ABSTRACT
Background
Docetaxel (DTX) is commonly employed in patients with castration‐resistant prostate cancer (CRPC) following failure of androgen receptor signaling inhibitors (ARSIs). However, the impact of prior ARSI treatment on the efficacy of subsequent DTX therapy remains unclear. This study aimed to compare oncological outcomes between enzalutamide (ENZ)–DTX and abiraterone acetate plus prednisolone (ABI)–DTX sequential treatment strategies in patients with CRPC.
Methods
The ENABLE study for PCa was an investigator‐initiated, multicenter, randomized controlled trial conducted in Japan to compare ENZ and ABI. This subanalysis evaluated the efficacy of subsequent DTX therapy in patients who had received either ENZ or ABI.
Results
Between February 2015 and July 2019, 203 patients were enrolled, of whom 184 were randomized to receive ENZ or ABI (92 per arm). Among them, 20 and 21 patients subsequently initiated DTX therapy following ENZ and ABI, respectively. Median prostate cancer‐specific survival (PCSS) in the ENZ–DTX and ABI–DTX groups was 22.7 and 32.1 months, respectively (p = 0.1724). Median PCSS from the initiation of DTX was 16.1 months in the ENZ–DTX group and 25.3 months in the ABI–DTX group (p = 0.0966). In the overall cohort (n = 41), patients who received additional ARSIs after ARSI–DTX therapy had significantly longer PCSS from the initiation of DTX compared with those who did not (median 21.6 vs. 13.8 months, p = 0.0157).
Conclusions
ENZ–DTX and ABI–DTX sequential therapies demonstrated comparable survival outcomes in patients with CRPC. Notably, the administration of additional ARSIs following ARSI–DTX therapy may confer a survival benefit, suggesting a potential role for continued ARSI use in this treatment sequence.
Trial Registration
The trial was registered with the University Hospital Medical Information Network (UMIN) Center under the identifier UMIN000015529 on November 1, 2014
Keywords: abiraterone, docetaxel, enzalutamide, sequential therapy, survival
1. Introduction
Among male cancers, prostate cancer is diagnosed most often and is the second major cause of cancer‐related deaths in the United States [1]. Prostate cancer rates have been on a steady upward trend in Japan [2]. In metastatic prostate cancer, androgen deprivation therapy (ADT) that targets androgen receptor (AR) activity is the mainstay of therapy, but the majority of tumors progress to castration resistance (CRPC) within a few years [3, 4, 5, 6, 7]. Recent clinical trials have demonstrated that AR signaling inhibitors (ARSIs) can improve radiographic progression‐free survival (rPFS) and overall survival (OS) in patients with metastatic CRPC [8, 9]. Enzalutamide (ENZ) functions as an antagonist at the AR by binding directly to its ligand‐binding domain [9], whereas abiraterone acetate with prednisolone (ABI) reduces androgen production through inhibition of CYP17A1, a key enzyme in steroidogenesis [10]. Since both ARSIs act on the same signaling cascade, the possibility of shared resistance mechanisms has become a clinical concern. Therefore, chemotherapy—based on a distinct anticancer mechanism—is generally recommended as a sequential treatment [11]. Our primary publication on the ENABLE study showed no meaningful distinctions in the specified survival endpoints between patients treated with ENZ and those receiving ABI [12]. However, it remains unclear how these ARSIs influence the efficacy of subsequent chemotherapy—specifically docetaxel (DTX)—in patients with CRPC. Therefore, we conducted a subanalysis of the ENABLE study for PCa to compare oncological outcomes between ENZ–DTX and ABI–DTX sequential therapies.
2. Methods
2.1. Study Design
The ENABLE study for PCa was designed as an investigator‐initiated, multicenter randomized controlled trial that evaluated the comparative effectiveness of ENZ and ABI in patients with CRPC. Detailed descriptions of the study design, eligibility criteria, and treatment procedures have been documented extensively in our earlier publications [12, 13, 14, 15, 16]. Briefly, randomization was performed centrally at the Innovative Clinical Research Center of Kanazawa University (iCREK), assigning participants in equal proportions to receive either ENZ (160 mg once daily; four 40‐mg tablets) or ABI (1000 mg once daily; four 250‐mg tablets) together with prednisolone (10 mg/day administered as 5 mg twice daily). Following discontinuation of the allocated study drug, subsequent therapeutic choices—including systemic treatments—were left entirely to the discretion of the attending physicians, as the protocol did not impose restrictions on posttrial management.
