Prognostic significance of third‑line treatment for patients with metastatic castration‑resistant prostate cancer: comparative assessments between cabazitaxel and other agents

Hideaki Miyake1 · Ryo Sato1 · Kyohei Watanabe1 · Yuto Matsushita1 · Hiromitsu Watanabe1 · Daisuke Motoyama1 · Toshiki Ito1 · Takayuki Sugiyama1 · Atsushi Otsuka1
Received: 5 April 2021 / Accepted: 27 May 2021
© Japan Society of Clinical Oncology 2021

Abstract

Background Cabazitaxel has played an important role in the treatment of patients with metastatic castration-resistant pros- tate cancer (mCRPC); however, several types of sequential therapy against mCRPC have been performed in routine clinical practice. The objective of this study was to investigate the impact of third-line treatment on prognostic outcomes of mCRPC patients.
Methods This study retrospectively analyzed the clinical outcomes of 166 patients who received 3 agents following the diagnosis of mCRPC, consisting of 81 sequentially treated with either abiraterone or enzalutamide and then docetaxel, followed by third-line cabazitaxel (group A) and 85 treated with 3 agents, including abiraterone, enzalutamide, and docetaxel (group B).
Results There were no significant differences in major characteristics at the introduction of the third-line agent between these 2 groups. The proportion of patients with prostate-specific antigen (PSA) reduction > 50% by cabazitaxel in group A was significantly greater than that by either third-line agent in group B. Both PSA progression-free survival (PFS) and overall survival (OS) following third-line therapy in group A were significantly longer than those in group B. Furthermore, OS after the diagnosis of mCRPC in group A was significantly longer than that in group B. Multivariate analysis identified independ- ent predictors of favorable prognostic outcomes after third-line therapy as follows: high-performance status (PS), low PSA level and third-line cabazitaxel for PSA PFS, and high PS, low lactate dehydrogenase level and third-line cabazitaxel for OS.
Conclusions The introduction of cabazitaxel as a third-line agent could markedly improve the prognostic outcomes of mCRPC patients.
Keywords Metastatic castration-resistant prostate cancer · Cabazitaxel · Third-line treatment

Introduction

In recent years, multiple novel agents with different mech- anisms of action have been demonstrated to significantly improve the survival of patients with metastatic castration- resistant prostate cancer (mCRPC); thus, several types of sequential therapy combining these agents have been cur- rently conducted for this category of patients in real-world clinical practice [1, 2]. Of such novel agents, cabazitaxel, a tubulin-binding taxane drug, has been widely accepted as an efficacious agent against mCRPC based on the promis- ing findings of the pivotal phase III TROPIC trial, which included docetaxel-refractory mCRPC patients and showed the significant prognostic advantage of cabazitaxel com- pared with mitoxantrone [3, 4]. However, despite the pow- erful activity of cabazitaxel, it may be common to intro- duce agents other than cabazitaxel in mCRPC patients after the failure of docetaxel [5, 6], since novel androgen receptor-axis-targeted (ARAT) agents, abiraterone acetate and enzalutamide, were also approved as standard agents against docetaxel-refractory mCRPC [7, 8] Recently, the CARD trial demonstrated that cabazitaxel improved clinical outcomes, including overall survival (OS), progression-free survival (PFS) and response rate, compared with an ARAT agent in patients with mCRPC who were previously treated with docetaxel and an alternative ARAT agent [9]. The findings of the CARD trial suggested the sig- nificant advantage of cabazitaxel as a third-line agent for mCRPC patients; however, to date, there has been limited data regarding the optimal agent against mCRPC follow- ing the failure of an ARAT agent and docetaxel, in routine clinical practice. In this study, therefore, we retrospectively included a total of 166 patients treated with 3 agents follow- ing the diagnosis of mCRPC, and compared clinical out- comes between 81 treated with third-line cabazitaxel and 85 sequentially receiving agents other than cabazitaxel to analyze the prognostic significance of the introduction of cabazitaxel as a third-line treatment for mCRPC patients.

Patients and methods

Patients
The design of this study was approved by the Research Eth- ics Committee of our institution, and the need to obtain informed consent to be involved in this study from all patients was waived due to its retrospective manner. This study included a total of 166 consecutive Japanese patients who received 3 agents after the diagnosis of mCRPC between September 2014 and June 2019 in a routine clinical setting. All 166 patients were pathologically diagnosed as having adenocarcinoma of the prostate, and initially received androgen-deprivation therapy (ADT) by medical or surgi- cal castration. Based on either the Prostate Cancer Work- ing Group 2 (PCWG2) criteria [10] or Response Evaluation Criteria in Solid Tumors [11], disease progression against primary ADT was defined as prostate-specific antigen (PSA) or radiographic progression, respectively, in patients with a serum testosterone level < 50 ng/dL.

