755O - A randomized phase 3 study comparing first-line docetaxel/prednisone (DP) to DP plus custirsen in men with metastatic castration-resistant prostate...

Date 28 September 2014
Event ESMO 2014
Session Genitourinary tumours, prostate 1
Topics Anti-Cancer Agents & Biologic Therapy
Prostate Cancer
Presenter Kim Chi
Citation Annals of Oncology (2014) 25 (suppl_4): iv255-iv279. 10.1093/annonc/mdu336
Authors K.N. Chi1, C. Higano2, J. Reeves3, S. Feyerabend4, G. Gravis5, J. Ferrero6, C. Jacobs7, O. Barnett-Griness8, A. Pande9, J.S. De Bono10
  • 1Oncology, BC Cancer Agency - Vancouver Centre, V5Z4E6 - Vancouver/CA
  • 2Department Of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, 98109 - Seattle/US
  • 3N/a, Florida Cancer Specialists, Fort Myers/US
  • 4Urology/oncology, Studienpraxis Urologie Nuertingen, Nuertingen/DE
  • 5Department Of Medical Oncology, Institut Paoli Calmettes, 13009 - Marseille/FR
  • 6Medical Oncology, Centre Antoine Lacassagne, FR-06189 - Nice CEDEX/FR
  • 7Senior Management, OncoGenex Pharmaceuticals, Bothell/US
  • 8Biostatistics, Teva Pharmaceuticals Industries, Netanya/IL
  • 9Oncology Clinical Development, Teva North America, North Wales/US
  • 10Division Of Cancer Therapeutics, Royal Marsden Hospital, SM25PT - Sutton/GB

Abstract

Aim

Clusterin is a pro-survival chaperone protein upregulated in response to apoptotic stressors such as chemotherapy. Custirsen (C) is a second-generation antisense oligonucleotide that inhibits production of human clusterin. This randomized, open-label, multicenter, international phase 3 study (SYNERGY; ClinicalTrials.gov #NCT01188187) sought to determine if addition of C to standard first-line chemotherapy with docetaxel (D) and prednisone (P) prolongs overall survival (OS) versus DP alone.

Methods

Patients (pts) with chemotherapy-naive mCRPC were randomized 1:1 to D (75 mg/m2 IV D1 q21d) + P (5 mg PO bid) ± C (640 mg IV weekly after loading dose period) for up to 10 cycles or until disease progression/unacceptable toxicity/withdrawal. Randomization was stratified by opioid use and radiographic evidence of progression. The primary endpoint was OS and the secondary endpoint was proportion of pts alive without disease progression on day 140. Survival data were compared using a stratified log-rank test.

Results

1022 pts were randomized from Dec 2010 to Nov 2012 (DPC, n = 510; DP, n = 512). Median (range) number of cycles received was 8 (1-32) for DPC and 9 (1-20) for DP. Following a target 509 events, median OS was 23.4 months with DPC and 22.2 months with DP (HR for death 0.93, 95% CI 0.78-1.11; log-rank 1-sided P = 0.21). Incidence of any subsequent therapy was 75 and 76% for DPC and DP (53 vs 54% abiraterone, 19 vs 20% enzalutamide; 17 vs 18% cabazitaxel). More pts in the DPC arm discontinued due to an adverse event (AE) (41 vs 29%). Most common grade ≥3 AEs for DPC vs DP included fatigue (11 vs 8%), febrile neutropenia (11 vs 7%), asthenia (7 vs 3%), diarrhea (6 vs 3%), pulmonary embolism (5 vs 4%), and pneumonia (4 vs 2%); grade ≥3 hematology laboratory toxicities were neutropenia (43 vs 29%), lymphopenia (37 vs 24%), and anemia (13 vs 5%).

Conclusions

Addition of custirsen to first-line DP did not significantly improve OS in pts with mCRPC and was associated with some increased toxicity. The majority of patients received subsequent life-prolonging therapy. Data on disease progression, response, and serum clusterin will be presented.


Sponsors: Teva Pharmaceuticals and OncoGenex Pharmaceuticals

Disclosure

K.N. Chi: Grant to conduct clinical trial from OncoGeneX;C. Higano: Grants: Amgen, Dendreon, Bayer, Medivation, Aragon, Algeta, Genentech, AstraZeneca, Sanofi, Oncogenex Consulting fees/travel support: Amgen, BHR, Dendreon, Bayer, Medivation, Pfizer, Janssen, Abbvie, Novartis, Genentech;J. Ferrero: Board membership: Novartis, Roche, Sanofi;C. Jacobs: Travel support: Teva Employee/stockholder: OncoGenex;O. Barnett-Griness: Employee: Teva Pharmaceuticals Industries;A. Pande: Employee/stockholder: Teva Pharmaceuticals. All other authors have declared no conflicts of interest.