This investigation adhered to the Ethical Guidelines for Medical and Health Research Involving Human Subjects and was carried out in line with the principles outlined in the Declaration of Helsinki (1975, revised in 2013). Before enrollment, all individuals provided written informed consent, after which they underwent the prostate cancer‐related assessments and treatments specified in the study framework. The study protocol was first reviewed and approved by the Medical Ethics Committee of Kanazawa University in Kanazawa, Japan. Subsequent approval was then obtained from the ethics committees of the additional 15 participating institutions.
2.2. Definition of Endpoints
Time to PSA progression (TTPP) was evaluated according to the recommendations of the Prostate Cancer Working Group 2 (PCWG2) [4]. For participants who demonstrated a reduction in PSA levels at week 13, progression was identified when the PSA value showed a confirmed rise of at least 25% and ≥ 2 ng/mL above the nadir. Confirmation required a second consecutive measurement obtained no earlier than 3 weeks after the initial increase. For individuals who did not experience a PSA decline at week 13, progression was determined using the same thresholds—an increase of ≥ 25% and ≥ 2 ng/mL—calculated relative to the baseline value, again requiring verification by a subsequent measurement after a minimum interval of 3 weeks. If treatment was discontinued before week 13 without any PSA reduction, the discontinuation date was assigned as the PSA progression date. TTPP was defined as the duration between randomization and the first PSA progression event that met the above confirmation criteria.
The study endpoints were defined as follows. A PSA response was recorded when the serum PSA level showed a reduction of at least 50% from baseline. OS was measured from the date of randomization until death from any cause. rPFS was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for soft‐tissue disease assessed by computed tomography or magnetic resonance imaging, and the PCWG2 criteria for bone lesions assessed by bone scintigraphy. Earlier progression‐free survival (earlier PFS) was determined by identifying whichever occurred first—PSA progression or radiographic progression. Docetaxel‐free survival (DFS) was defined as the interval between randomization and the initiation of docetaxel therapy. Prostate cancer‐specific survival (PCSS) was calculated from randomization to death attributable to prostate cancer. Safety assessments were based on the incidence and severity of adverse events, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/About.html).
2.3. Statistical Analyses
Details of the statistical methodology used in this study have been described extensively in our earlier publication [12]. In the present analysis, baseline characteristics were compared between the ENZ–DTX and ABI–DTX groups. Continuous variables were examined using unpaired t‐tests, whereas categorical parameters—including performance status and metastatic distribution—were evaluated with Fisher's exact test. Gleason score distributions were assessed using a chi‐square test for trend. Survival endpoints were estimated using the Kaplan–Meier method, and differences between treatment sequences were tested with the log‐rank procedure. PSA response rates were analyzed with Fisher's exact test. Adverse events (AEs) associated with ARSI therapy were evaluated in all treated patients, and the frequencies of overall AEs as well as those of grade ≥ 3 severity were compared between groups using Fisher's exact test. All statistical tests were two‐sided, and a p < 0.05 was considered indicative of significance.
2.4. Statement on the Use of Artificial Intelligence Tools
Microsoft Copilot was utilized solely for linguistic refinement and for improving the readability of the manuscript. The tool was not involved in generating scientific ideas, analyzing data, or drawing any study‐related conclusions. All aspects of data interpretation and analytical decision‐making were performed independently by the authors.
3. Results
Between February 2015 and July 2019, 203 individuals were enrolled in the study. Of these, 184 participants proceeded to randomization and subsequently received protocol‐assigned treatment, with equal allocation to the ENZ and ABI groups (92 patients in each arm). The number and types of second‐line therapies were detailed in the previous report [12]. Among these, 20 and 21 patients actually received DTX therapy following ENZ and ABI treatment, respectively.
