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Prognosis of metastatic castration‐resistant prostate cancer in the era of the second‐generation androgen receptor‐targeted agents: A retrospective multicenter study

DOI: 10.1111/iju.14392 The therapeutic landscape for mCRPC changed dramatically with the approval of 2ndARTAs, such as ABI and ENZ. Although these agents have improved the prognosis of mCRPC in phase III trials, the results of the trials do not always apply to real-world practice owing to the differences in patients’ backgrounds. We aimed to determine whether the prognosis of mCRPC has improved after the approval of 2nd-ARTAs in our practice. The present study included 431 patients with mHNPC who were initially treated with androgen deprivation therapy between January 2011 and March 2018 from 14 hospitals in the Michinoku Japan Urological Cancer Study Group database. Of those, we identified 339 patients with mCRPC, and divided the patients into two groups: the DOC-alone era (between 2011 and 2014) or the 2nd-ARTA era (between 2015 and 2018) according to the mCRPC diagnosis dates (Fig. 1a). Each treatment was selected according to the physicians’ decision. OS after CRPC and that after mHNPC diagnosis were compared using the Kaplan–Meier with log–rank test and multivariate Cox regression analyses. This study was approved by the ethics review board of each institution. Of the 339 patients, 163 and 176 were treated in the DOC-alone and 2nd-ARTA era, respectively. Median age, initial PSA, Gleason score, tumor burden, PSA nadir, time to CRPC and follow-up periods were not significantly different between the groups (Table S1). A significantly shorter OS after CRPC was observed in patients in the DOC-alone era than those in the 2nd-ARTA era (P = 0.002; Fig. 1b). Similarly, patients in the DOC-alone era showed significantly shorter OS after mHNPC diagnosis than those in the 2nd-ARTA era (P < 0.001; Fig. 1c). Multivariate analyses showed that the era of 2nd-ARTA was an independent prognostic factor for OS after CRPC (HR 0.54, P = 0.004; Fig. 1d) and OS after mHNPC diagnosis (HR 0.41, P < 0.001; Fig. 1e, Table S2). The administration of cabazitaxel was not significantly associated with prognosis (Table S3). The present results showed that the OS after CRPC and that after the mHNPC diagnosis significantly improved in the 2nd-ARTA era, even after controlling for potential confounders. Previous population-based studies suggested that the prognosis of mCRPC improved between preand post-DOC eras (cancer-specific survival HR 0.87; OS HR 0.88). However, a few studies have compared the prognoses of patients with mCRPC treated between the DOC-alone era and the 2nd-ARTA era. They showed that patients in newer therapy era (since 2010) demonstrated an OS advantage (2.8 vs 2.2 years) with a 41% decreased risk of death (HR 0.59, 95% CI 0.47–0.74; P < 0.0001) than those treated before 2010. Therefore, the present results support a prognostic benefit of 2nd-ARTAs in real-world practice. We recognized that any comparisons could not be fair comparisons due to several biases. The present study included four subgroups, such as the “pure DOC-alone group (patients treated with DOC alone and final follow up/death within 2014),” “extended group (patients treated with DOC alone followed by vintage agents after 2014),” “overlap group (patients treated with DOC followed by 2nd-ARTA after 2014)” and “study group (2nd-ARTA era)” (Fig. 1a). The exclusion of the extended group might lead to a strong bias for rapid progression disease in the pure DOC-alone group, whereas the inclusion of the overlap group might lead to a strong selection and lead-time bias for slow progression disease (Fig. S1a–c). Also, the inclusion of the overlap group might result in an unfair comparison between the control and study groups, because we could not exclude the influence of 2nd-ARTA treatment in the control group. We believe the control (DOC-alone era) group should not be treated with 2nd-ARTA, and this classification might minimize selection biases and probably contribute to the improved prognosis. Although the present study included several limitations in the sample size, retrospective design, lack of information about the dose of drugs, use of vintage therapy and adverse events, and the possibility that the 2nd-ARTA era potentially included more favorable patients compared with the DOC-alone era, we showed that the prognoses of patients with mCRPC has improved in the 2nd-ARTA era compared with that in the DOC-alone era in real-world practice.