Abstract
PurposeSystemic Therapy for Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy is a randomized controlled trial using a multiarm, multistage, platform design. It recruits men with high-risk, locally advanced or metastatic prostate cancer who were initiating long-term hormone therapy. We report survival data for two celecoxib (Cel)-containing comparisons, which stopped accrual early at interim analysis on the basis of failure-free survival.Patients and MethodsStandard of care (SOC) was hormone therapy continuously (metastatic) or for ≥ 2 years (nonmetastatic); prostate (± pelvic node) radiotherapy was encouraged for men without metastases. Cel 400 mg was administered twice a day for 1 year. Zoledronic acid (ZA) 4 mg was administered for six 3-weekly cycles, then 4-weekly for 2 years. Stratified random assignment allocated patients 2:1:1 to SOC (control), SOC + Cel, or SOC + ZA + Cel. The primary outcome measure was all-cause mortality. Results were analyzed with Cox proportional hazards and flexible parametric models adjusted for stratification factors.ResultsA total of 1,245 men were randomly assigned (Oct 2005 to April 2011). Groups were balanced: median age, 65 years; 61% metastatic, 14% N+/X M0, 25% N0M0; 94% newly diagnosed; median prostate-specific antigen, 66 ng/mL. Median follow-up was 69 months. Grade 3 to 5 adverse events were seen in 36% SOC-only, 33% SOC + Cel, and 32% SOC + ZA + Cel patients. There were 303 control arm deaths (83% prostate cancer), and median survival was 66 months. Compared with SOC, the adjusted hazard ratio was 0.98 (95% CI, 0.80 to 1.20; P = .847; median survival, 70 months) for SOC + Cel and 0.86 (95% CI, 0.70 to 1.05; P =.130; median survival, 76 months) for SOC + ZA + Cel. Preplanned subgroup analyses in men with metastatic disease showed a hazard ratio of 0.78 (95% CI, 0.62 to 0.98; P = .033) for SOC + ZA + Cel.ConclusionThese data show no overall evidence of improved survival with Cel. Preplanned subgroup analyses provide hypotheses for future studies.
Highlights
Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer
There were 184 deaths in the combination group as compared with 262 in the androgen-deprivation therapy (ADT)-alone group; the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease
There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group; the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease
Summary
We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). The intermediate primary outcome was failure-free survival, defined as the time to the first of the following forms of treatment failure: biochemical (prostate-specific antigen [PSA]) failure (see the protocol, available with the full text of this article at NEJM.org); progression of local, lymph-node, or distant metastases; or death from prostate cancer. Eligible patients had prostate cancer that was newly diagnosed and metastatic, node-positive, or high-risk locally advanced (with at least two of following: a tumor stage of T3 or T4, a Gleason score of 8 to 10, and a PSA level ≥40 ng per milliliter) or disease that was previously treated with radical surgery or radiotherapy and was relapsing with high-risk features (in men no longer receiving therapy, a PSA level >4 ng per milliliter with a doubling time of 20 ng per milliliter, nodal or metastatic relapse, or 12 months without treatment). Patients with clinically significant cardiovascular disease (e.g., severe angina, recent myocardial infarction, or a history of cardiac failure) were excluded
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