Table 1 summarizes the baseline characteristics of the patients. No significant differences were observed between the ENZ–DTX and ABI–DTX groups in any baseline characteristics.
TABLE 1.
Baseline characteristics at randomization.
| Total (N = 41) | ENZ–DTX (n = 20) | ABI–DTX (n = 21) | P | |
|---|---|---|---|---|
| Age (years) | 72 (46–88) | 72 (46–85) | 72 (58–88) | 0.5735 |
| Performance status | > 0.9999 | |||
| 0 | 33 (80%) | 16 (80%) | 17 (81%) | |
| 1 | 8 (20%) | 4 (20%) | 4 (19%) | |
| Gleason score | 0.3428 | |||
| 5, 6 | 0 | 0 | 0 | |
| 7 | 4 (10%) | 1 (5%) | 3 (14%) | |
| 8 | 6 (15%) | 2 (10%) | 4 (19%) | |
| 9 | 23 (56%) | 14 (70%) | 9 (43%) | |
| 10 | 7 (17%) | 3 (15%) | 4 (19%) | |
| Not available | 1 (2%) | 0 | 1 (5%) | |
| Local treatment a | > 0.9999 | |||
| Prostatectomy | 1 (2%) | 0 | 1 (5%) | |
| Irradiation b | 12 (29%) | 6 (30%) | 6 (29%) | |
| None | 27 (66%) | 14 (70%) | 13 (62%) | |
| Regional lymph node metastasis | > 0.9999 | |||
| Yes | 22 (54%) | 11 (55%) | 11 (52%) | |
| No | 19 (46%) | 9 (45%) | 10 (48%) | |
| Distant metastasis | 0.4537 | |||
| Bone | 28 (68%) | 13 (65%) | 15 (71%) | |
| Lymph node | 8 (20%) | 5 (25%) | 3 (14%) | |
| Lung | 6 (15%) | 2 (10%) | 4 (19%) | |
| Liver | 2 (5%) | 1 (5%) | 1 (5%) | |
| Others | 1 (2%) | 0 | 1 (5%) | |
| No | 9 (22%) | 3 (15%) | 6 (29%) | |
| No. of previous systemic therapy c | 3 (1–5) | 3 (1–5) | 2.5 (1–4) | 0.8707 |
| Prostate specific antigen (ng/mL) | ||||
| At diagnosis | 112.4 (0.9–4730) | 124.2 (5.4–4730) | 67.9 (0.9–1899) | 0.1243 |
| At nadir before registration d | 0.811 (0.003–185.1) | 0.452 (0.003–185.1) | 0.882 (0.022–28.3) | 0.3345 |
| At registration | 13.2 (2.0–241.5) | 12.3 (2.0–241.5) | 14.8 (2.4–67.2) | 0.3386 |
| Time from diagnosis of prostate cancer to randomization (months) | 18.3 (3.0–177) | 22.7 (3.0–148) | 17.9 (4.5–177) | 0.5393 |
| Time from castration resistance to randomization (months) e | 1.1 (0.0–37.4) | 0.6 (0.0–11.4) | 1.3 (0.0–37.4) | 0.2414 |
Note: Data are median (range), n (%).
Abbreviations: ABI, abiraterone plus prednisolone; ENZ, enzalutamide.
Data of 1 in ABI–DTX is not available.
Including high and low dose rate brachytherapy, and external beam radiation therapy for primary site.
Medical or surgical castration is counted as 1, and data of 1 in ABI–DTX is not available.
Data of 1 in ENZ–DTX and 4 in ABI–DTX I are not available.
Data of 2 in ENZ–DTX and 2 in ABI–DTX are not available.
In the analysis of ARSI treatment effect before DTX induction, there was no significant difference between groups in terms of PSA response rate (60% and 48%, respectively; p = 0.5359, Figure 1). Median TTPP and rPFS in the ENZ–DTX and ABI–DTX groups were 7.1 and 4.1 months, and 12.0 and 7.0 months, respectively (p = 0.1388 and p = 0.1408, Figure 2A,B). Median earlier PFS in the ENZ–DTX and ABI–DTX groups was 6.1 and 3.7 months, respectively (p = 0.2992, Figure 2C). Median DFS in the ENZ–DTX and ABI–DTX groups was 6.8 and 7.4 months, respectively (p = 0.6789, Figure 2D). During ARSI treatment, any‐grade and grade ≥ 3 AEs were observed in 13 (65%) and 0 patients in the ENZ–DTX group, and in 12 (57%) and 2 (10%) patients in the ABI–DTX group, respectively. There were no significant differences in the incidence of any‐grade or grade ≥ 3 AEs between the groups (Table 2).
