Abstract
Background: Despite the rapid introduction of androgen receptor-targeted agents (ARTA) into clinical practice for castration-resistant prostate cancer (CRPC), the optimal treatment strategy after first-line ARTA remains unclear. The object of this study was to clarify clinical outcomes of second-line therapy for CRPC after first-line ARTA. Patients and Methods: The medical records of 130 consecutive patients with CRPC with disease progression during first-line ARTA and who started second-line therapy at our Institution between 2014 and 2020 were analyzed. Results: A total of 130 patients with CRPC were identified. Ninety patients underwent ARTA-ARTA treatment, and 40 patients underwent ARTA-docetaxel treatment. The median observation period after second-line ARTA or docetaxel administration was 14.2 months. The prostate-specific antigen response rates overall, and after second-line ARTA, and docetaxel were 26.8%, 24.7%, and 31.6%, respectively. The median progression-free survival (PFS) and 1- and 2-year PFS rates of second-line therapy were 7.9 months and 34.6% and 15.4%, respectively. The median overall survival (OS) and 1- and 2-year OS rates were 27.4 months and 81.8%, and 54.9%, respectively. Multivariate analyses for OS disclosed that a C-reactive protein over the upper limit of normal and time from first-line ARTA to progression under 12 months were associated with shorter OS. Prostate-specific antigen response, PFS and OS of second-line therapy were not significantly different between second-line ARTA and docetaxel. Conclusion: There was no significant difference in OS between ARTA-ARTA and ARTA-docetaxel groups in the present study, suggesting that second-line ARTA might be the preferred treatment after initial failure of ARTA.
Abiraterone acetate (AA) and enzalutamide are oral agents that act through the androgen receptor signaling pathway (1–4). In Japan, AA and enzalutamide were approved in 2014 for castration-resistant prostate cancer (CRPC), regardless of prior docetaxel treatment, based on positive results from a significant randomized phase III trial (1–4). Due to their excellent efficacies and manageable toxicities, both AA and enzalutamide were rapidly introduced into clinical practice in Japan. Together with other newly approved therapeutic agents, the treatment strategy for CRPC was completely developed in this decade (5–8).
Recently, these novel androgen receptor-targeted agents (ARTAs), AA and enzalutamide, were approved as therapeutic agents for metastatic hormone-sensitive prostate cancer, and most of these patients receive ARTA treatment without disease progression (9, 10). As such, ARTAs as therapeutic agents for CRPC need to be examined as they have been mainly used as first-line therapy for CRPC.
Many clinical questions concerning the treatment strategy of CRPC remain unanswered. Among them, the outcome and prognostic variables after disease progression on first-line ARTA are one of the most critical clinical concerns because most patients experience disease progression during first-line ARTA therapy. The 2019 CARD study results demonstrated that cabazitaxel should be offered as third-line therapy after docetaxel and AA or enzalutamide for CRPC. Moreover, the early administration of docetaxel rather than second-line ARTA is often recommended (11). However, Japanese patients with prostate cancer are relatively hormone-sensitive compared to patients in Western countries, and there has been no clear evidence on whether they should be treated with docetaxel or ARTA after first-line ARTA (12, 13). The aim of this study was to clarify the clinical outcome and prognostic variables of second-line therapy for patients with CRPC for whom first-line ARTA therapy failed. In addition, we compared the outcomes between patients treated with docetaxel and those treated with other ARTA agents as second-line therapy.
Patients and Methods
Study design. In this retrospective study, we reviewed the records of patients with CRPC whose disease progressed during first-line ARTA therapy and who started second-line therapy between 2014 and 2020 at our Institute. This study was conducted under the Declaration of Helsinki and was approved by the institutional review boards (approval number #2012-1008).
Patients. Standard doses of AA or enzalutamide were started in all patients until disease progression, with the Prostate Cancer Working Group 3 (14). Because of toxicities, dose reduction was allowed at the discretion of individual physicians. In addition, dose, and schedule modifications of second-line docetaxel or ARTA were allowed. Patients who had received first-line treatment with ARTA which was discontinued due to intolerable toxicity were excluded from this study to assess the antitumor effect of subsequent treatments.
Statistics. Clinical and pathological characteristics were compared between the ARTA-ARTA group and the ARTA-docetaxel group using the chi-square test for categorical variables and the Mann–Whitney U-test for continuous variables. The Kaplan–Meier method was used to estimate the time to progression or death. The statistical significance of the Kaplan–Meier curve was tested by log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards model. The progression-free (PFS) and overall (OS) survival were defined as the time from initial administration of second-line ARTA or docetaxel until prostate-specific antigen (PSA) or radiological progression, or death, respectively. All statistical analyses were calculated using JMP software version 12.1 (SAS Institute Inc., Cary, NC, USA) and R 4.0.1 software (R Foundation for Statistical Computing, Vienna, Austria), and values of p<0.05 were considered statistically significant. All applied tests were two-tailed.
