CUA 2017: Fatigue in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Enzalutamide: Data from Randomized Clinical Trials

Toronto, Ontario (UroToday.com) Enzalutamide (Enza) is a novel androgen inhibitor with established efficacy in metastatic castration-resistant prostate cancer (CRPC). The AFFIRM and PREVAIL trials established its efficacy in the post-chemotherapy and pre-chemotherapy phases (***). Along with abiraterone (Abi), it is one of two approved oral agents for this disease state. However, the decision to utilize one over the other is often determined by adverse event profiles and contraindications. 

Fatigue, defined as a state of generalized weakness, with a pronounced inability to summon sufficient energy to accomplish daily activities, is an adverse event commonly attributed to Enza, more so than with Abi. However, as the authors of this multi-institutional study note, fatigue is common in men with advanced prostate cancer and may be related to disease progression, ongoing systemic therapy, comorbidities, concomitant medications, or a combination of these factors. 

To that effect, they evaluated the fatigue adverse events (AEs) across four double-blind, randomized, placebo- or bicalutamide-controlled trials of Enza for men with metastatic castration-resistant prostate cancer (AFFIRM, PREVAIL, TERRAIN, and STRIVE). Specifically, they assessed incidence, timing, and effect of age on fatigue.

In terms of results, they identified 2051 men in the ENZ arms and 1630 in the control arms. Total treatment exposure patient-years were longer for ENZ (range 219−1294) vs. control (range 143−560). The unadjusted percentages of men reporting fatigue for all grades were slightly higher in Enza arms (range 28−38% vs range 20−29%). Grade 3 fatigue AEs were reported by <10% of men and in similar proportions in both arms (1−6% for ENZ vs. 1−7% for control). 

Adjusting for the length of exposure, the incidence rates of fatigue AEs were similar or lower in the Enza arms (24−47 and 28−71 events per 100 patient-years, respectively). In the first six months, the fatigue incidence in Enza treated men was slightly higher vs. control (26−30% and 17−28%, respectively). Time to fatigue onset in the Enza and control arms was similar. 

In all trials, younger men (<75 years) experienced less fatigue vs. older men (20−35% vs. 21−42%, respectively), regardless of treatment.

Based on this nice analysis, the authors conclude that early-onset fatigue occurred slightly more frequently in Enza-treated patients. However, regardless of treatment, fatigue was more common in men ≥75 years. Grade 3 fatigue was only present in a small percentage of men.

Clinically, this allows us to counsel men that while fatigue can manifest with Enza administration, it is generally not much more than in untreated patients. It should not be a limiting factor for treatment decision making.

Presented By: Fred Saad, MD, FRCS, Urology, Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canad

Co-Authors: Simon Chowdhury1, Neal D Shore2, Celestia S Higano3, Karim Fizazi4, Peter Iversen5, Kurt Miller6, Axel Heidenreich7, Choung Soo Kim8, De Phung9, Andrew Krivoshik10, Fong Wang11, Bertrand Tombal12

Institutions: Oncology, Guy’s, King’s and St Thomas’ Hospitals, London, United Kingdom1; Urology, Carolina Urologic Research Center, Myrtle Beach, SC, United States2; Medicine, University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, WA, United States3; Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Paris, France4; Urology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark5; Urology, Charite´ Campus Benjamin Franklin, Berlin, Germany6; Urology, Cologne University, Cologne, Germany7; Urology, Prostate Cancer, Urologic Cancer Center, Asan Medical Center, Seoul, Korea8; Data Science , Astellas Pharma, Inc., Leiden, Netherlands9; Medical Oncology, Astellas Pharma Global Development, Astellas Pharma, Inc., Northbrook, IL, United States10; Clinical Development, Medivation, Inc., San Francisco, CA, United States11; Urology, Cliniques Universitaires Saint-Luc, Brussels, Belgium12

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto   Twitter: @tchandra_uromd at the  72nd Canadian Urological Association Annual Meeting - June 24 - 27, 2017 - Toronto, Ontario, Canada

References:
1. Increased survival with enzalutamide in prostate cancer after chemotherapy.
Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Fléchon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS; AFFIRM Investigators. N Engl J Med. 2012 Sep 27;367(13):1187-97. Epub 2012 Aug 15.

2. Enzalutamide in metastatic prostate cancer before chemotherapy.
Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B; PREVAIL Investigators. N Engl J Med. 2014 Jul 31;371(5):424-33. doi: 10.1056/NEJMoa1405095. Epub 2014 Jun 1.

3. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study.
Shore ND, Chowdhury S, Villers A, Klotz L, Siemens DR, Phung D, van Os S, Hasabou N, Wang F, Bhattacharya S, Heidenreich A. Lancet Oncol. 2016 Feb;17(2):153-63. doi: 10.1016/S1470-2045(15)00518-5. Epub 2016 Jan 14.

4. Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial.
Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, Dunshee C, Wang F, Wu K, Krivoshik A, Phung D, Higano CS. J Clin Oncol. 2016 Jun 20;34(18):2098-106. doi: 10.1200/JCO.2015.64.9285. Epub 2016 Jan 25.
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