for the oligometastatic disease was not
222
available in this study. Second, very few men in this cohort (n = 8, 5.5%) received the current standard of care
223
(upfront DTX or ABI) when they had hormone-naïve PCa because of long-term periods of this study. Third, the
224
exclusion of more half of men with mCRPC who received vintage agents alone or non-sequence life-extending
225
therapy (alive or dead after single therapy of ABI, ENZ or DTX) is strong selection bias in this study. However,
226
we observed no statistical difference in CRPC-free survival between the included and excluded patients and
227
confirmed the feasibility of patient selection. Fourth, we could not address the response rate and progression-free
228
survival after life-extending therapy in this study due to the lack of information in the database as the response to
229
first-line therapy for mCRPC may have a significant association with overall survival. Fifth, our results cannot be
230
generalized to non-Asian populations because of racial difference. Furthermore, limitation existed in quality of
231
life measures and side effects. Finally, we could not obtain information regarding baseline clinical data such as
232
comorbidities, and the influence of metastatic organs and PSA doubling time at the CRPC diagnosis, which are
233
significantly associated with mortality. Despite these limitations, our study revealed no significant difference in
234
OS in patients with mCRPC among the treatment sequences in real-world practice. 13
235
Conclusions
236
The most prescribed treatment sequence was DTX followed by ART. No significant difference was
237
observed in OS among the treatment sequences in real-world practice. Further study is needed to validate our
238
observation.
239
240
241
Acknowledgments We would like to thank Takuma Narita, Hirotake Kodama, Toshikazu Tanaka, Itsuto Hamano, Naoki
242
Fujita, Hiromichi Iwamura, Teppei Okamoto, Yuki Fujita, Yukie Nishizawa, and the entire staff of the Department
243
of Urology in Hirosaki University for their invaluable help with the data collection. The authors would also like to
244
thank Enago (www.enago.jp) for the English language review.
245
Funding: This work was supported by a Grant-in-Aid for Scientific Research (Grant Nos. 17K11119, 18K16681,
246
and 18K09157) from the Japan Society for the Promotion of Science.
247
Conflict of Interest: The authors declare that they have no conflict of interest.
248
Ethics statement
249
The present retrospective, multicenter study was performed in accordance with the ethical standards of the
250
Declaration of Helsinki, and it was approved by the ethics review board of the Hirosaki University School of
251
Medicine (authorization number: 2018–062) and all hospitals. Pursuant to the provisions of the ethics committee
14
252
and the ethics guidelines in Japan, written informed consent is not required for public disclosure of study
253
information in the case of a retrospective and/or observational study using materials, such as existing documents
254
(opt-out approach).
255
Authors’ Contribution
256
Kazutaka Okita: Manuscript writing, data analysis, data collection
257
S Hatakeyama: Manuscript editing, data analysis, data collection
258
S Narita, M Takahashi, T Sakurai, S Kawamura, S Hoshi, M Ishida, T Kawaguchi, S Ishidoya, J Shimoda, H Sato,
259
K Mitsuzuka: Project development, data collection
260
A Ito, N Tsuchiya, Y Arai, T Habuchi, and C Ohyama: Project development, critical review and supervision
261
15
262
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263
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with prostate cancer recurrence after surgery? Int J Urol. 2019;26:804-811.
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Conteduca V, Wetterskog D, Sharabiani MTA, et al. Androgen receptor gene status in plasma
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prostate cancer: a multi-institution correlative biomarker study. Ann Oncol. 2017;28:1508-1516.
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Sumiyoshi T, Mizuno K, Yamasaki T, et al. Clinical utility of androgen receptor gene aberrations
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in circulating cell-free DNA as a biomarker for treatment of castration-resistant prostate cancer.
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41.
Chi KN, Annala M, Sunderland K, et al. A randomized phase II cross-over study of abiraterone +
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prednisone (ABI) vs enzalutamide (ENZ) for patients (pts) with metastatic, castration-resistant
383
prostate cancer (mCRPC). Journal of Clinical Oncology. 2017;35:5002-5002.
384
385
Figure legends
386
Figure 1. Patient selection
387
Of the 837 patients, 546 (65%) developed mCRPC. Of those, 400 patients were excluded because they 22
388
had vintage agents alone (flutamide, estramustine phosphate, and/or ethinylestradiol) (n = 193), non-sequential (=
389
single) life-extending therapy (n = 207). Finally, 146 patients who received sequential life-extending therapies for
390
mCRPC were included.
