Open AccessReduction in serum clusterin is a potential therapeutic biomarker in patients with castration‐resistant prostate cancer treated with custirsen
Author(s) -
Blumenstein Brent,
Saad Fred,
Hotte Sebastien,
Chi Kim N.,
Eigl Bernhard,
Gleave Martin,
Jacobs Cindy
Publication year - 2013
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.93
Subject(s) - clusterin , medicine , docetaxel , prostate cancer , oncology , mitoxantrone , chemotherapy , population , hazard ratio , gastroenterology , urology , cancer , confidence interval , apoptosis , biology , biochemistry , environmental health
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.