New England Section of the American Urological Association

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ARCHES - Efficacy of Androgen Deprivation Therapy with Enzalutamide or Placebo in Metastatic Hormone-Sensitive Prostate Cancer: Prostate-Specific Antigen Results
Phillip Lammers, MD1, Arnulf Stenzl, MD2, Russell Z. Szmulewitz, MD3, Daniel Petrylak, MD4, Jeffrey Holzbeierlein, MD5, Arnauld Villers, MD6, Arun Azad, MD7, Antonio Alcaraz, MD8, Boris Alekseev, MD9, Taro Iguchi, MD10, Neal D. Shore, MD11, Brad Rosbrook, MD12, Benoit Baron, MD13, Futoshi Kunieda, MDS14, Robert Morlock, MD15, Krishnan Ramaswamy, MD16, Andrew J. Armstrong, MD17
1Baptist Cancer Center, Memphis, TN; 2University Hospital, Eberhard Karls University of Tübingen, Tübingen, Germany, 3The University of Chicago, Chicago, IL; 4Yale Cancer Center, New Haven, CT; 5The University of Kansas Medical Center, Kansas City, KS; 6University Hospital Centre, Lille University, Lille, France, 7Monash Health, Melbourne, Victoria, Australia, 8Hospital Clinic de Barcelona, Barcelona, Barcelona, Spain, 9Hertzen Moscow Cancer Research Institute, Moscow, Russian Federation, 10Osaka City University Graduate School of Medicine, Osaka, Japan, 11Carolina Urologic Research Center, Myrtle Beach, SC; 12Pfizer Inc., San Diego, CA; 13Astellas Pharma, Inc., Leiden, Netherlands, 14Astellas Pharma, Inc., Northbrook, IL,, IL; 15Astellas Pharma, Inc., Northbrook, IL; 16Pfizer Inc., New York, NY; 17Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, NC

Introduction and Objective: Potent androgen receptor inhibitor enzalutamide (ENZA) provides benefit in men with castration-resistant prostate cancer (CRPC). ARCHES, a multinational, double-blind, placebo (PBO)-controlled, phase 3 study (NCT02677896), examined the efficacy of ENZA with androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC). As an important marker of prostate cancer, here we report prostate-specific antigen (PSA) results for ARCHES.
Methods: Patients (pts) with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume and prior docetaxel. Up to 3 months of ADT (≤ 6 months if with docetaxel), with no radiographic disease progression or rising PSA levels prior to day 1. PSA at initial diagnosis was not collected. Baseline PSA prior to study entry may reflect treatment prior to study entry. The primary endpoint was radiographic progression-free survival (rPFS) [scans assessed centrally] or death within 24 weeks of treatment discontinuation. Prespecified analyses included rPFS (overall and by baseline PSA levels), time to PSA progression, time to castration resistance, PSA undetectable rate, and PSA reduction from baseline. Treatment continued until disease progression or unacceptable toxicity.
Results: 1150 pts were randomized (ENZA + ADT, n = 574; PBO + ADT, n = 576). Baseline characteristics were balanced between groups; 91% had prior ADT. Overall median baseline PSA level was 5.21 ng/mL; median follow-up was 14.4 months. ENZA + ADT significantly improved rPFS overall, regardless of baseline PSA level (Table). ENZA + ADT significantly improved time to PSA progression and time to castration resistance. The proportions of pts with undetectable PSA or a PSA reduction of ≥ 50% or ≥ 90% from baseline during the study were higher with ENZA + ADT. Adverse events were reported in 85.1% of ENZA + ADT pts vs 85.9% of PBO + ADT pts, with no unexpected adverse events.
Conclusions: ENZA + ADT significantly improved rPFS vs PBO + ADT in pts with mHSPC, regardless of baseline PSA level, suggesting the limitation of baseline PSA as a predictive factor in this population in which most pts received prior ADT. However, ENZA + ADT significantly improved PSA-related efficacy endpoints. Preliminary safety analysis appears consistent with the safety profile of ENZA in previous CRPC clinical trials.

ResultsENZA + ADTPBO + ADTHR (95% CI)
Median baseline PSA, no. (ng/mL)572 (5.36)574 (5.07)-
rPFS: overall population, no. (median, mo)574 (NR)576 (19.4)0.39* (0.30-0.50)
rPFS: baseline PSA ≤ median, no. (median, mo)293 (NR)305 (NR)0.37* (0.26-0.54)
rPFS: baseline PSA > median, no. (median, mo)279 (NR)269 (16.7)0.41* (0.29-0.58)
Time to PSA progression, no. (median, mo)574 (NR)576 (NR)0.19* (0.13-0.26)
Time to castration resistance, no. (median, mo)574 (NR)576 (13.9)0.28* (0.22-0.36)
PSA reduction from baseline, no. (%)
≥ 50%
≥ 90%
533 (92.9)
418 (72.8)
327 (56.8)
173 (30.0)
-
-
PSA undetectable (< 0.2 ng/mL) rate, no. (%)348 (68.1*)89 (17.6)-
*P < .0001; Pts with detectable PSA at baseline.
Abbreviations: ADT, androgen deprivation therapy; CI, confidence interval; ENZA, enzalutamide; HR, hazard ratio; NR, not reached; PBO, placebo; PSA, prostate-specific antigen.


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