391
Figure 2. Treatment sequences in real-world patients
392
A sankey diagram showed treatment patterns of 146 patients in real-world setting (A). Treatment
393
patterns in the first-, second-, third-, and fourth-line therapy was evaluated (B). The number of patients who
394
received sequential therapy such as DTX followed by ART (DTX–ART), ART followed by another ART (ART –
395
ART), ART followed by DTX (ART–DTX), and DTX followed by CBZ (DTX–CBZ) was 68 (47%), 35 (24%),
396
33 (23%), and 10 (6.9%), respectively (C).
397
Figure 3. Overall survival (OS)
398
Unadjusted OS among the treatment sequences was evaluated using Kaplan–Meier method and
399
compared with the log-rank test (A). Unadjusted OS between the ART-1st vs DTX-1st (B), between the ART-ART
400
sequence vs DTX-mixed sequence (C), and between the first-line abiraterone acetate (ABI-1st) and enzalutamide
401
(ENZ-1st) (D) was evaluated using Kaplan–Meier method and compared with the log-rank test.
402
Figure 4. IPTW-adjusted Cox regression analysis for OS and OS after mCRPC diagnosis
403
An IPTW-adjusted multivariate Cox proportional hazards regression analyses on OS (A) and OS after
404
mCRPC diagnosis (B) was performed. No significant difference was observed among the treatment sequences.
405
Variables included in the IPTW model were age, initial PSA at diagnosis, Gleason score, CHAARTED 23
406
high-volume disease, time to CRPC, and treatment era (ART era: after June 2014).
407
Figure S1. Background comparison between the non-sequential (excluded from the analysis) and sequential
408
therapies
409
As the patients with vintage agents alone were not targeted patients in this study, we evaluated baseline
410
data between the patients with non-sequential and sequential therapies. We observed no significant difference
411
between the patients with non-sequential and sequential therapies in age (A: 70 versus 71, respectively: P =
412
0.620), initial PSA (B: 383 versus 324 ng/mL, respectively: P = 0.996), GS (C: 9 versus 9, P = 0.070),
413
CHAARTED-high volume (D: 75% versus 73%, respectively: P = 0.621), PSA nadir (E: 0.783 versus 0.975
414
ng/mL, respectively: P = 0.193), and time to CRPC (F: 14 versus 14 months, respectively: P = 0.720), except for
415
ECOG PS >1 (G: 12% versus 2.1%, respectively: P < 0.001), and EOD (H: 2 versus 1, respectively: P < 0.001).
416
These results may suggest that clinical response might be similar between the groups while baseline data of
417
ECOG PS and EOD were significantly worse in the non-sequential patients.
24
Table 1 Background of patients at the diagnosis of metastatic hormone-naïve prostate cancer Treatment sequences ART-ART
ART-DTX
DTX-ART
DTX-CBZ
35
33
68
10
73 (67-77)
72 (66-77)
68 (63-75)
68 (66-73)
0.037*
ECOG PS 0/1/>1
33 / 1 / 1
30 / 2 / 1
66 / 1 / 1
9/1/0
0.400
Initial PSA (IQR)
181 (53-2828)
127 (43-478)
493 (119-1368)
256 (10-937)
0.087*
9 (8-9)
9 (8-10)
9 (9-9)
9 (9-9)
0.575*
32 (91%)
18 (55%)
47 (69%)
9 (90%)
0.003
5 (14%)
3 (9.1%)
8 (12%)
3 (30%)
0.346
1.2 (0.17-10)
0.96 (0.15-4.1)
0.97 (0.15-4.5)
0.94 (0.15-3.4)
0.475*
Number
P value
of
patients Age,
median
(IQR)
Gleason
score
(IQR) High-volume disease, n (%) Visceral metastasis PSA kinetics PSA nadir,
ng/dL Time to CRPC, median
21 (9-40)
11 (8-16)
15 (9-25)
10 (6-20)
0.052*
8 (23%)
7 (21%)
36 (53%)
2 (20%)
0.002
2 (2-3)
2 (2-3)
2 (2-3)
2 (2-2)
0.194
6 (17%)
26 (79%)
