Adding Celecoxib With or Without Zoledronic Acid for Hormone-Naïve Prostate Cancer: Long-Term Survival Results From an Adaptive, Multiarm, Multistage, Platform, Randomized Controlled Trial
Malcolm D Mason, Noel W Clarke, Nicholas D James, David P Dearnaley, Melissa R Spears, Alastair W S Ritchie, Gerhardt Attard, William Cross, Rob J Jones, Christopher C Parker, J Martin Russell, George N Thalmann, Francesca Schiavone, Estelle Cassoly, David Matheson, Robin Millman, Cyrill A Rentsch, Jim Barber, Clare Gilson, Azman Ibrahim, John Logue, Anna Lydon, Ashok D Nikapota, Joe M O'Sullivan, Emilio Porfiri, Andrew Protheroe, Narayanan Nair Srihari, David Tsang, John Wagstaff, Jan Wallace, Catherine Walmsley, Mahesh K B Parmar, Matthew R Sydes, STAMPEDE Investigators, Malcolm D Mason, Noel W Clarke, Nicholas D James, David P Dearnaley, Melissa R Spears, Alastair W S Ritchie, Gerhardt Attard, William Cross, Rob J Jones, Christopher C Parker, J Martin Russell, George N Thalmann, Francesca Schiavone, Estelle Cassoly, David Matheson, Robin Millman, Cyrill A Rentsch, Jim Barber, Clare Gilson, Azman Ibrahim, John Logue, Anna Lydon, Ashok D Nikapota, Joe M O'Sullivan, Emilio Porfiri, Andrew Protheroe, Narayanan Nair Srihari, David Tsang, John Wagstaff, Jan Wallace, Catherine Walmsley, Mahesh K B Parmar, Matthew R Sydes, STAMPEDE Investigators
Abstract
Purpose Systemic 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 Methods Standard 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. Results A 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. Conclusion These data show no overall evidence of improved survival with Cel. Preplanned subgroup analyses provide hypotheses for future studies.
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References
- Parmar MK, Barthel FM, Sydes M, et al. Speeding up the evaluation of new agents in cancer. J Natl Cancer Inst. 2008;100:1204–1214.
- Sydes MR, Parmar MK, James ND, et al. Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: The MRC STAMPEDE trial. Trials. 2009;10:39.
- James ND, Sydes MR, Clarke NW, et al. 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. 2016;387:1163–1177.
- Vale CL, Burdett S, Rydzewska LH, et al. Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: A systematic review and meta-analyses of aggregate data. Lancet Oncol. 2016;17:243–256.
- Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive orostate cancer. N Engl J Med. 2015;373:737–746.
- Gravis G, Boher JM, Joly F, et al. Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: Impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial. Eur Urol. 2016;70:256–262.
- NHS England: Clinical commissioning policy statement: Docetaxel in combination with androgen deprivation therapy for the treatment of hormone naïve metastatic prostate cancer–NHS England Reference: [B15/PS/a]: NHS England. .
- Parker C, Gillessen S, Heidenreich A, et al. Cancer of the prostate: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26:v69–v77.
- Eberhart CE, Coffey RJ, Radhika A, et al. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 1994;107:1183–1188.
- Masferrer JL, Leahy KM, Koki AT, et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res. 2000;60:1306–1311.
- Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part II) J Natl Cancer Inst. 1998;90:1609–1620.
- Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part I) J Natl Cancer Inst. 1998;90:1529–1536.
- Basler JW, Piazza GA. Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective inhibitors for prostate cancer chemoprevention. J Urol 171:S59- S62, 2004; discussion 562-563.
- Nelson JE, Harris RE. Inverse association of prostate cancer and non-steroidal anti-inflammatory drugs (NSAIDs): results of a case-control study. Oncol Rep. 2000;7:169–170.
- Roberts RO, Jacobson DJ, Girman CJ, et al. A population-based study of daily nonsteroidal anti-inflammatory drug use and prostate cancer. Mayo Clin Proc. 2002;77:219–225.
- Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96:879–882.
- Montague R, Hart CA, George NJ, et al: Differential inhibition of invasion and proliferation by bisphosphonates: anti-metastatic potential of Zoledronic acid in prostate cancer. Eur Urol 46:389-401, 2004; discussion 401-402.
- Dearnaley DP, Mason MD, Parmar MKB, et al. Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: Long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol. 2009;10:872–876.
- James ND, Sydes MR, Mason MD, et al. Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: First results from the STAMPEDE multiarm, multistage, randomised controlled trial. Lancet Oncol. 2012;13:549–558.
- Sydes MR, Parmar MK, Mason MD, et al. Flexible trial design in practice - stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: A multi-arm multi-stage randomized controlled trial. Trials. 2012;13:168.
- Royston P, Parmar MKB, Qian W. Novel designs for multi-arm clinical trials with survival outcomes with an application in ovarian cancer. Stat Med. 2003;22:2239–2256.
- James ND, Spears MR, Clarke NW, et al. Failure-free survival and radiotherapy in patients with newly diagnosed nonmetastatic prostate cancer: Data from patients in the control arm of the STAMPEDE trial. JAMA Oncol. 2016;2:348–357.
- Royston P, Parmar MK. Flexible parametric proportional-hazards and proportional-odds models for censored survival data, with application to prognostic modelling and estimation of treatment effects. Stat Med. 2002;21:2175–2197.
- Pantziarka P, Sukhatme V, Bouche G, et al. Repurposing Drugs in Oncology (ReDO)-diclofenac as an anti-cancer agent. Ecancermedicalscience. 2016;10:610.
- Witters LM, Crispino J, Fraterrigo T, et al. Effect of the combination of docetaxel, zoledronic acid, and a COX-2 inhibitor on the growth of human breast cancer cell lines. Am J Clin Oncol. 2003;26:S92–S97.
- Brown M, Roulson JA, Hart CA, et al. Arachidonic acid induction of Rho-mediated transendothelial migration in prostate cancer. Br J Cancer. 2014;110:2099–2108.
- Gillessen S, Gilson C, James N, et al. Repurposing metformin as therapy for prostate cancer within the STAMPEDE Trial Platform. Eur Urol. 2016;70:906–908.
- Attard G, Sydes MR, Mason MD, et al. Combining enzalutamide with abiraterone, prednisone, and androgen deprivation therapy in the STAMPEDE trial. Eur Urol. 2014;66:799–802.
- Warde P, Mason M, Ding K, et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: A randomised, phase 3 trial. Lancet. 2011;378:2104–2111.
- Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): An open randomised phase III trial. Lancet. 2009;373:301–308.
Source: PubMed