Abstract

Objective

Abiraterone acetate and docetaxel are promising treatment options for metastatic castration-resistant prostate cancer patients. However, the optimal sequencing of these agents is unclear, and no previous reports discuss Japanese metastatic castration-resistant prostate cancer patients. The purpose of this analysis is to reveal the outcomes of Japanese metastatic castration-resistant prostate cancer patients treated with abiraterone acetate followed by docetaxel.

Methods

We retrospectively reviewed Japanese Phase 1 and Phase 2 trials of metastatic castration-resistant prostate cancer patients treated with abiraterone acetate until disease progression and subsequently treated with docetaxel. The primary outcome measure was the rates of prostate-specific antigen declines ≧30 and ≧50%, respectively, with docetaxel. Secondary outcome measures included progression-free survival with docetaxel, and overall survival after initiation of abiraterone acetate and docetaxel. We performed correlation analysis between previous prostate-specific antigen response to abiraterone acetate and subsequent prostate-specific antigen response to docetaxel.

Results

We identified 15 patients had experienced disease progression with abiraterone acetate and subsequently were treated with docetaxel. Prostate-specific antigen declines ≧30 and ≧50% with docetaxel were observed in five patients (33%) and two patients (13%), respectively. The median progression-free survival with docetaxel was 3.7 months (95% confidence interval: 2.9–4.6). The median overall survival from initiation of docetaxel and abiraterone acetate were 14.4 months (95% confidence interval: 6.3–22.4), and 25.7 months (95% confidence interval: 20.1–30.7), respectively. No significant correlation was observed between these prostate-specific antigen responses (Pearson r = 0.206, P = 0.46).

Conclusion

The efficacy of docetaxel in Japanese mCRPC patients that was resistant to abiraterone acetate was modest. The prostate-specific antigen response to previous abiraterone acetate could not predict the efficacy of subsequent docetaxel. Larger prospective trials are needed to validate these findings.

Introduction

The primary treatment for patients with metastatic prostate cancer is still androgen deprivation therapy such as, surgical or medical castration with or without anti-androgen administration, and this treatment was initially responded very well (1,2). However, unfortunately, almost all patients experience disease progression within several years despite obtaining castrate testosterone levels, at which point they are described as having metastatic castration-resistant prostate cancer (mCRPC) (3). mCRPC still remains an incurable and life-threating disease. In Japan, >11 000 patients die annually due to mCRPC, and this number is still increasing.

Until recently, docetaxel was the only approved agent with survival benefit for patients with mCRPC. However, more recently, several new agents have demonstrated improvement of overall survival (OS) in randomized Phase 3 trials, such as abiraterone acetate (AA) (4,5), enzalutamide (6,7), cabazitaxel (8), radium-223 (9) and sipuleucel-T (10). In Japan, AA, enzalutamide and cabazitaxel were approved in 2014 for patients with mCRPC, and are now gradually being introduced into daily clinical practice. Furthermore, AA and enzalutamide have demonstrated survival benefit and have been approved in not only post- but also pre-docetaxel windows. Associated with this rapid introduction of new agents, new clinical questions and dilemmas have appeared, such as the optimal sequential treatment and timing of initiation of docetaxel. Reliable evidence is lacking from head to head direct comparison or prospective sequencing trials among these agents.

Several in vivo and in vitro investigations have suggested a potential for cross-resistance between AA and docetaxel (11,12). In fact, an indirect comparison between the COU-AA 301 and 302 trials showed that prostate-specific antigen (PSA) response to AA was lower in post-docetaxel patients than pre-docetaxel patients (4,5). Furthermore, a small retrospective study in patients with mCRPC treated with AA followed by docetaxel reported that no PSA response to docetaxel was observed in patients who did not achieve a PSA decline ≧50% on prior AA treatment. In contrast, other retrospective studies concluded that the activity of docetaxel subsequent to AA treatment was not related to a prior PSA response to AA treatment. Therefore, although previous observations might suggest a potential for cross-resistance, no definite conclusion has been reached. In addition, to the best of our knowledge, no previous reports have been published regarding Japanese mCRPC patients treated sequentially with new agents and docetaxel.