Results
Patients. The patient characteristics are shown in Table I. Among patients with CRPC seen at our Institution during the study period, a total of 130 were identified who had received sequential treatments. After second-line ARTA or docetaxel administration, the median observation period was 14.2 months (interquartile range=7.3-25.5 months). Among these patients, 90 (69%) underwent ARTA-ARTA treatment, and 40 (31%) underwent ARTA-docetaxel treatment.
Patient characteristics at initiation of first-line therapy.
PSA response, PFS, and OS of second-line therapy for metastatic CRPC. Waterfall plots of maximal PSA declines during second-line treatment are depicted in Figure 1A. PSA response was observed in 26.8% of all patients (Figure 1A). A total of 79 (60.8%) out of the 130 patients experienced disease progression during the second-line drug period, and 48 patients (36.9%) died. The median PFS and 1- and 2-year PFS rates for second-line therapy for CRPC were 7.9 months, and 34.6% and 15.4%, respectively (Figure 1B). In addition, the median OS and 1- and 2-year OS rates for second-line therapy for CRPC were 27.4 months and 81.8%, and 54.9%, respectively (Figure 1C).
Prostate-specific antigen (PSA) response (A), progression-free survival (B), and overall survival (C) after second-line therapy for patients with metastatic castration-resistant prostate cancer.
Risk factors for short survival from second-line drug administration. Next, we investigated the variables that predict a shorter OS for patients with CRPC treated with this sequential treatment. Multivariate analyses for OS disclosed that serum C-reactive protein (CRP) above the upper limit of normal (ULN) and a time from first-line ARTA to progression of less than 12 months were associated with a shorter OS, whereas the impact of the sequential treatment methods on the ARTA-ARTA group or the ARTA-docetaxel group was not significant for OS duration (Table II). These factors, which included CRP >ULN and time from first-line ARTA to progression under 12 months, succeeded in separating the OS curves (Figure 2A and B). Application of the prognostic model with these factors [favorable risk group: number of risk factors: 0, n=47 (36.2%); intermediate-risk group: number of risk factors: 1, n=64 (49.2%); and poor-risk group: number of risk factors: 2, n=19 (14.6%)] showed that the OS curve was clearly divided according to each grouping (n=130, p<0.001, Figure 2C). The median OS and 1- and 2-year OS rates for the favorable risk group were 45.9 months, 97.8%, and 78.8%; those of the intermediate-risk group were 23.0 months, 79.4%, and 49.7%; whereas those of the poor-risk group were 13.0 months, 51.8%, and 19.4%, respectively.
Cox proportional hazards analysis for overall survival from second-line androgen receptor-targeted agent (ARTA) or docetaxel.
Risk factors for short overall survival from second-line drug administration. C-reactive protein (CRP) above the upper limit of normal (ULN) (A) and time of less than 12 months from the first androgen receptor-targeted agent (ARTA) administration to progression (B), succeeded in separating the OS curves. Favorable-risk group: number of risk factors=0; intermediate-risk group: number of risk factors=1; and poor-risk group: number of risk factors=2.
Comparison of PSA response, PFS, and OS between patients treated with docetaxel and patients treated with another ARTA as second-line agents. Lastly, we compared the treatment outcomes between patients treated with docetaxel and patients treated with another ARTA as second-line agents. A comparison of the basic characteristics is shown in Table I. Although the patients treated with docetaxel were significantly younger, there were no other differences between the groups (Table I). Figure 3A shows waterfall plots of the maximum PSA decrease during second-line treatment. PSA responses were observed in 24.7% and 31.6% of patients treated with ARTA-ARTA and ARTA-docetaxel, respectively (Figure 3A). The PSA response rates of the two groups were not significantly different (p=0.351).
Comparison of PSA-response (A), PFS (B), and OS (C) between the ARTA-ARTA and ARTA-docetaxel groups.
In this cohort, 61 (67.8%) out of 90 patients in the ARTA-ARTA group and 18 (45%) out of the 40 patients in the ARTA-docetaxel group experienced disease progression. The 1-year PFS of the ARTA-ARTA group and the ARTA-docetaxel group was 29.5% and 45.0%, respectively (p=0.079, Figure 3B). Moreover, in this period, 32 (35.6%) patients in the ARTA-ARTA group and 16 (40.0%) in the ARTA-docetaxel group died. The 1-year OS from second-line treatment of the ARTA-ARTA group and the ARTA-docetaxel group was 82.8% and 79.3%, respectively (Figure 3D), and there was no significant difference (p=0.250).