Treatment
After the failure of the primary ADT, the 166 patients received several patterns of sequential therapy using ARAT agents (abiraterone acetate and enzalutamide), docetaxel and/or cabazitaxel according to the preference of the physi- cians as well as patients without strictly determined crite- ria. In this study, clinical outcomes were analyzed by divid- ing the 166 patients into the following 2 groups: group A receiving sequential therapy consisting of an ARAT agent, docetaxel and cabazitaxel as first-, second-, and third-line agents, respectively; and group B receiving sequential ther- apy consisting of an ARAT agent, alternative ARAT agent, and docetaxel (group B1), or that consisting of an ARAT agent, docetaxel and an alternative ARAT agent, as first-, second- and third-line agents (group B2), respectively.
In this series, ARAT agents and cabazitaxel were gener- ally administered according to the standard dosing sched- ules, as previously described [3, 7, 8]; however, as a rule, docetaxel was given at a dose of 70 mg/m2 every 3 weeks considering its severe toxic effects on Japanese patients [12]. Either agent was continued to be administered until the occurrence of disease progression, judged according to the same definition as that applied to the primary ADT. When treatment-associated adverse events corresponding to grade ≥ 3 were observed, dose modification and/or treatment delay of either agent was permitted.

Evaluation
All clinicopathological data in each patient were obtained from the medical records. During the sequential treat- ment against mCRPC, the PSA level in addition to bone marrow, renal and liver functions were measured at least every 12 weeks, and radiological examinations were per- formed based on the discretion of the treating physicians. Prior to the introduction of each agent, the Eastern Coop- erative Oncology Group (ECOG) performance status (PS) was evaluated, and the number and location of metastatic lesions were assessed by computed tomography and radionu- clide bone scans. Findings on radionuclide bone scans were semiquantitatively evaluated based on the extent of disease (EOD) [13]. All laboratory data, including hemoglobin (Hb), albumin (Alb), lactate dehydrogenase (LDH) and PSA lev- els, were measured in each patient by standard clinical test- ing methods before the start of each line of therapy.

Statistical analysis
Statview 5.0 software (Abacus Concepts, Inc., Berkley, CA, USA) was used to perform all statistical analyses, and a P value < 0.05 was considered significant. The unpaired t-test and Chi-squared test were employed to evaluate differences in several parameters between the two groups. PSA PFS and OS rates were assessed by the Kaplan–Meier method, and differences were determined by the log-rank test. The impacts of certain factors on PSA PFS and OS were ana- lyzed with the Cox proportional hazards regression model.

Results

Of the 166 patients included in this study, 81 (48.8%) and 85 (51.2%) were classified into groups A and B, respec- tively. As first-line therapy, abiraterone acetate was intro- duced into 49 (60.5%) and 48 (56.5%) patients in groups A and B, respectively, while the remaining 32 (39.5%) and 37 (43.5%) in groups A and B, respectively, received enza- lutamide. As shown in Table 1, there were no significant