68 (100%)
10 (100%)
<0.001
4 (11%)
10 (30%)
17 (25%)
10 (100%)
<0.001
56 (37-77)
38 (26-56)
46 (33-79)
33 (25-59)
13 (37%)
12 (36%)
30 (44%)
7 (70%)
(IQR) CRPC diagnosis in ART era Number of sequence therapy Use of DTX, n (%) Use of CBZ, n (%) Median follow-up, months (IQR) Deceased, n (%) *, Kruskal–Wallis test ART, androgen receptor-targeted agents; CBZ, cabazitaxel; CRPC, castration-resistant prostate cancer;
DTX, docetaxel; CBZ, cabazitaxel; IQR, interquartile range; PSA, prostate-specific antigen
Table 2
IPTW-adjusted Cox regression analysis for OS and OS after mCRPC diagnosis
OS
HR
DTX-1st
1 (ref)
ART-1st
0.84
DXT-mixed sequences ART-ART sequences
95%CI
P value
0.475-1.44
0.530
0.35-1.94
0.650
1 (ref) 0.82
ABI-1st
1 (ref)
ENZ-1st
1.58
0.56-4.41
0.384
OS after mCRPC diagnosis
HR
95%CI
P value
0.52-1.50
0.636
0.51-2.25
0.866
DTX-1st
1 (ref)
ART-1st
0.88
DXT-mixed sequences ART-ART sequences
1 (ref) 1.07
ABI-1st
1 (ref)
ENZ-1st
1.58
0,56-4.46
0.392
IPTW, inverse probability of treatment weighting; ART, androgen receptor-targeted agents; CBZ, cabazitaxel; DTX, docetaxel; CBZ, cabazitaxel; ABI, abiraterone acetate; ENZ, enzalutamide
Fig. 1
mHNPC n=837 CRPC n=546
Vintage agents alone n=193
Non-sequential therapy n=207 (excluded from this study)
DTX, ABI, or ENZ n=353
Sequential therapy n=146 (included in this study)
Fig. 2
B
Treatment paterns
A
7%
100
2nd line
3rd line
4th line
% of patients
1st line
n=78 (53%)
ART DTX CBZ
35%
23%
53%
100%
18%
50
47%
70%
47%
0 1st line
2nd line
3rd line
4th line
Treatment line
C
Treatment sequence n=146 50
(1st → 2nd-line)
40
47%
30
24%
23%
20
6.9%
10
C B Z → TX D
R T→ D TX A
A R T R T→ A
→
A R T
0
TX
n=68 (47%)
% of patients
CRPC
D
mCRPC n=146
ART → ART → DTX → DTX →
100
Percent survival
B
OS (Unadjusted n=146)
80 60
ART n=35 DTX n=33 ART n=68 CBZ n=10
40 20
100
P=0.057 P=0.365
OS (Unadjusted n=146)
Percent survival
A
0
ART-1st n=68 DTX-1st n=78
80
P=0.461 60 40 20 0
0
12 24 36 48 60 72 84 96 108 120
0
Months
C
D OS (Unadjusted n=68)
ART-ART seq. n=35 DTX-mixed seq. n=111 P=0.163
60 40 20 0 0
12 24 36 48 60 72 84 96 108 120
Months
100
Percent survival
80
12 24 36 48 60 72 84 96 108 120
Months
OS (Unadjusted n=146) 100
Percent survival
Fig. 3
ABI-1st n=32 ENZ-1st n=36 P=0.246
80 60 40 20 0 0
12 24 36 48 60 72 84 96 108 120
Months
Fig. 4
A
IPTW-adjusted Cox regression model for OS DTX-1st
B
IPTW-adjusted Cox regression model for OS after CRPC diagnosis DTX-1st
ref.
ref.
0.84
0.88
ART-1st
ART-1st
ref.
DTX-mixed
ref.
DTX-mixed
0.82
1.07
ART-ART
ART-ART
ref.
ABI-1st
ref.
ABI-1st
1.58
1.58
ENZ-1st
ENZ-1st 0.3
1.0
HR
3.2
10.0
0.3
1.0
HR
3.2
10.0
Fig. S1
11
P=0.996
10000
years
ng/mL
80
1000 100
60 10 1
40 n=207
E
F
PSA nadir
100
P=0.193 Percent survival
ng/mL
1 0.1 0.01
0.001 non-sequencing Sequencing n=207
n=146
9 8 7
non-sequencing n=207 Sequencing n=146 Median: 14 vs 14 mo HR 0.96 (95%CI 0.78-1.19) P=0.720
40
40
0 non-sequencing Sequencing n=207
n=146
ECOG PS >1 15
60
60
20
n=207
G
P=0.621
80
6
n=146
CRPC-free survival
80
100
non-sequencing Sequencing
100
10
CHAARTED-high vol.
5 n=207
n=146
P=0.070
10
non-sequencing Sequencing
non-sequencing Sequencing
D
GS
% of patients
100000
P=0.620
H
EOD 5
P<0.001
n=146
P<0.001
4
% of patients
100
C
Initial PSA
score (0-4)
B
Age
Gleason score (6-10)
A
10
5
3 2 1
20
0
0
0 0
50
Months
100
non-sequencing Sequencing n=207
n=146
non-sequencing Sequencing n=207
n=146