ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer
Andrew J Armstrong, Russell Z Szmulewitz, Daniel P Petrylak, Jeffrey Holzbeierlein, Arnauld Villers, Arun Azad, Antonio Alcaraz, Boris Alekseev, Taro Iguchi, Neal D Shore, Brad Rosbrook, Jennifer Sugg, Benoit Baron, Lucy Chen, Arnulf Stenzl, Andrew J Armstrong, Russell Z Szmulewitz, Daniel P Petrylak, Jeffrey Holzbeierlein, Arnauld Villers, Arun Azad, Antonio Alcaraz, Boris Alekseev, Taro Iguchi, Neal D Shore, Brad Rosbrook, Jennifer Sugg, Benoit Baron, Lucy Chen, Arnulf Stenzl
Abstract
Purpose: Enzalutamide, a potent androgen-receptor inhibitor, has demonstrated significant benefits in metastatic and nonmetastatic castration-resistant prostate cancer. We evaluated the efficacy and safety of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC).
Methods: ARCHES (ClinicalTrials.gov identifier: NCT02677896) is a multinational, double-blind, phase III trial, wherein 1,150 men with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg/day) or placebo, plus androgen deprivation therapy (ADT), stratified by disease volume and prior docetaxel chemotherapy. The primary end point was radiographic progression-free survival.
Results: As of October 14, 2018, the risk of radiographic progression or death was significantly reduced with enzalutamide plus ADT versus placebo plus ADT (hazard ratio, 0.39; 95% CI, 0.30 to 0.50; P < .001; median not reached v 19.0 months). Similar significant improvements in radiographic progression-free survival were reported in prespecified subgroups on the basis of disease volume and prior docetaxel therapy. Enzalutamide plus ADT significantly reduced the risk of prostate-specific antigen progression, initiation of new antineoplastic therapy, first symptomatic skeletal event, castration resistance, and reduced risk of pain progression. More men achieved an undetectable prostate-specific antigen level and/or an objective response with enzalutamide plus ADT (P < .001). Patients in both treatment groups reported a high baseline level of quality of life, which was maintained over time. Grade 3 or greater adverse events were reported in 24.3% of patients who received enzalutamide plus ADT versus 25.6% of patients who received placebo plus ADT, with no unexpected adverse events.
Conclusion: Enzalutamide with ADT significantly reduced the risk of metastatic progression or death over time versus placebo plus ADT in men with mHSPC, including those with low-volume disease and/or prior docetaxel, with a safety analysis that seems consistent with the safety profile of enzalutamide in previous clinical trials in castration-resistant prostate cancer.
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References
- Fitzmaurice C, Akinyemiju TF, Al Lami FH, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: A systematic analysis for the global burden of disease study. JAMA Oncol. 2018;4:1553–1568.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.
- Helgstrand JT, Røder MA, Klemann N, et al. Diagnostic characteristics of lethal prostate cancer. Eur J Cancer. 2017;84:18–26.
- Scher HI, Solo K, Valant J, et al. Prevalence of prostate cancer clinical states and mortality in the United States: Estimates using a dynamic progression model. PLoS One. 2015;10:e0139440.
- Fizazi K, Jenkins C, Tannock IF. Should docetaxel be standard of care for patients with metastatic hormone-sensitive prostate cancer? Pro and contra. Ann Oncol. 2015;26:1660–1667.
- Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373:737–746.
- Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): A randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:149–158.
- 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.
- de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005.
- Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377:352–360.
- James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377:338–351.
- Mottet N, van den Bergh RCN, Briers E, et al: EAU Guidelines. Presented at the EAU Annual Congress Copenhagen, Denmark, March 16 to 20, 2018 (ed 2018). Arnhem, The Netherlands, EAU Guidelines Office, 2018. .
- National Comprehensive Cancer Network: NCCN Clinical practice guidelines in oncology (NCCN Guidelines). Prostate cancer. Version 4. .
- Zytiga (abiraterone acetate) highlights of prescribing information. .
- Zytiga (abiraterone acetate) summary of product characteristics. .
- Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–790.
- Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424–433.
- Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187–1197.
- Shore ND, Chowdhury S, Villers A, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): A randomised, double-blind, phase 2 study. Lancet Oncol. 2016;17:153–163.
- Penson DF, Armstrong AJ, Concepcion R, et al. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: The STRIVE trial. J Clin Oncol. 2016;34:2098–2106.
- Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378:2465–2474.
- Tombal B, Borre M, Rathenborg P, et al. Long-term antitumor activity and safety of enzalutamide monotherapy in hormone naïve prostate cancer: 3-year open label followup results. J Urol. 2018;199:459–464.
- Tombal B, Borre M, Rathenborg P, et al. Enzalutamide monotherapy in hormone-naive prostate cancer: Primary analysis of an open-label, single-arm, phase 2 study. Lancet Oncol. 2014;15:592–600.
- Tombal B, Borre M, Rathenborg P, et al. Long-term efficacy and safety of enzalutamide monotherapy in hormone-naïve prostate cancer: 1- and 2-year open-label follow-up results. Eur Urol. 2015;68:787–794.
- Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26:1148–1159.
- Skaltsa K, Longworth L, Ivanescu C, et al. Mapping the FACT-P to the preference-based EQ-5D questionnaire in metastatic castration-resistant prostate cancer. Value Health. 2014;17:238–244.
- van Andel G, Bottomley A, Fosså SD, et al. An international field study of the EORTC QLQ-PR25: A questionnaire for assessing the health-related quality of life of patients with prostate cancer. Eur J Cancer. 2008;44:2418–2424.
- Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247.
- Braun DP, Gupta D, Staren ED. Predicting survival in prostate cancer: The role of quality of life assessment. Support Care Cancer. 2012;20:1267–1274.
- Tombal B, Saad F, Penson D, et al: Patient-reported outcomes following enzalutamide or placebo in men with non-metastatic castration-resistant prostate cancer (PROSPER): A multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 20:556-569, 2019.
- Basch E. Patient-related outcomes for metastatic prostate cancer. Lancet Oncol. 2015;16:477–478.
- Endocyte announces FDA acceptance of radiographic progression free survival (rPFS) as an alternative primary endpoint of the VISION trial in addition to overall survival (OS). .
- Beaver JA, Kluetz PG, Pazdur R. Metastasis-free survival – A new end point in prostate cancer trials. N Engl J Med. 2018;378:2458–2460.
- Rathkopf DE, Beer TM, Loriot Y, et al. Radiographic progression-free survival as a clinically meaningful end point in metastatic castration-resistant prostate cancer: The PREVAIL randomized clinical trial. JAMA Oncol. 2018;4:694–701.
- Morris MJ, Molina A, Small EJ, et al. Radiographic progression-free survival as a response biomarker in metastatic castration-resistant prostate cancer: COU-AA-302 results. J Clin Oncol. 2015;33:1356–1363.
- Halabi S, Vogelzang NJ, Ou SS, et al. Progression-free survival as a predictor of overall survival in men with castrate-resistant prostate cancer. J Clin Oncol. 2009;27:2766–2771.
- : Enzalutamide in first line androgen deprivation therapy for metastatic prostate cancer (ENZAMET). .
- 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.
- Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: Long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018;36:1080–1087.
Source: PubMed