Table 1 Patient characteristics prior to third-line therapy
V ariables (%)
Age (years, range)a Group A (n = 81)
69.8 (55–82) Group B (n = 85)
70.4 (53–88) P value
0.41
ECOG performance status (%) 0.78
0 or 1 68 (84.0) 70 (82.4)
≥ 2 13 (16.0) 15 (17.6)
Hemoglobin (g/dl, range)a 11.9 (7.3–14.7) 11.6 (7.0–14.3) 0.32
Albumin (mg/dl, range)a 3.7 (3.0–8.3) 3.5 (3.0–7.9) 0.56
Lactate dehydrogenase (IU/l, range)a 297.5 (181.4–467.3) 288.3 (187.7–455.2) 0.46
Alkaline phosphatase (IU/l, range)a 412.9 (160.4–2274.3) 420.2 (179.7–2314.6) 0.14
Prostate-specific antigen (ng/ml, range)a 78.3 (6.4–701.3) 79.6 (8.9–729.8) 0.23
Gleason score on diagnostic biopsy (%) 0.96
≤ 7 15 (18.5) 16 (18.8)
≥ 8 66 (81.5) 69 (81.2)
Bone metastasis based on EOD (%) 0.74
0 20 (24.7) 19 (22.4)
1 36 (44.4) 33 (38.8)
2 19 (23.5) 24 (28.2)
3 or 4 6 (7.4) 9 (10.6)
Lymph node metastasis (%) 0.8
Negative 47 (58.0) 51 (60.0)
Positive 34 (42.0) 34 (40.0)
Visceral metastasis (%) 0.54
Negative 66 (81.5) 66 (77.6)
Positive 15 (18.5) 19 (22.4)
ECOG Eastern Cooperative Oncology Group; EOD extent of disease
aExpressed as median value differences in major clinicopathological characteristics prior to the introduction of a third-line agent against mCRPC between groups A and B. In this series, 21 patients (25.9%) in group A received fourth-line therapy, consisting of 18 and 3 treated with an alternative ARAT agent and radium-223, respectively, while 19 (22.4%) in group B received fourth- line therapy, consisting of 15 and 4 treated with cabazitaxel and radium-223, respectively; however, no patient received fifth-line therapy with an approved agent against mCRPC.
After treatment with the third-line agent, 23 (28.4%) and 8 (9.4%) patients in groups A and B, respectively, achieved PSA reduction > 50%; therefore, the PSA response rate in group A was significantly higher than that in group B (P = 0.0011).
During the observation period of this study after the introduction of the third-line agent (median, 8.2 months; range, 2.1–26.2 months), PSA progression occurred in 67 (82.7%) and 74 (88.1%) patients in groups A and B,
respectively, and 50 (61.7%) and 66 (78.6%) in groups A and B, respectively, died. The median PSA PFS was 4.2 and 2.8 months in groups A and B, respectively, while the median OS was 14.9 and 7.1 months in groups A and B, respectively. As shown in Fig. 1, both the PSA PFS and OS in group A were significantly superior to those in group B
(P = 0.031 and < 0.001, respectively). Furthermore, there was no significant difference in the PSA PFS (median, 3.0 and 2.6 months, respectively, P = 0.26) or OS (median,
7.3 and 7.0 months, respectively, P = 0.44) between groups B1 and B2, and no significant difference in the PSA PFS (group A: median, 4.3 and 4.0 months, respec- tively, P = 0.47; group B: median, 2.9 and 2.6 months, respectively, P = 0.39) or OS (group A: median, 15.2 and
14.8 months, respectively, P = 0.44; group B: median, 7.1 and 7.0 months, respectively, P = 0.48) was noted between patients receiving abiraterone acetate and those receiving enzalutamide as first-line therapy (data not shown).
The impacts of several clinicopathological factors on the PSA PFS and OS in the 166 patients after starting third-line therapy were subsequently evaluated (Table 2). Univariate analyses identified the significant parameters as follows: ECOG PS, LDH level, PSA level and third-line agent for PSA PFS, and ECOG PS, Hb level, LDH level, PSA level, and third-line agent for OS. Furthermore, on multivariate analyses of these significant parameters, the following factors were shown to have independent prog- nostic impacts: ECOG PS, PSA level and third-line agent on PSA PFS, and ECOG PS, LDH level, and third-line agent on OS.
Fig. 1 A Progression-free survival of the 166 patients with meta- static castration-resistant prostate cancer (mCRPC) after the intro- duction of a third-line agent. B Overall survival of the 166 patients with mCRPC after the introduction of a third-line agent. Group A: 81 patients receiving an androgen-receptor axis targeted (ARAT) agent, then docetaxel, followed by cabazitaxel as third-line therapy; Group B: 85 patients receiving sequential therapy with 2 ARAT agents and docetaxel

Table 2 Uni- and multivariate analyses of impacts of various parameters on prostate-specific antigen progression-free survival (PSA PFS) and overall survival (OS) after initiation of third-line therapy
Variablesa PSA PFS OS
Univariate analysis Multivariate analysis
HR P value HR P value HR P value HR P value
Age (years) (≤ 70.2 versus > 70.2) 0.8 0.61 – – 0.52 0.1 – –
ECOG performance status (0 or 1 versus ≥ 2) 0.22 0.015 0.25 0.034 0.19 0.0091 0.28 0.034
Hemoglobin (g/dl) (≤ 11.7 versus > 11.7) 1.37 0.44 – – 2.22 0.042 1.44 0.27
Albumin (mg/ml) (≤ 3.6 versus > 3.6) 1.16 0.55 – – 1.26 0.4 – –
Lactate dehydrogenase (IU/l) (≤ 292.3 versus > 292.3) 0.29 0.037 0.51 0.22 0.2 0.012 0.24 0.032
Alkaline phosphatase (IU/l) (≤ 417.4 versus > 417.4) 0.53 0.2 – – 0.57 0.29 – –
Prostate-specific antigen (ng/ml) (≤ 79.1 versus > 79.1) 0.18 0.014 0.35 0.44 0.29 0.041 0.39 0.089
Gleason score (≤ 7 versus ≥ 8) 0.6 0.33 – – 0.49 0.23 – –
Bone metastasis (EOD 0 versus ≥ 1) 0.52 0.21 – – 0.59 0.27 – –
Lymph node metastasis (negative versus positive) 0.61 0.56 – – 0.66 0.46 – –
Visceral metastasis (negative versus positive) 0.43 0.19 – – 0.42 0.079 – –
Third-line agent (cabazitaxel versus others) 0.23 0.016 0.28 0.039 0.22 0.019 0.31 0.045
ECOG Eastern Cooperative Oncology Group; EOD extent of disease
aCutoff point of each continuous variable was the median value prior to third-line therapy among the 165 patients included in this study
Finally, OS after the diagnosis of mCRPC between groups A and B were compared. As shown in Fig. 2, OS in group A was significantly longer than that in group B (P = 0.0014). Furthermore, univariate analysis of several parameters at the diagnosis with mCRPC identified the following significant predictors of OS: ECOG PS, Hb level, LDH level, and third- line agent, of which only ECOG PS and third-line agent were shown to be independently associated with OS after the diagnosis of mCRPC (Table 3).