In recent daily practice, patients are frequently treated with AA followed by docetaxel because of a favorable toxicity profile of AA during long-term treatment. The objectives of the current retrospective analysis are to reveal the clinical outcomes of Japanese patients with mCRPC who were treated with AA followed by docetaxel, and to determine whether a prior AA response influences the response to subsequent docetaxel. In order to investigate these clinical questions, we conducted multicenter retrospective analysis.

Patients and methods

Patients

Patients with mCRPC who had been treated with AA until the time of disease progression in Phase 1 (JPN-101) and Phase 2 (JPN-201) clinical trials and subsequently treated with subsequent docetaxel were eligible for this retrospective analysis. This retrospective analysis was performed and the data analyzed in five institutions (National Cancer Center Hospital East, Yokohama City University Hospital, Kitasato University Hospital, Toho University Sakura Medical Center and Niigata University Hospital). This study was carried out in accordance with the Declaration of Helsinki and Japanese ethical guidelines for epidemiological research. We obtained institutional review board waivers from all the participating institutional review board chairpersons to conduct this study.

The patient eligibility criteria for the clinical trials of AA have already been reported (13,14). The summary of eligibility is as follows: patients had mCRPC and had not received cytotoxic chemotherapy. CRPC was defined based on the basis of evidence of disease progression (clinical, radiographic or PSA elevation) despite castrate serum testosterone levels and continuous luteinizing hormone-releasing hormone analogues/antagonist treatment. The treatment by AA with concomitant prednisone 5 mg orally twice daily was continued until the time of disease progression according to the Prostate Cancer Working Group 2 criteria (15), unacceptable toxicity or withdrawal.

The timing and choice of treatment drug after AA, and measurement and judgment of subsequent treatment, were made according to the discretion of individual physicians. In this study, only patients who were treated with docetaxel after AA were eligible. All doses and schedules of docetaxel were allowed in this study.

All data concerning patient characteristics and treatment outcomes with AA and docetaxel were collected from medical records of individual institutions. Information on the following parameters had to be available for all patients: Age, Gleason score, prior treatment of hormonal therapy, serum PSA at the time of baseline AA and docetaxel initiation, number and site of metastasis, Eastern Cooperative Oncology Group (ECOG) performance status, serum PSA level during treatment, treatment duration with AA and docetaxel and survival status. Patients whose clinical or pathological parameters were not available were excluded from this analysis. Between termination of AA and initiation of docetaxel, patients who were treated with hormonal agents were eligible, but those who were treated with cytotoxic or investigational agents were excluded. Patients who discontinued treatment with AA due to unacceptable toxicity or withdrawn were also excluded. Therefore, in this analysis, all patients experienced disease progression with AA.

Statistical analysis

The primary outcome measure in this study is to reveal the rates of PSA decline ≧30 and ≧50% from baseline with subsequent docetaxel treatment. Secondary outcome measures were progression-free survival (PFS) on docetaxel and OS on AA and docetaxel. PFS was defined as the time from initiation of docetaxel to progression of PSA or radiographic progression according to PCWG2 criteria, or clinical progression. OS was defined as the time from initiation of AA or docetaxel to death from any reason or censoring on 30 September 2014.

Patients were subdivided into two subgroups according to previous response to AA, such as an acquired resistance group and a primary resistance group. Acquired resistance was defined as the resistance in patients who experienced a PSA decline ≧50% from baseline during AA treatment. Residual patients who were not included in acquired resistance group were categorized as primary resistance group. This subgrouping was used in the previous investigation as given in reference (16). Differences between these subgroups are compared using the Wilcoxon–Mann–Whitney test for continuous variables or Fisher's exact test for categorical variables. Survival distributions were estimated using the Kaplan–Meier method for PFS and OS, and the Log-rank test was used to compare survival in different strata. All tests were two-sided and considered significant at P < 0.05. All statistical analyses were performed with the SPSS 22.0 statistical package for Windows (SPSS, IBM, Chicago, IL, USA).

