Nicholas D. James, MD
Adding celecoxib and zoledronic acid to standard treatment extended survival in men with metastatic prostate cancer commencing first-line hormone therapy, according to updated data from the STAMPEDE trial.1
“In the metastatic subset, [the combination] improves failure-free and overall survival," Nicholas James, MD, of the University of Warwick and Queen Elizabeth Hospital Birmingham in the United Kingdom, said when presenting the data at the 2016 Genitourinary (GU) Cancers Symposium. “At the very least, we feel these data merit further evaluation,” he added.
The multiarm, multi-stage STAMPEDE trial accrued men with high-risk, locally advanced, metastatic or recurrent hormone-naive prostate cancer commencing standard of care (SOC) first-line treatment, defined as long-term androgen deprivation therapy with or without radiotherapy.
The analysis presented at the GU symposium included 1245 patients randomized in a 2:1:1 ratio between October 2005 and April 2011 to SOC (n = 622), SOC plus the COX-2 inhibitor celecoxib (n = 312), or SOC plus celecoxib and zoledronic acid (n = 311).
The median patient age was 65 years, 94% of patients were newly diagnosed, 77% of patients had a WHO PS of 0, and the median PSA was 66 ng/nl. Sixty-one percent of patients were metastatic, 14% were N+/X M0, and 25% were N0M0.
Patients received celecoxib twice daily for up to 1 year. Zoledronic acid was given at an induction dose of 4 mg every 3 weeks for 6 cycles, and then every 4 weeks for up to 2 years. The primary outcome measure was overall survival (OS), with secondary endpoints including failure-free survival (FFS) and safety.
James noted that accrual to the 2 celecoxib arms from the STAMPEDE trial had previously been halted by an independent committee after a failure to show that the treatment improved FFS when compared with SOC. The analysis presented at the GU Symposium was part of a preplanned analysis included in the trial design for all of the treatment arms.
At the time of the analysis, 459 (36%) men had died of prostate cancer, 113 (9%) had died of other causes, and 668 (55%) were alive. There were 295 control arm deaths, 82% of which were due to prostate cancer.
The addition of celecoxib alone to SOC did not significantly improve FFS (HR, 0.88; 95% CI, 0.75-1.04; P
= .122) or OS (HR, 1.00; 95% CI, 0.82-1.22; P
= .986). The median OS was 68 months with a 5-year OS of 54% for both SOC alone and with the addition of celecoxib.
In the overall population, adding zoledronic acid to celecoxib and SOC also did not significantly improve FFS or OS versus SOC alone. Median FFS was 24 months in the combination arm versus 19 months in the control arm (HR, 0.85; 95% CI, 0.72-1.01; P
= .058). Median OS was 74 months versus 68 months, respectively (HR, 0.86; 95% CI, 0.70-1.06; P
However, in a subgroup of patients with metastases at baseline, there was a significant improvement in both OS (HR, 0.78; 95% CI, 0.62-0.99; P
= .040) and FFS (HR, 0.77; 95% CI, 0.63-0.93; P
= .008) for the celecoxib/zoledronic acid arm compared with the control arm.
Toxicities were similar across the treatment arms. Grade 3/5 adverse events (AEs) were reported in 31% of the celecoxib/zoledronic acid arm, 33% of the celecoxib arm, and 35% of the SOC arm. The most frequently reported grade 3/5 AEs were endocrine disorder (10%, 11%, 14%, respectively), musculoskeletal (5%, 8%, 7%), renal (5%, 4%, 6%), and gastrointestinal disorder (5%, 4%, 3%). The rate of grade 3/5 cardiac disorder was 3% for each arm.
Data on salvage therapy were also collected. James said there was no differences in the time to first post-progression therapy of any type, including life-prolonging therapy, among the 3 arms. Exposure rates to subsequent treatments was also similar among the 3 groups.
Previously reported data from STAMPEDE showed that adding docetaxel to SOC improved OS; however, an OS improvement was not observed when adding zoledronic acid to SOC, either alone or in combination with docetaxel.2
James compared the impact of the celecoxib/zoledronic acid combination in the metastatic setting to the benefit demonstrated with the addition of docetaxel.
“The magnitude of the [celecoxib/zoledronic] effect is very similar to the effect that we showed with docetaxel last year.”
James ND, Sydes MR, Clarke NW, et al.Celecoxib with or without zoledronic acid for hormone-naïve prostate cancer: Survival results from STAMPEDE (NCT00268476). J Clin Oncol 34, 2016 (suppl 2S; abstr 162)
James ND, Sydes MR, Clarke NW Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2015. pii:S0140 6736(15)01037-5.
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