FIGURE 1.
Waterfall plot of prostate‐specific antigen (PSA) response, defined as a ≥ 50% decline from baseline, in 20 patients receiving enzalutamide–docetaxel sequential therapy (ENZ–DTX) and 20 patients receiving abiraterone–docetaxel sequential therapy (ABI–DTX). No significant difference in PSA response rate was observed between the two groups (60% vs. 48%, p = 0.5359). Data for one patient in the ABI‐DTX group were not available.
FIGURE 2.
Comparisons of survival endpoints between the enzalutamide–docetaxel sequential therapy (ENZ–DTX) and abiraterone–docetaxel sequential therapy (ABI–DTX) groups during study treatment. (A) Time to prostate‐specific antigen (PSA) progression (TTPP, p = 0.1388). (B) Radiographic progression‐free survival (rPFS, p = 0.1408). (C) Earlier progression‐free survival (PFS, p = 0.2992). (D) Docetaxel‐free survival (DFS, p = 0.6789).
TABLE 2.
Adverse events during study treatment.
| ENZ–DTX (n = 20) | ABI–DTX (n = 21) | P | |
|---|---|---|---|
| Any grade | 13 (65%) | 12 (57%) | 0.7513 |
| Grade ≥ 3 | 0 | 2 (10%) | 0.4878 |
Note: Data are n (%).
Abbreviations: ABI, abiraterone plus prednisolone; DTX, docetaxel; ENZ, enzalutamide.
Median OS and PCSS in the ENZ–DTX and ABI–DTX groups were 22.7 and 32.1 months, and 22.7 and 32.1 months, respectively (p = 0.2247 and p = 0.1724, Figure 3A,B). Median OS and PCSS from the initiation of DTX treatment in the ENZ–DTX and ABI–DTX groups were 16.1 and 21.6 months, and 16.1 and 25.3 months, respectively (p = 0.1268 and p = 0.0966, Figure 3C,D). As systemic therapies after DTX treatment for prostate cancer, cabazitaxel was the most frequently used agent in both the ENZ–DTX and ABI–DTX groups, administered to 8 (40%) and 10 (48%) patients, respectively (Table 3). Unused ARSIs, including flutamide, were the second most frequently used agents, administered to 4 (20%) and 8 (38%) patients in the ENZ–DTX and ABI–DTX groups, respectively. One‐fourth of patients in both groups received DTX only.
FIGURE 3.
Comparisons of survival endpoints between the enzalutamide–docetaxel sequential therapy (ENZ–DTX) and abiraterone–docetaxel sequential therapy (ABI‐DTX) groups. (A) Overall survival (OS, p = 0.2247). (B) Prostate cancer‐specific survival (PCSS, p = 0.1724). (C) OS from the initiation of DTX therapy (p = 0.1268). (D) PCSS from the initiation of DTX therapy (p = 0.0966).
TABLE 3.
Systemic therapies after DTX for prostate cancer.
| ENZ–DTX (n = 20) | ABI–DTX (n = 21) | |
|---|---|---|
| Cabazitaxel | 8 (40%) | 10 (48%) |
| Counterpart (ABI or ENZ) | 3 (15%) | 8 (38%) |
| Flutamide | 1 (5%) | 0% |
| Estradiol | 3 (15%) | 5 (24%) |
| Radium‐223 | 2 (10%) | 2 (10%) |
| Dexamethasone | 0 | 1 (5%) |
| DTX only | 5 (25%) | 5 (24%) |
Abbreviations: ABI, abiraterone plus prednisolone; DTX, docetaxel; ENZ, enzalutamide.