Results

Patient characteristics and outcomes with previous AA treatment

The total number of JPN-101 and JPN 201 trial was 75 patients. A total of 43 patients were treated with AA in two clinical trials in five institutions, and 15 patients, who experienced disease progression during AA treatment and were subsequently treated with docetaxel, were eligible for this analysis. Patient and tumor characteristics at the time of initiation of AA are shown in Table 1. Only 33% of patients had received radical prostatectomy or radical radiation therapy previously. Almost all patients (80%) had a bone metastasis, however, 93% of patients had a good general condition with ECOG PS 0 or 1.The median duration of previous hormonal treatment before initiation of AA was 12.9 months, and 87% of patients received three or more hormonal treatment products, not including luteinizing hormone-releasing hormone agonist/antagonist, before initiation of AA. The treatment outcomes of AA are also summarized in Table 1. PSA declines of ≧30 and ≧50% were observed in 60 and 40% of patients, respectively. The Median PFS for patients treated with AA was 5.6 months [95% confidence interval (CI): 4.3–6.9 months].

Table 1.

Patient characteristics and treatment outcomes with previous AA treatment

Baseline characteristics
 
Gleason score, n (%) 
 6–7 3 (20) 
 8–10 11 (73) 
 Unknown 1 (7) 
Prior radical prostatectomy, n (%) 2 (13) 
Prior radical radiation therapy, n (%) 3 (20) 
Patient characteristics at time of AA initiation 
 Median age, years (range) 71 (47–84) 
Base line ECOG PS, n (%) 
 0–1 14 (93) 
 ≥2 1 (7) 
Number of previous hormone therapies, n (%) 
 1 2 (13) 
 2 9 (60) 
 3 3 (20) 
 4 1 (7) 
Median duration of previous hormone treatments, months (range) 20.2 (9.0–103.0) 
Metastatic site, n (%) 
 Bone 12 (80) 
 Lymph node 6 (40) 
 Lung 2 (1) 
 Liver 1 (7) 
PSA (ng/ml), median (range) 67.0 (10.2–1014.0) 
Hemoglobin (g/l), median (range) 11.8 (9.5–15.2) 
WBC (/μl), median (range) 5960 (3180–9200) 
Neutrophil cell (/μl), median (range) 3640 (1790–5060) 
LDH (U/l), median (range) 205 (151–5122) 
ALP (U/l), median (range) 337 (159–2936) 
Albumin (g/l), median (range) 4.2 (2.2–4.5) 
Treatment outcomes with previous AA treatment 
 PSA response to AA, n (%) 
  PSA decline ≥ 30% 9 (60) 
  PSA decline ≥ 50% 6 (40) 
 Median PFS from initiation of AA, months (range) 5.6 (0.8–21.2) 
 Reason for AA discontinuation, n (%) 
  PSA PD 9 (60) 
  Radiographic PD 4 (27) 
  Clinical PD 2 (13) 
Baseline characteristics
 
Gleason score, n (%) 
 6–7 3 (20) 
 8–10 11 (73) 
 Unknown 1 (7) 
Prior radical prostatectomy, n (%) 2 (13) 
Prior radical radiation therapy, n (%) 3 (20) 
Patient characteristics at time of AA initiation 
 Median age, years (range) 71 (47–84) 
Base line ECOG PS, n (%) 
 0–1 14 (93) 
 ≥2 1 (7) 
Number of previous hormone therapies, n (%) 
 1 2 (13) 
 2 9 (60) 
 3 3 (20) 
 4 1 (7) 
Median duration of previous hormone treatments, months (range) 20.2 (9.0–103.0) 
Metastatic site, n (%) 
 Bone 12 (80) 
 Lymph node 6 (40) 
 Lung 2 (1) 
 Liver 1 (7) 
PSA (ng/ml), median (range) 67.0 (10.2–1014.0) 
Hemoglobin (g/l), median (range) 11.8 (9.5–15.2) 
WBC (/μl), median (range) 5960 (3180–9200) 
Neutrophil cell (/μl), median (range) 3640 (1790–5060) 
LDH (U/l), median (range) 205 (151–5122) 
ALP (U/l), median (range) 337 (159–2936) 
Albumin (g/l), median (range) 4.2 (2.2–4.5) 
Treatment outcomes with previous AA treatment 
 PSA response to AA, n (%) 
  PSA decline ≥ 30% 9 (60) 
  PSA decline ≥ 50% 6 (40) 
 Median PFS from initiation of AA, months (range) 5.6 (0.8–21.2) 
 Reason for AA discontinuation, n (%) 
  PSA PD 9 (60) 
  Radiographic PD 4 (27) 
  Clinical PD 2 (13) 

