Abbreviations & Acronyms 1CTP = cross-linked telopeptide parts of type I collagen ADT = androgen deprivation therapy ALP = alkaline phosphatase ARTA = androgen receptor-targeted agent BAP = bone alkaline phosphatase BMA = bone-modifying agent BSI = Bone Scan Index CRP = C-reactive protein HSN = hot spot number

Abstract. Background

Background Recent studies have shown that an early prostate‐specific antigen (PSA) response to androgen receptor‐targeting agents in metastatic castration‐resistant prostate cancer (mCRPC) is associated with a better prognosis. We analyzed the early PSA response to enzalutamide (ENZ) by measuring the PSA doubling time (PSADT) and PSA velocity (PSAV) while monitoring oncologic outcomes and survival in Japanese patients. Methods We analyzed a total of 241 patients with mCRPC who were treated with ENZ. The patients’ median age was 75 ± 7.9 years (range, 53‐93 years). There were 171 (71%) predocetaxel cases, and 70 (29%) post docetaxel cases. PSA‐progression‐free survival (PFS) and overall survival (OS) were assessed according to Prostate Cancer Working Group 2 criteria. This study was approved by the Institutional Review Board of Gunma University Hospital (No. 1595). Results We observed 77 good response (GR; case in which PSA remained low after treatment) cases (31.9%), 125 acquired resistance (AR; decline in PSA after treatment followed by progression) cases (51.9%), and 39 primary resistance (PR; lack of decline in PSA) cases (16.2%). Predocetaxel, PSA‐PFS, and OS were significantly higher compared with post docetaxel (PSA‐PFS: 47.0 vs 13.4 weeks, P < .001; OS: not yet reached vs 80.7 weeks, P < .001). Multivariate analysis of prognostic factors, including PSA response at 4 weeks, was performed using Cox regression analysis. ECOG PS (0 vs 1‐2), hemoglobin (Hb; ≥ 12.2 vs < 12.2 g/dL), time to CRPC ( ≥ 12 vs < 12 m), docetaxel treatment history (no vs yes), and a PSA reduction of 50% at 4 weeks were significant predictors of OS (all, P < .05). In cases of AR (n = 125), multivariate analysis showed that PSA kinetic factors, such as PSADT and PSAV (ng/mL/m), Hb, time to CRPC, PSADT ( ≥ 2 vs < 2 m), and PSAV ( < 20 vs ≥ 20 ng/mL/m), were all predictive of OS following PSA‐progression (P < .05). Conclusions Our study has demonstrated that PSA dynamics after ENZ administration may be a useful prognostic factor for mCRPC patients.

Background/Aim: The purpose of the present study was to clarify whether treatment with YM155, a novel small-molecule inhibitor of survivin, reversed cabazitaxel resistance in castration-resistant prostate cancer (CRPC). Materials and Methods: Cabazitaxel resistance was induced in the castration-resistant prostate cancer cell line, 22Rv1-CR. In vitro and in vivo models were used to test the efficacy of YM155 and cabazitaxel. Results: Survivin gene expression was significantly higher in 22Rv1-CR than its parent cells (22Rv1). In 22Rv1-CR cells, YM155 significantly reduced expression of the survivin gene in a concentration-dependent manner. YM155 alone was poorly effective; however, it significantly enhanced the anticancer effects of cabazitaxel on 22Rv1-CR in vitro and in vivo. Conclusion: Inhibition of survivin by YM155 overcomes cabazitaxel resistance in CRPC cells.Cabazitaxel was more efficacious in terms of producing a significant difference in patients with castration-resistant prostate cancer (CRPC) compared with the control group in the TROPIC trial (1). Hence, cabazitaxel is now employed as the standard treatment for most patients with CRPC. However, treatment outcomes are not always completely successful. Thus, the development of a new therapeutic regimen is required.Survivin is a member of a family of eight different proteins that function as inhibitors of apoptosis (2). In 1997, Altieri et al. reported, for the first time, that survivin controlled apoptosis in cancer cells (3). It was also reported that survivin is overexpressed in several kinds of cancer and is involved in the survival of cancer cells and cell division.Conversely, cancer cell apoptosis is induced when the function of survivin is restrained. Additionally, because survivin expression level correlates with malignant disease prognosis and drug resistance, it is considered a potential target of future cancer therapeutics.A novel small-molecule inhibitor of survivin, YM155, was identified by cell-based high-throughput screening (4). YM155 suppresses the transactivation of survivin by directly binding to its promoter (5). Subsequently, Cheng et al. reported that YM155-mediated inhibition of survivin expression occurs, at least in part, through inhibition of survivin transcription by disrupting Sp1 interaction with the -149 to -71 region in the survivin core promoter (6).YM155 exhibits potent antitumor activity in vitro, and induces tumor regression in established non-small cell lung cancer, non-Hodgkin lymphoma, melanoma, and hormonerefractory prostate cancer xenografts (4, 7-9). The anticancer efficacy of YM155 as monotherapy or in combination with docetaxel (10) or platinum compounds, such as cisplatin and carboplatin (11) has been shown in Xenograft models (4,12).The purpose of this study was to determine the efficacy of YM155 and whether YM155 treatment could reverse acquired cabazitaxel resistance in the prostate cancer cell line 22Rv1-CR both in vitro and in vivo. Materials and MethodsCells and chemicals. The human prostate cancer cell l...

The baseline characteristics of the Prostatic Cancer Registry of Standard Hormonal and Chemotherapy Using Bone Scan Index database have been established. This collaborative study can now proceed with clarifying the role of the bone scan index for patient management including treatment strategies and prognosis.