Since PCSS from the initiation of DTX treatment appeared marginally better in the ABI–DTX group compared to the ENZ–DTX group (p = 0.0966, Figure 3D), we further investigated systemic therapies administered after DTX, focusing on ARSIs, which showed a large difference in usage between the groups. In the ABI–DTX group, median PCSS and PCSS from the initiation of DTX treatment in patients who received ENZ or not were 37.4 and 23.5 months, and 25.3 and 13.4 months, respectively (p = 0.4386 and p = 0.0969, Figure 4A,B). In the ENZ–DTX group, median PCSS and PCSS from the initiation of DTX treatment in patients who received ABI or flutamide, or not were 28.7 and 22.7 months, and 18.8 and 13.8 months, respectively (p = 0.2156 and p = 0.1100, Figure S1). To exclude the potential influence of flutamide, we further analyzed patients who had received ABI alone. Median PCSS and PCSS from the initiation of DTX treatment in patients who received ABI, or not were 25.4 and 22.7 months, and 17.5 and 15.7 months, respectively (p = 0.7953 and p = 0.6952, Figure S2). We next examined the impact of ARSI use on PCSS in the entire cohort. Baseline characteristics of patients who did or did not receive ARSIs after DTX are presented in Table S1. Median PCSS in patients who received ARSIs or did not was 33.7 and 22.7 months, respectively (p = 0.1005, Figure 4C). However, there was a significant difference in PCSS from the initiation of DTX treatment between patients who received ARSIs or not (median 21.6 vs. 13.8 months, p = 0.0157, Figure 4D). To exclude the potential influence of flutamide, we further analyzed patients who had received ABI or ENZ alone. Baseline characteristics of patients who did or did not receive ABI or ENZ after DTX are presented in Table S2 Median PCSS in patients who received ABI or ENZ, or not was 30.5 and 23.3 months, respectively (p = 0.2871, Figure S3A). However, there was a significant difference in PCSS from the initiation of DTX treatment between patients who received ABI or ENZ, or not (median 25.3 vs. 13.8 months, p = 0.0481, Figure S3B).
FIGURE 4.
Comparisons of prostate cancer–specific survival (PCSS) between patients who received additional androgen receptor signaling inhibitors (ARSIs) and those who did not. (A) PCSS in the abiraterone–docetaxel sequential therapy (ABI–DTX) group with or without additional enzalutamide (ENZ) (p = 0.4386). (B) PCSS from the initiation of DTX in the ABI–DTX group with or without additional ENZ (p = 0.0969). (C) PCSS in the entire cohort with or without additional ARSIs (p = 0.1005). (D) PCSS from the initiation of DTX in the entire cohort with or without additional ARSIs (p = 0.0157).
4. Discussion
Previously, we reported that there were no significant differences in TTPP or other survival endpoints between the ENZ and ABI arms according to the intention‐to‐treat analysis of the ENABLE study for PCa [12]. Furthermore, we demonstrated that ENZ and ABI exhibit comparable efficacy and safety in both younger and older patients, and that dose reduction of ABI was associated with better TTPP compared with the standard dose [15, 16]. In the present study, we investigated which treatment sequence yields better outcomes when DTX is administered following ENZ or ABI, as no optimal sequential treatment strategy has yet been established for patients with CRPC.
Our data clearly showed that there were no differences in OS or PCSS between the ENZ–DTX and ABI–DTX groups. Prior to the initiation of DTX, no significant differences were observed in PSA response, TTPP, rPFS, earlier PFS, DFS, or baseline characteristics between the groups, suggesting that the effect of DTX is independent of prior treatment and exerts a similar impact on survival outcomes. Our results are consistent with previous studies comparing ENZ and ABI in CRPC patients, which showed that OS—the strongest endpoint—was similar between ENZ and ABI, even though smaller differences were observed in other, less robust endpoints. The optimal sequencing of ENZ and ABI was investigated in Canada, where ENZ following ABI was suggested as a more effective treatment strategy for metastatic CRPC, as the time to second PSA progression was longer in patients treated with ABI followed by ENZ compared with those treated with ENZ followed by ABI. However, no significant difference in OS was observed [17]. A retrospective multicenter cohort study involving 5779 patients with CRPC who initiated treatment with either ENZ or ABI demonstrated that ENZ was associated with statistically significant, albeit modest, improvements in OS compared with ABI, with restricted mean survival times of 24.3 and 23.4 months, respectively, at 4 years [18]. Hence, our data suggest that prior ARSI with either ENZ or ABI does not affect OS or PCSS when DTX is used sequentially.