AA, abiraterone acetate; ECOG, Eastern Cooperative Oncology Group; PS, performance states; PSA, prostate-specific antigen; WBC, white blood cells count; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; PD, progressive disease; DOC, docetaxel.

Patient characteristics and outcomes with subsequent docetaxel treatment

Patient characteristics at the time of docetaxel initiation are shown in Table 2. Baseline characteristics, such as PS, metastatic site and laboratory data, including serum PSA level, were slightly deteriorated compared with those at the time of AA initiation. Eleven patients (73%) were started docetaxel treatment at standard dose and schedule. PSA decline ≧30% was observed in five patients (33%), and PSA decline ≧50% was observed in only two patients (13%). Some PSA decline, regardless of degree during docetaxel treatment was observed in 80% of patients. A waterfall plot of maximal PSA decline from baseline with subsequent docetaxel treatment is shown in Fig. 1. Almost all patients (80%) discontinued docetaxel treatment due to disease progression. The median PFS with docetaxel treatment was 3.7 months (95% CI: 2.9–4.6 months, Fig. 2A). Until the censoring date, nine patients (60%) died and all death was due to mCRPC. The median OS from initiation of docetaxel and from initiation of AA were 14.4 months (95% CI: 6.3–22.4 months, Fig. 2B), and 25.7 months (95% CI: 20.1–30.7 months, Fig. 2C), respectively.

Table 2.