Discussion
Despite the development of recent medical treatment for CRPC, most patients experience disease progression during first-line ARTA therapy, and these patients will subsequently start second-line therapy. A PSA response in patients overall, and with another ARTA, and with docetaxel as second-line therapy were observed in 26.8%, 24.7%, and 31.6%, respectively. The median PFS, and 1- and 2-year PFS rates for second-line therapy for CRPC were 7.9 months and 34.6% and 15.4%, respectively, with corresponding OS for second-line therapy of 27.4 months and 81.8%, and 54.9%, respectively. Because there are few reports on second-line therapy for metastatic CRPC after first-line ARTA therapy, these results are highly informative to clinical practice.
In the CARD trial, a randomized, open-label trial comparing the outcomes of first-line ARTA and docetaxel followed by cabazitaxel or second-line ARTA for the treatment of metastatic CRPC, the median OS was 13.6 months with cabazitaxel and 11.0 months with another ARTA (hazard ratio=0.64, p=0.008) (11). In addition, in another essential trial on second-line therapy for metastatic CRPC, the PROfound trial, the median OS was 19.1 months with olaparib and 14.7 months with another ARTA (hazard ratio=0.69, p=0.02) (15). The OS period of our retrospective study was numerically longer than those of these prospective studies. These results might be due to the earlier exposure of docetaxel to patients with hormone-sensitive prostate cancer in Western countries. Since the successful results of the CHARRTED trial, initial docetaxel is considered an effective standard therapy for metastatic hormone-sensitive prostate cancer in Western countries. However, in Japan, docetaxel was only very recently approved (September 2021) as a therapeutic agent for metastatic hormone-sensitive prostate cancer, and most patients received docetaxel therapy in the CRPC state (16). In addition, the CARD and PROfound trials were limited to patients with progression within 12 months of first-line ARTA and patients harboring mutations of DNA-repair genes, respectively (11, 15). Moreover, our results might partly be explained by the fact that many new drugs for CRPC are covered by social health insurance in Japan. Therefore, a wide variety of therapies may also have been used after second-line treatment (Table II).
We established that the poor prognostic factors, namely, CRP >ULN and time to first-line ARTA progression <12 months are risk factors for short survival in patients in this cohort. CRP is a readily available biomarker and can be assayed in Japan at no extra cost. In addition, CRP is prognostic in many solid tumor types (17). Similarly, in CRPC, an elevation in pretreatment CRP level is prognostic for patients treated with ARTA and docetaxel (18, 19). CRP is considered to be an acute-phase protein produced in response to cytokines such as interleukin-6, and its circulating concentrations increase quickly in response to systemic inflammation. Recently, we reported that the neutrophil: lymphocyte ratio, which is another marker of systemic inflammation, was a poor prognostic variable for enzalutamide therapy for CRPC (20). Inflammation seems to be one of the key factors in CRPC progression.
Similarly to the results of the CARD trial, a time of less than 12 months from the induction of first-line ARTA to progression was extracted as another risk factor for shorter OS. These results seem to indicate that disease in these patients had already acquired castration resistance. Nonetheless, as the second-line treatment after first-line ARTA, no significant differences between docetaxel and another ARTA were demonstrated in PFS and OS. A post-hoc analysis of the COU-AA-302 trial, a phase III trial of abiraterone in patients with chemotherapy-naive metastatic CRPC, suggested that docetaxel is superior to ARTA in oncological outcomes as a second-line treatment for patients with disease progression after treatment with AA (21). In addition, according to the results of the CARD study, the early administration of docetaxel rather than another ARTA may be more often recommended as second-line therapy for CRPC. However, because of the sensitivity to hormonal therapy, medical therapy for prostate cancer in Japan differs from that in the West. Recently, as first-line therapy for metastatic CRPC, two independent Japanese groups demonstrated superior efficacy with ARTA compared to docetaxel (12, 13).
This study had several limitations. This was a retrospective study of a relatively small cohort of patients at a single institution so that there is a possible bias in extracting the prognostic factors. External validation is important before our findings can be put into daily clinical practice. In addition, scheduled imaging studies were not completed. Therefore, it may be not easy to compare the results of this study with those of clinical trials.
In conclusion, this retrospective study demonstrated second-line therapy treatment efficacy and risk factors for Japanese patients with metastatic CRPC. Furthermore, there was no significant difference in OS between ARTA-ARTA and ARTA-docetaxel groups in the present study, suggesting that second-line ARTA might be the preferred treatment after the initial failure of ARTA.
Footnotes
Authors’ Contributions
MF contributed to the analysis and interpretation of the data and article writing; TY contributed to the design and conception of the study. All Authors contributed to essential revisions of the article and approved the final submitted version.
Conflicts of Interest
The Authors have no conflicts of interest to declare.
- Received January 23, 2022.
- Revision received February 20, 2022.
- Accepted February 21, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