Discussion

To date, favorable therapeutic impacts of cabazitaxel on docetaxel-refractory mCRPC patients have been shown in both a randomized clinical trial and several real-world studies [4, 14–18]. For example, Carles et al. reported that 189 mCRPC patients treated with cabazitaxel in rou- tine clinical practice had similar oncological outcomes
sequential therapy for mCRPC patients after the failure of docetaxel is still unclear, since ARAT agents, abiraterone acetate and enzalutamide, were simultaneously introduced as promising agents against docetaxel-refractory mCRPC [7, 8], and no clinical trials have directly compared pat- terns of sequential therapy in a post-chemotherapy setting. Collectively, these findings suggest that it is necessary to characterize the impact of treatment of mCRPC patients with cabazitaxel as a third-line therapy; therefore, we ret- rospectively evaluated the prognostic outcomes of 166 mCRPC patients receiving 3 agents following the diag- nosis of mCRPC, consisting of 81 sequentially treated with an ARAT agent and then docetaxel, followed by third-line cabazitaxel and 85 sequentially treated with 3 agents, including abiraterone acetate, enzalutamide, and
Fig. 2 Overall survival of the 166 patients after the diagnosis of met- astatic castration-resistant prostate cancer (mCRPC). Group A: 81 patients receiving an androgen-receptor axis targeted (ATAT) agent, then docetaxel, followed by cabazitaxel as third-line therapy; Group B: 85 patients receiving sequential therapy with 2 ARAT agents and docetaxel and safety profiles compared with those in the TROPIC trial, and most of these patients had a maintained or an improved health-related quality of life [14]. We also pre- viously conducted a retrospective study including a total of 63 Japanese mCRPC patients receiving cabazitaxel as a third-line agent and showed that satisfactory oncologi- cal outcomes similar to those in the TROPIC trial could be achieved in these patients [15]. However, despite such an excellent antitumor activity of cabazitaxel, optimal docetaxel.
Although there have been a number of studies suggesting the development of cross-resistance between ARAT agents, resulting in the limited efficacy of sequential treatment with these agents in mCRPC patients, several types of sequential treatment against mCRPC, including that administering 2 ARAT agents, have been performed [5, 6]. In this series as well, approximately half of the included patients received sequential therapy using both abiraterone acetate and enza- lutamide. However, there were no significant differences in major clinicopathological characteristics between the groups A and B, suggesting that the 2 cohorts of this study may be optimal to assess the significance of introducing cabazitaxel as a third-line agent against mCRPC.
Recently, cabazitaxel was demonstrated to significantly improve several prognostic outcomes, as compared with an

Table 3 Uni- and multivariate analyses of impacts of various parameters on overall survival
Variablesa Univariate analysis Multivariate analysis
(OS) at diagnosis with mCRPC HR P value HR P value
Age (years) (≤ 67.8 versus > 67.8) 0.55 0.11 – –
ECOG performance status (0 or 1 versus ≥2) 0.16 0.0082 0.21 0.016
Hemoglobin (g/dl) (≤ 12.8 versus >12.8) 2.33 0.045 1.74 0.19
Albumin (mg/ml) (≤ 4.1 versus >4.1) 1.2 0.43 – –
Lactate dehydrogenase (IU/l) (≤ 251.5 versus > 251.5) 0.18 0.01 0.34 0.12
Alkaline phosphatase (IU/l) (≤ 388.1 versus > 388.1) 0.51 0.27 – –
Prostate-specific antigen (ng/ml) (≤ 41.1 versus > 41.1) 0.41 0.091 – –
Gleason score (≤ 7 versus ≥ 8) 0.48 0.2 – –
Bone metastasis (EOD 0 versus ≥ 1) 0.67 0.34 – –
Lymph node metastasis (negative versus positive) 0.69 0.4 – –
Visceral metastasis (negative versus positive) 0.4 0.073 – –
Third-line agent (cabazitaxel versus others) 0.18 0.011 0.23 0.027

