STOCKHOLM – Celecoxib shows no evidence of activity when it’s added to hormone therapy in men with metastatic or high-risk nonmetastatic prostate cancer, according to first results from the six-arm STAMPEDE trial.
The use of celecoxib (Celebrex) plus hormone therapy did not extend failure-free survival, compared with hormone therapy alone (adjusted hazard ratio, 0.98). The 305 failure-free survival events were largely prostate-specific antigen (PSA) failures in 78% of both groups and new metastases in 16% of both groups, Dr. Noel W. Clarke reported on behalf of the STAMPEDE investigators at the European Multidisciplinary Cancer Congress.
Other failure-free survival events were local progression in 2% of both groups, lymph node invasion in 2% of the hormone-only group and in 0% of the hormone-plus-celecoxib group, and prostate cancer-related death in 1% and 4%, respectively.
Toxicity among the 874 patients was not significantly different, with 23% of the hormone-only group and 25% of the celecoxib group experiencing any grade 3-5 toxicity, he said.
Based on the lack of benefit, accrual to the celecoxib arm was halted. Celecoxib treatment was also discontinued in a second arm of the trial that coupled the cyclooxygenase-2 (COX-2) inhibitor with hormone therapy and zoledronic acid (Zometa), said Dr. Clarke, honorary professor of urological cancer at the University of Manchester (England).
STAMPEDE uses a novel and ambitious multiarm, multistage design to simultaneously assess whether the addition of one or two of three agents – docetaxel (Taxotere), zoledronic acid, or celecoxib – improves overall survival in men who have metastatic or high-risk nonmetastatic prostate cancer and are starting long-term hormone therapy. Accrual continues in the remaining arms, and assessment of a new agent, abiraterone (Zytiga), is now underway, he said.
The rationale for using celecoxib is threefold: COX-2 is associated with carcinogenesis in prostate and other cancers, case-control studies show a reduction in the risk of prostate cancer associated with nonsteroidal drugs, and pathological studies show that COX-2 is up-regulated in prostate cancer, Dr. Clarke explained.
Invited discussant Dr. Karim Fizazi of Institut de Cancérologie Gustave Roussy in Villejuif, France, said that the rationale for using celecoxib is much weaker than that for the other agents. Docetaxel has demonstrated an overall survival benefit in castrate-resistant prostate cancer, whereas zoledronic acid is known to delay skeletal-related events in this setting.
He also faulted the study’s heterogeneous population and the inclusion of PSA failure in the definition of failure-free survival, because active agents – such as zoledronic acid, denosumab (Xgeva), and sipuleucel-T (Provenge) – do not typically induce a PSA decrease.
Strengths of STAMPEDE include its ability to accrue almost 70 patients per month, its flexibility in dropping an arm if a drug is inactive rather than starting a separate new trial, and its homogeneous endocrine therapy that included 98% of patients taking LHRH (luteinizing hormone-releasing hormone) agonists, Dr. Fizazi said.
STAMPEDE has randomized 2,043 patients overall, including 583 to standard hormone therapy and 291 to hormone therapy plus celecoxib 400 mg twice daily for up to 1 year, or until a failure-free survival event. The median age in the current analysis was 65 years, and 77% had a performance status of 0. The median PSA was 67 ng/mL in the hormone group and 58 ng/mL in the celecoxib group.
Surprisingly, just 42% of patients who were randomized to celecoxib completed treatment, with a significant number dropping off within the first year because of either disease progression (28%) or excessive toxicity (11%), Dr. Clarke said at the joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiotherapy and Oncology (ESTRO).
STAMPEDE is led by Dr. Nicholas James of Queen Elizabeth Hospital in Birmingham, England, and is sponsored by the U.K. Medical Research Council, Cancer Research U.K., Novartis, Sanofi-Aventis, and Pfizer. Dr. Clarke reported no conflicts of interest, although several coauthors are employed by the Medical Research Council. Dr. Fizazi reports serving on advisory boards or as a speaker for Amgen, Dendreon, Exelixis, Janssen, Novartis, and Sanofi-Aventis.