Treatment failure is the major barrier to extending survival in patients (pts) with advanced cancer. Clusterin (CLU) is a cytoprotective protein upregulated by chemotherapy in cancer cells. Custirsen (C) inhibits CLU production in vivo. This international phase 3 study (AFFINITY; Clinicaltrials.gov NCT01578655) evaluated C in combination with cabazitaxel/prednisone (Cbz/P) in pts with mCRPC. Co-primary objectives were to evaluate overall survival (OS) in pts receiving Cbz/P/C compared to pts receiving Cbz/P alone for all randomized (ITT) pts and a poor prognosis subgroup.
Pts with progressive disease after docetaxel, adequate organ function, and Karnofsky score ≥70% were randomized to Cbz/P/C or Cbz/P. Treatment consisted of 21-day cycles of 25 mg/m2 IV Cbz on day 1 with 10 mg oral P daily with or without 640 mg IV C on days 1, 8, and 15 (plus 3 prior loading doses) until disease progression, unacceptable toxicity, or 10 cycles. Overall type I error probability (alpha) was one-sided 0.025, allocated as 0.01 and 0.015 for ITT and poor prognosis final analyses, respectively, with 85% power. Hypothesized HR for ITT was 0.75 at 547 events. Hypothesized HR for poor prognosis was 0.69 assuming 299 events.
635 men were randomized: median age 68 yrs, Karnofsky score ≤80% in 50%. Demographics and exposure to Cbz/P were similar for both arms. In ITT population (n = 635), median OS was 14.2 mo on Cbz/P/C and 13.4 mo on Cbz/P (two-sided p = 0.529; HR 0.946, 95% CI 0.796–1.124). 62% of pts (n = 392) met criteria for poor prognosis; OS was 11.1 mo on Cbz/P/C (n = 195) and 10.9 mo on Cbz/P (n = 197) in this subset (p = 0.470; HR 0.918, 95% CI 0.727–1.158). 28.9% of pts on Cbz/P/C and 25% on Cbz/P discontinued due to progressive disease, and 21.9% and 18.9% due to adverse events (AEs). Arms were comparable in ≥Grade 3 AEs (75.9% vs 66.3%) and SAEs (49.2% vs 42.3%). The most frequently reported ≥Gr3 AEs were neutropenia, anemia, fatigue, asthenia, bone pain, and febrile neutropenia.
In this phase 3 study, no survival benefit was seen in pts receiving Cbz/P/C compared to Cbz/P in both ITT population and poor prognosis subset.
Clinical trial identification
Legal entity responsible for the study
OncoGenex Pharmaceuticals, Inc.
OncoGenex Pharmaceuticals, Inc.
K. Fizazi: The author declares participation on advisory boards and honoraria from Orion, Bayer, Sanofi, Amgen, Genentech, Janssen, Astellas, and Takeda. F. Saad: Grants from OncoGenex during the conduct of the study; grants and personal fees from Sanofi, grants and personal fees from Astellas, grants and personal fees from Janssen, grants and personal fees from Amgen outside the submitted work. A. Flechon: Honoraria: Astellas, Janssen-Cilag, Sanofi, Ipsen Travel: Astellas, Janssen, Sanofi, MSD, Pfizer, Novartis, Bayer, Astra Zeneca. F. Joly: Outside the submitted work: Grant received: Astellas Board, scientific expertise, and congress: Roche, Novartis Board, scientific expertise: Sanofi, Astra Zeneca Congress: Amgen. P. Stewart: OncoGenex: Employee, stock ownership. C. Jacobs: OncoGenex: Employee, executive leadership, stock ownership. All other authors have declared no conflicts of interest.