mCRPC metastatic castration-resistant prostate cancer; ECOG Eastern Cooperative Oncology Group; EOD extent of disease aCutoff point of each continuous variable was the median value at diagnosis with mCRPC among the 165 patients included in this study
ARAT agent, in mCRPC patients who had received prior treatment with docetaxel and an alternative ARAT agent in the CARD trial [9]. In this study, we also confirmed sig- nificantly more favorable findings, including the response rate, PSA PFS and OS, in 81 mCRPC patients receiving cabazitaxel than in 85 receiving an agent other than cabazi- taxel as third-line therapy. Furthermore, 81 mCRPC patients receiving third-line cabazitaxel achieved significantly longer OS after the diagnosis of mCRPC than the remaining 85. As described in various previous studies, one of the main reasons explaining the outcomes of this study may be the poor attributed outcomes to the sequential use of 2 ARAT agents [5, 6], which target the same pathway and thus share common resistant mechanisms. On the other hand, taxanes have been shown to overcome mechanisms involved in the resistance to ARAT agents, such as increased AR signal- ing and AR splice variant 7 expression [19–21]. Consid- ering these findings, it may be recommended to introduce docetaxel after the failure of a first-line ARAT agent, fol- lowed by third-line treatment with cabazitaxel, by avoiding the sequential administration of 2 ARAT agents in mCRPC patients.
Despite not being introduced in routine clinical practice, several prognostic factors in mCRPC patients treated with cabazitaxel have been reported [22–24]. For example, Shiota et al. showed that a high Gleason score, presence of pain, and LDH level had independent impacts on PFS, and the number of docetaxel cycles, PS and LDH level did on OS [22], while Rouyer et al. revealed that grade ≥ 3 adverse events, visceral metastases, polymedication and > 5 bone metastases were independently associated with shorter OS [23]. However, limited information remains available with respect to prognostic factors in mCRPC patients receiv- ing third-line therapies using several types of agent. In this study, the following factors were identified as independent predictors of favorable outcomes after third-line therapy: high PS, low PSA level, and third-line cabazitaxel for PSA PFS, and high PS, low LDH level, and third-line cabazi- taxel for OS. Taken together, the therapeutic effect of third- line therapy for mCRPC patients could be maximized by introducing cabazitaxel in the presence of a comparatively favorable condition in each mCRPC patient.
Here, several limitations of the present study should be mentioned. Firstly, this was a retrospective study with an insufficient sample size; therefore, the present findings should be confirmed by performing a prospective study including a larger number of patients. Secondly, thera- peutic agents during sequential therapy against mCRPC were not selected based on strictly determined criteria. Such a study design could affect the findings of this study. Thirdly, this study focused on an issue associated with can- cer control; however, comprehensive assessments, such as the safety profile, should be performed to achieve more reliable findings on an optimal agent as third-line therapy for mCRPC patients. In fact, a quality of life survey was also performed for patients included in the CARD trial, revealing that cabazitaxel did not impair the quality of life when com- pared with an ARAT agent [25]. Fourthly, when interpreting the findings presented in this study, it should be considered that the therapeutic landscape for advanced PC has shifted toward treatment with active agents during earlier stages of the disease.
In conclusion, this study included a total of 166 patients who received 3 agents following the diagnosis of mCRPC, and showed significantly more favorable prognostic out- comes in 81 patients receiving an ARAT agent and then docetaxel followed by third-line cabazitaxel than in 85 receiving sequential therapy consisting of 2 ARAT agents and docetaxel. Accordingly, it is strongly recommended to provide sequential therapy employing cabazitaxel as a third- line agent to improve the prognostic outcomes of mCRPC patients.

Declarations
Conflict of interest H. Miyake, R. Sato, K. Watanabe, Y. Matsushita,
H. Watanabe, D. Motoyama, T. Ito, T. Sugiyama and A. Otsuka declare that they have no conflict of interest.
Research involving human participants All procedures performed in studies involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amend- ments or comparable ethical standards.
Informed consent Informed consent was waived for individual partici- pants included in the study given the retrospective nature of this work.

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