Patient characteristics and outcomes with DOC treatment

 All patients (n = 15) Primary AA resistance (n = 9) Acquired AA resistance (n = 6) 
Patient characteristics at time of DOC initiation 
 Median age, years (range) 71 (47–85) 70 (47–85) 73 (65–78) 
Baseline ECOG PS, n (%) 
 0–1 12 (80) 6 (67) 6 (100) 
 ≥2 3 (20) 3 (34) 0 (0) 
Number of hormone treatment lines between AA and DOC, n (%) 
 0 13 (86) 8 (89) 5 (83) 
 1 0 (0) 0 (0) 0 (0) 
 2 1 (7) 1 (11) 0 (0) 
 3 1 (7) 0 (0) 1 (17) 
Metastatic site, n (%) 
 Bone 12 (80) 8 (89) 4 (44) 
 Lymph node 7 (47) 4 (44) 3 (33) 
 Lung 2 (13) 1 (11) 1 (11) 
 Liver 2 (13) 2 (22) 0 (0) 
PSA (ng/ml), median (range) 113.1 (3.1–731.2) 122.9 (56.8–473.0) 37.7 (3.1–731.2) 
Hemoglobin (g/l), median (range) 12.0 (8.8–14.8) 11.1 (8.8–14.8) 12.1 (10.1–14.0) 
WBC (/μl), median (range) 6410 (2800–11 600) 6410 (2800–11 600) 6500 (4500–9500) 
Neutrophil cell (/μl), median (range) 4880 (2060–7310) 4880 (2060–7310) 4800 (2680–7150) 
LDH (U/l), median (range) 260 (153–1142) 284 (153–1142) 223 (170–469) 
ALP (U/l), median (range) 414 (105–3296) 414 (254–2656) 305 (105–3296) 
Albumin (g/l), median (range) 4.0 (3.2–4.4) 4.0 (3.2–4.4) 3.85 (3.4–4.3) 
Outcomes with DOC treatment 
 DOC dose/schedule, n (%) 
  75 mg/m2, triweekly 11 (73) 7 (78) 4 (67) 
  Others 4 (27) 2 (22) 2 (33) 
 Reason for DOC discontinuation, n (%) 
  PSA PD 3 (20) 1 (11) 0 (0) 
  Radiographic PD 2 (13) 1 (11) 2 (40) 
  Clinical PD 7 (47) 6 (67) 1 (20) 
  Toxicity 3 (20) 1 (11) 2 (40) 
 PSA response to DOC, n (%) 
  PSA decline ≥ 30% 5 (33) 3 (33) 2 (33) 
  PSA decline ≥ 50% 2 (13) 0 (0) 2 (33) 
Median PFS from initiation of DOC, months (range) 3.7 (0.7–15.5) 4.6 (0.7–15.5) 3.0 (1.4–3.9) 
Median OS from initiation of DOC, months (range) 14.4 (2.5–32.2) 11.5 (2.5–29.2) 23.0 (2.5–32.2) 
Median OS from initiation of AA, months (range) 25.7 (7.8–44.0) 14.6 (7.8–40.9) NYR (24.4–44.0) 
 All patients (n = 15) Primary AA resistance (n = 9) Acquired AA resistance (n = 6) 
Patient characteristics at time of DOC initiation 
 Median age, years (range) 71 (47–85) 70 (47–85) 73 (65–78) 
Baseline ECOG PS, n (%) 
 0–1 12 (80) 6 (67) 6 (100) 
 ≥2 3 (20) 3 (34) 0 (0) 
Number of hormone treatment lines between AA and DOC, n (%) 
 0 13 (86) 8 (89) 5 (83) 
 1 0 (0) 0 (0) 0 (0) 
 2 1 (7) 1 (11) 0 (0) 
 3 1 (7) 0 (0) 1 (17) 
Metastatic site, n (%) 
 Bone 12 (80) 8 (89) 4 (44) 
 Lymph node 7 (47) 4 (44) 3 (33) 
 Lung 2 (13) 1 (11) 1 (11) 
 Liver 2 (13) 2 (22) 0 (0) 
PSA (ng/ml), median (range) 113.1 (3.1–731.2) 122.9 (56.8–473.0) 37.7 (3.1–731.2) 
Hemoglobin (g/l), median (range) 12.0 (8.8–14.8) 11.1 (8.8–14.8) 12.1 (10.1–14.0) 
WBC (/μl), median (range) 6410 (2800–11 600) 6410 (2800–11 600) 6500 (4500–9500) 
Neutrophil cell (/μl), median (range) 4880 (2060–7310) 4880 (2060–7310) 4800 (2680–7150) 
LDH (U/l), median (range) 260 (153–1142) 284 (153–1142) 223 (170–469) 
ALP (U/l), median (range) 414 (105–3296) 414 (254–2656) 305 (105–3296) 
Albumin (g/l), median (range) 4.0 (3.2–4.4) 4.0 (3.2–4.4) 3.85 (3.4–4.3) 
Outcomes with DOC treatment 
 DOC dose/schedule, n (%) 
  75 mg/m2, triweekly 11 (73) 7 (78) 4 (67) 
  Others 4 (27) 2 (22) 2 (33) 
 Reason for DOC discontinuation, n (%) 
  PSA PD 3 (20) 1 (11) 0 (0) 
  Radiographic PD 2 (13) 1 (11) 2 (40) 
  Clinical PD 7 (47) 6 (67) 1 (20) 
  Toxicity 3 (20) 1 (11) 2 (40) 
 PSA response to DOC, n (%) 
  PSA decline ≥ 30% 5 (33) 3 (33) 2 (33) 
  PSA decline ≥ 50% 2 (13) 0 (0) 2 (33) 
Median PFS from initiation of DOC, months (range) 3.7 (0.7–15.5) 4.6 (0.7–15.5) 3.0 (1.4–3.9) 
Median OS from initiation of DOC, months (range) 14.4 (2.5–32.2) 11.5 (2.5–29.2) 23.0 (2.5–32.2) 
Median OS from initiation of AA, months (range) 25.7 (7.8–44.0) 14.6 (7.8–40.9) NYR (24.4–44.0) 

NYR, not yet reached. Acquired AA resistance defined as patients who experienced a PSA decline ≥50% from baseline during treatment of abiraterone acetate. Primary AA resistance defined as patients other than ‘acquired AA resistance’.