The data of interest were that the OS and PCSS curves in the ABI–DTX group exhibited longer tails than those in the ENZ–DTX group, a pattern that emerged from the initiation of DTX, although no statistically significant differences were observed. Systemic therapies administered after DTX for prostate cancer differed between the ENZ–DTX and ABI–DTX groups, with ARSIs showing the greatest variation in usage. Therefore, we further investigated the impact of additional ARSIs administered after DTX on survival outcomes. As shown in Figure 4A,B, the addition of ENZ to the ABI–DTX group did not improve PCSS, although PCSS from the initiation of DTX remained marginally different. We subsequently examined the impact of ARSI use on PCSS in the entire cohort and found significantly better PCSS from the initiation of DTX in patients who received additional ARSIs compared with those who did not. These results remained consistent even after excluding flutamide from the ARSI category. Differences in the number of patients who received ARSI after DTX may have contributed to the favorable OS and PCSS observed in the ABI–DTX group. Tagawa et al. reported that patients treated with ENZ alone had a 29% lower risk of mortality compared with those treated with ABI alone (median OS, 25.9 vs. 17.2 months, p < 0.0001) [19]. They also showed that patients who received ENZ followed by chemotherapy—including DTX, cabazitaxel, or mitoxantrone hydrochloride—had a nonsignificant trend toward longer OS compared with those who received ABI followed by chemotherapy (median OS, 26.2 vs. 23.4 months, p = 0.2341) [19]. However, there are no available data regarding the impact of administering an additional ARSI after DTX on survival outcomes. This lack of evidence may be attributable to the fact that the use of a second ARSI after an ARSI–chemotherapy sequence is not common in clinical practice. Our findings suggest that different ARSI treatments following ARSI–DTX sequential therapy may still influence survival outcomes in CRPC patients.
However, these results may not align with the currently recommended treatment sequence of ARSIs followed by DTX, as ARSIs target the same pathway and concerns regarding cross‐resistance have been raised. In general, the efficacy of ARSIs decreases in patients who have previously received DTX [5, 18]. Nevertheless, the present study suggests that ARSIs may retain some efficacy in DTX‐resistant CRPC patients. This effect may be partially explained by the fact that ENZ and ABI were initially approved for CRPC as post‐DTX therapies that demonstrated a survival benefit [20, 21]. In addition, the efficacy of ENZ in patients previously treated with ABI has been reported [22]. Although the proportion of patients was relatively small, the effect of ABI on PSA decline in those who had received ENZ was also observed [23]. The “seesaw theory” regarding alternate therapy between ARSIs and DTX has been proposed previously. Briefly, the effect of DTX is restrictive for hormone‐hypersensitive prostate cancer. In contrast, ARSIs reduce the number of hormone‐hypersensitive prostate cancer cells but may be ineffective against androgen‐independent prostate cancer cells. When DTX is subsequently administered, the number of androgen‐independent prostate cancer cells decreases, but surviving hormone‐hypersensitive prostate cancer cells may increase again [24]. These findings suggest that ARSIs may retain therapeutic activity following ARSI–DTX sequential therapy and thus may be reconsidered as a potential treatment option in this setting.
The present study has several limitations. First, the sample size was small, which became particularly critical when the 41 patients who received sequential DTX were further divided into the ENZ–DTX and ABI–DTX groups. To obtain reliable statistical results, a larger number of patients is absolutely necessary; therefore, our findings should not be used as a clinical decision‐making tool. Second, our records included information on PSA response, radiographic changes, and AEs during ARSI treatment, but not after the initiation of DTX. Importantly, because the study did not collect the time of DTX failure, the duration of DTX response could not be determined. As a result, the true efficacy of ARSI administration after DTX may not have been fully assessed. Third, the DTX treatment regimen depended on the discretion of the treating physician, and modifications to DTX therapy may have influenced patient outcomes [25]. Moreover, accurate survival time after the initiation of additional ARSIs following ARSI–DTX was not obtained, and subsequent treatments may have affected patient survival. Fourth, the study included only Japanese patients, and individuals from other racial backgrounds were not represented. In addition, there are potential biases related to dose selection, drug discontinuation, and interpretation of treatment course data, as the study was conducted in an open‐label design. Finally, except for certain predefined conditions, patients with comorbidities were allowed. These limitations may reduce the strength of the evidence regarding oncological outcomes and safety analyses.
