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Phase III SYNERGY trial: Docetaxel +/- custirsen and overall survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and poor prognosis.
Background: Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a 2nd-generation antisense that inhibits clusterin production. The SYNERGY trial evaluated docetaxel +/- custirsen as 1st-line therapy in men with mCRPC (N = 1022). Following 509 deaths, median overall survival (OS) was 23.4 months (m) vs. 22.2 m for custirsen and control arms, respectively (hazard ratio [HR] 0.93; P = 0.42). To explore the hypothesis that clusterin inhibition may be more relevant in poor prognosis disease, we evaluated outcomes by prognostic sub-groups retrospectively. Methods: A prognostic scoring system was developed in the control arm using multiple variable modeling. The modeling included evaluation of interactions and used hierarchical step down. Results of the final model included the following main effects: liver mets, opioid use, Karnofsky < 90, PSA, LDH, alk phos, and hemoglobin. The median score dichotomized pts into good and poor prognosis. Outcomes included survival and PSA progression as defined by PCWG1 and PCWG2. Results: The analysis included 984 pts with complete data. Median survival for the poor and good prognosis groups in the control arm was 14.0 m and 30.4 m, respectively (HR = 3.66). The custirsen HR effect differed between poor and good prognosis groups (interaction P = 0.069). The HR estimate for custirsen survival benefit was 0.73 (95% CI: 0.0589 to 0.902) for poor prognosis and 1.02 (95% CI: 0.760 to 1.37) for good prognosis. The poor prognosis group was analyzed separately for treatment effect (n = 492). The median OS was 17.0 m in the custirsen arm vs. 14.0 m in the control arm (stratified HR = 0.72, 95%CI: 0.579 to 0.892, P = 0.0026). PSA progression in the poor prognosis group also favored custirsen with a HR of 0.73 (95% CI: 0.589 to 0.907) for PCWG1 and 0.808 (95% CI: 0.633 to 1.031) for PCWG2. Conclusions: CRPC pts with a poor prognosis appeared to benefit from custirsen when added to docetaxel as 1st-line therapy. This finding underscores the importance of enriching for a study population based on the mechanism of action for targeted agents. Clinical trial information: NCT01188187
Abstracts by Kim N. Chi:
Correlation of a novel whole blood RT-PCR assay measuring AR-V7 expression with outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate (ABI).Meeting: 2016 Genitourinary Cancers Symposium | Abstract No: 223
Dehydroepiandrosterone in metastatic castration-resistant prostate cancer: Preliminary results from the SU2C-PCF West Coast Dream Team (WCDT).Meeting: 2016 Genitourinary Cancers Symposium | Abstract No: 179
Analysis of AR-driven resistance mechanisms in a phase 1/2 study of EPI-506, a novel AR N-terminal domain inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC) with progression after enzalutamide or abiraterone.Meeting: 2016 ASCO Annual Meeting | Abstract No: TPS5030