Figure 1.

Waterfall plot showing maximal prostate-specific antigen (PSA) response (%) from baseline during subsequent docetaxel treatment.

Figure 1.

Waterfall plot showing maximal prostate-specific antigen (PSA) response (%) from baseline during subsequent docetaxel treatment.

Figure 2.

Kaplan–Meier curve for (A) progression-free survival with subsequent docetaxel, (B) overall survival with docetaxel, (C) overall survival with abiraterone acetate (AA), (D) progression-free survival with docetaxel in two subgroups.

Figure 2.

Kaplan–Meier curve for (A) progression-free survival with subsequent docetaxel, (B) overall survival with docetaxel, (C) overall survival with abiraterone acetate (AA), (D) progression-free survival with docetaxel in two subgroups.

Subgroups analysis of primary and acquired resistance to AA

Patients were subdivided into two subgroups, such as primary resistance (n = 9) or acquired resistance (n = 6) groups, in accordance with their PSA response to previous AA treatment. Patient characteristics and docetaxel dose/schedule of these two groups were similar. A PSA decline ≧30% was observed in 33% of patients of both subgroups. However, two of six (33%) patients of the acquired resistance group achieved a PSA decline ≧50%, none of the patients in the primary resistance group achieved that level. The median PFS on docetaxel was 4.6 months (95% CI: 2.6–6.5 months) in the primary resistance group and 3.1 months (95% CI: 2.1–4.0 months) in the acquired resistance group. The PFS difference between the two subgroups was not statistically significant (P = 0.06 Fig. 2D). The median OS from the initiation of docetaxel was longer in the acquired resistance group but not significant (11.5 vs. 23.0 months P = 0.22, Figure not shown).

We performed a correlation analysis of the PSA responses to AA and docetaxel treatments. No significant correlation was observed between these PSA response (Pearson r = 0.206, P = 0.46, Fig. 3).

Figure 3.

Scatter plot showing the correlation between PSA response to previous AA treatment and PSA response to subsequent docetaxel treatment

Figure 3.

Scatter plot showing the correlation between PSA response to previous AA treatment and PSA response to subsequent docetaxel treatment

Discussion

We evaluated and analyzed the treatment outcomes in 15 patients with mCRPC who were treated with AA followed by docetaxel. To the best of our knowledge, this is the first report on Japanese patients with mCRPC who were treated according to this sequence. The present investigation revealed that docetaxel treatment subsequent to development of AA resistance was modestly effective. Docetaxel activity, estimated as PSA decline ≧50%, PFS and OS, seemed to be inferior to the activity in previous reports on similar non-Japanese populations. In published, non-Japanese data, a PSA decline ≧50%, was observed in 26–38% of patients, the median PFS was 4.0–4.6 months and the OS was 11.7–12.5 months (16–18). The conceivable reasons for these differences might depend on differences in hormonal treatment history before initiation of docetaxel treatment. In Japan, a maximum androgen blockade is selected more frequently as the initial hormonal treatment than luteinizing hormone-releasing hormone analogues/antagonist monotherapy. After maximum androgen blockade had failed, Japanese patients ordinarily received second- or third-line hormonal treatment, such as alternative anti-androgen and glucocorticoid. Thus, at the time of subsequent docetaxel initiation, the characteristics and disease burden of Japanese patients might be worse than those of non-Japanese patients. In fact, in the present study, data such as PSA level, hemoglobin level and the number of bone metastases, seemed to suggest more advanced disease as compared with those of published data. However, we cannot compare baseline characteristics because they were not reported in foreign studies at the time of AA initiation.