The ENABLE study for PCa compared the efficacy of ENZ–DTX and ABI–DTX treatment sequences. Both groups demonstrated similar efficacy in terms of OS and PCSS. The use of additional ARSIs after ARSI–DTX sequential therapy may represent a potential treatment option, as prolonged PCSS from the initiation of DTX was observed.
Author Contributions
Manabu Kamiyama: investigation, writing – original draft. Yuki Kato: investigation. Takashi Shima: investigation. Takahiko Mitsui: supervision, investigation, writing – original draft. Kouji Izumi: conceptualization, methodology, software, investigation, validation, formal analysis, supervision, funding acquisition, visualization, project administration, resources, writing – review and editing, writing – original draft. Takashi Fukagai: investigation. Shogo Inoue: investigation. Seiji Hoshi: investigation. Ippei Chikazawa: investigation. Koji Mita: investigation. Shuichi Tatarano: investigation. Yuko Yoshio: investigation. Shizuko Takahara: data curation, investigation. Atsushi Mizokami: investigation, supervision. Kazuyoshi Shigehara: investigation. Noriyasu Kawai: investigation. Kohei Hashimoto: investigation. Takehiko Okamura: investigation. Nobumichi Tanaka: investigation.
Funding
This work was supported by the Japanese Foundation for Multidisciplinary Treatment of Cancer.
Ethics Statement
The current study was approved by the Medical Ethics Committee of Kanazawa University, Kanazawa, Japan (reference number: 2014–031).
Consent
Written informed consent was obtained from all participants prior to study enrollment, after which all examinations and treatments related to prostate cancer were administered.
Conflicts of Interest
Nobumichi Tanaka is affiliated with an endowed chair funded by Nihon Medi‐Physics Co. Takahiko Mitsui and Takashi Fukagai are the Editorial Board members of the International Journal of Urology and the coauthors of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication. Kohei Hashimoto, Managing Editor of the International Journal of Urology, is a coauthor of this article, and Naoya Masumori, the Editor‐in‐Chief, is affiliated with an institute participating in the ENABLE study. Both individuals were excluded from all editorial decisions regarding the acceptance and publication of this manuscript.
Supporting information
Figure S1: Prostate cancer‐specific survivals in the ENZ–DTX group with or without additional ABI or flutamide.
Figure S2: Prostate cancer‐specific survivals in the ENZ–DTX group with or without additional ABI.
Figure S3: Prostate cancer‐specific survivals in overall patients with or without additional ABI or ENZ.
Table S1: Baseline characteristics (ARSI rechallenge vs. non‐rechallenge).
Table S2: Baseline characteristics (ABI or ENZ rechallenge vs. non‐rechallenge).
Acknowledgments
ENABLE study for PCa has received external funding from the Japanese Foundation for Multidisciplinary Treatment of Cancer. This funding is mainly used for software for patient randomization. This foundation does not affect the study design, analysis and interpretation of data, and the writing of the manuscript.
Data Availability Statement
Research data are not shared.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1: Prostate cancer‐specific survivals in the ENZ–DTX group with or without additional ABI or flutamide.
Figure S2: Prostate cancer‐specific survivals in the ENZ–DTX group with or without additional ABI.
Figure S3: Prostate cancer‐specific survivals in overall patients with or without additional ABI or ENZ.
Table S1: Baseline characteristics (ARSI rechallenge vs. non‐rechallenge).
Table S2: Baseline characteristics (ABI or ENZ rechallenge vs. non‐rechallenge).
Data Availability Statement
Research data are not shared.