Reduction in serum clusterin is a potential therapeutic biomarker in patients with castration-resistant prostate cancer treated with custirsen

Abstract

Elevated levels of clusterin (CLU), a stress-induced and secreted cytoprotective chaperone, are associated with advanced tumor stage, metastasis, treatment resistance, and adverse outcome in several cancers. Custirsen, a second-generation antisense oligonucleotide, inhibits CLU production in tumor cells and reduces serum CLU levels. A Phase 2 study evaluated custirsen in combination with second-line chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed while on or within 6 months of first-line docetaxel-based chemotherapy. Exploratory analyses evaluated serum CLU levels during custirsen treatment and correlative clinical effects on prostate-specific antigen (PSA) response, overall survival, and any relationship between serum CLU and PSA. Men with mCRPC were treated with mitoxantrone/prednisone/custirsen (MPC, n = 22) or docetaxel retreatment/prednisone/custirsen (DPC plus DPC-Assigned, n = 45) in an open-label, multicenter study. Subject-specific profiles of PSA and serum CLU levels during treatment were characterized using statistical modeling to compute subject-specific summary measures; these measures were analyzed for relationship to survival using proportional hazard regression. Estimated individual serum CLU response profiles were scored as below or at/above the median level for the population through 100 days postrandomization. Median survival was longer for subjects scoring below the median serum CLU level compared with subjects at/above the median level, respectively (MPC: 15.1 months vs. 6.2 months; DPC-Pooled: 17.0 months vs. 12.1 months). Lowered serum CLU levels during custirsen treatment when in combination with either chemotherapy regimen were predictive of longer survival in mCRPC. These results support further evaluation of serum CLU as a therapeutic biomarker.

Trial registration: ClinicalTrials.gov NCT00327340.

Keywords: Antisense oligonucleotide; chemotherapy; clusterin; custirsen; mCRPC.

Figure 1

Role of CLU in cancer cell survival.

Figure 2

Serial serum CLU and log PSA values by time. Shown is a sample from the graphs created to assess the general shape of the individual longitudinal outcomes. These graphs also show the fit of the quadratic model to each individual's data.

Figure 3

Serum CLU features and mean change by treatment group. For each group the extracted features of the 100-day CLU profile are plotted. These graphs show the general trend in response to the implementation of intervention.

Figure 4

Log PSA features and mean change by treatment group. For each group the extracted features of the 100-day log(PSA) profile are plotted. These graphs show the general trend in response to the implementation of intervention.

Figure 5

Kaplan–Meier estimates of survival by treatment group. The proportional hazard regression modeling (Table 2) suggested that Kaplan–Meier estimates from the four subgroups shown are a good representation of the data. In particular note that the difference between high versus low CLU response applies regardless of the type of chemotherapy.