In addition, the median OS from the final analysis of the COU-AA 302 trial recently published was 34.7 months (19), and this duration was 9 months longer than that of our result. We assume that this difference might also depend on the same conceivable reasons. At the time of AA initiation, 80 and 50% of patients had bone metastasis in the present study and the COU-AA 302 trial, respectively. The median PSA level was 67.0 and 42.0 ng/ml in the present study and 302 trials, respectively. Based on these differences, it is possible that the hormonal treatment duration of Japanese patients before initiation of AA might be longer than that of non-Japanese, and this difference might affect not only the activity of docetaxel or AA but also OS from initiation of AA.

Furthermore, to evaluate a potential bias, we performed the additional analysis ∼28 patients who were not enrolled in the present study. In baseline characteristics at the time of AA initiation, there were no significant differences except for PSA level between enrolled and non-enrolled patients. PSA level of enrolled patients were significantly higher than that of non-enrolled patients (median 67.0 vs. 19.9 ng/ml; P = 0.05). These data might suggest that enrolled patients had more advanced disease than non-enrolled patients. On the other hand, OS after initiation of AA was not significantly different between these two groups (P = 0.34) (data not shown). We assumed that this non-significant difference of OS was depended on short follow-up periods.

The present investigation also revealed another important finding that PSA response to a previous AA treatment could not predict the PSA response and PFS in subsequent docetaxel treatment. From the correlation analysis of present study, there was no significant correlation between the PSA response to a previous AA treatment and the PSA response to subsequent docetaxel treatment. And also, there was no significant relationship between the reason of AA discontinuation and PSA response to subsequent docetaxel treatment (P = 0.40).

The PSA decline ≧30% and PSA decline ≧50% of the two groups were not significantly different. Furthermore, the median PFS on docetaxel were not significantly different between the two groups too. Our data are comparable with the results of Canadian and US retrospective analyses (16,17). Collectively, all of these data suggest that the PSA response to a prior AA treatment might not be useful to selecting patients for subsequent treatment with docetaxel.

However, the potential for cross-resistance between AA and docetaxel has been reported in several basic and retrospective studies (11,18,20). A small retrospective analysis from the UK reported results that conflicted with those in the present study. Patients who were refractory to AA, defined as not achieving a PSA decline ≧50% from baseline with prior AA treatment, achieved no PSA decline with subsequent docetaxel treatment. There might be many minor reasons for the conflicting results, such as differences in baseline characteristics, follow-up duration or post-docetaxel treatment procedures. Finally the definition of disease progression and timing of changing the treatment may differ among studies conducted by different physicians. Therefore, we cannot directly compare these results. To reveal whether or not cross-resistance exists, a large prospective sequential study is necessary.

There are several potential limitations in the present study. First this cohort is small with only 15 patients, therefore, this analysis is potentially underpowered. Second, this is a retrospective design. Finally, the timing of docetaxel initiation, dose and schedule of docetaxel and definition of disease progression were not determined but depended on physicians. Thus, scanning intervals and scanning devices during docetaxel treatment varied among the patients. However, these procedures are similar to those of real-world clinical practice. Therefore, we assume that the results from present investigation will become useful references in daily clinical practice.

In conclusion, our investigation revealed the efficacy of subsequent docetaxel treatment in Japanese patients with mCRPC who had resistance to AA was modest. The PSA response to a previous AA treatment could not predict the efficacy of subsequent docetaxel treatment. It is necessary to validate these findings in a larger prospective trial.

Conflict of interest statement

No conflicts of interest to declare for Drs Yujiro Ueda, Itsuhiro Takizawa, Tsutomu Nishiyama, Ken-ichi Tabata, Takefumi Satoh, Naoto Kamiya, and Takashi Kawahara. Dr Nobuaki Matsubara has received honoraria and/or research grants from Janssen Pharmaceutical K.K., Sanofi K.K., Taiho Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd. Dr Hiroyoshi Suzuki has received honoraria and/or research grants from Janssen Pharmaceutical K.K., Astra Zeneca K.K., Astellas Pharma Inc., Sanofi K.K., Takeda Pharmaceutical Company Ltd. Dr Hiroji Uemura has received honoraria and/or research grants from Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Janssen Pharmaceutical K.K., Astellas Pharma Inc., Sanofi K.K.

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