Comorbid diseases influence patient outcomes, yet little is known about how comorbidities interact with treatments for metastatic castrate-resistant prostate cancer (mCRPC). No head-to-head trials have compared the efficacy of abiraterone and enzalutamide - oral androgen-receptor targeted agents (ARTAs) for mCRPC. In patients with comorbid disease, outcomes with ARTAs may differ due to disparate mechanisms of action, adverse events, and drug interactions.
Retrospective observational study of US veterans initiating treatment for mCRPC with abiraterone or enzalutamide between September 2014 and June 2017. Treatment duration and overall survival (OS) was compared based on age and comorbid diseases. The association between ARTA and OS was assessed using Cox proportional hazards and propensity-score matched modeling while adjusting for potential confounders. Sensitivity analyses were performed based on patient age, comorbidities, and subsequent treatments for mCRPC.
Of 5822 veterans treated for mCRPC, 43.0% initially received enzalutamide and 57.0% abiraterone. Veterans initially treated with enzalutamide versus abiraterone were older (mean 75.8 vs. 75.0 years) with higher mean Charlson comorbidity index (4.4 vs. 4.1), and higher rates of cardiovascular disease or diabetes (74.2% vs. 70.6%). In the entire population, veterans initially treated with enzalutamide had longer median OS compared to those initially treated with abiraterone (24.2 vs. 22.1 months, p = 0.001). In veterans with cardiovascular disease or diabetes, median treatment duration with enzalutamide was longer (11.4 vs. 8.6 months, p < 0.001) with longer median OS compared to abiraterone (23.2 vs. 20.5 months, p < 0.001). In a propensity score matched cohort, enzalutamide was associated with decreased mortality compared to abiraterone (HR 0.90, 95% CI 0.84–0.96).
Veterans with cardiovascular disease or diabetes had longer treatment duration and OS with enzalutamide compared to abiraterone. Further study of ARTA selection may benefit men with metastatic castrate resistant prostate cancer and likely hormone sensitive prostate cancer, especially among patients with comorbid diseases.
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de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl J Med. 2011;364:1995–2005.
Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl J Med. 2012;367:1187–97.
Halwani AS, Rasmussen KM, Patil V, Li CC, Yong CM, Burningham Z, et al. Real-world practice patterns in veterans with metastatic castration-resistant prostate cancer. Urologic Oncol. 2020;38:1 e–e10.
Khalaf DJ, Annala M, Taavitsainen S, Finch DL, Oja C, Vergidis J, et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. Lancet Oncol. 2019;20:1730–9.
Izumi K, Mizokami A, Namiki M, Inoue S, Tanaka N, Yoshio Y, et al. Enzalutamide versus abiraterone as a first-line endocrine therapy for castration-resistant prostate cancer (ENABLE study for PCa): a study protocol for a multicenter randomized phase III trial. BMC Cancer. 2017;17:677.
Wang X, Yang H, Hu X, Wang W, Yu X, Wang S, et al. Comparing the clinical efficacy and safety of abiraterone and enzalutamide in metastatic castration-resistant prostate cancer: A systematic review and meta-analysis. J Oncol Pharm Pr. 2021;27:614–22.
Tassinari D, Cherubini C, Roudnas B, Tamburini E, Drudi F, Bianchi E, et al. Treatment of metastatic, castration-resistant, docetaxel-resistant prostate cancer: a systematic review of literature with a network meta-analysis of randomized clinical Trials. Rev Recent Clin Trials. 2018;13:226–37.
McCool R, Fleetwood K, Glanville J, Arber M, Goodall H, Naidoo S. Systematic review and network meta-analysis of treatments for chemotherapy-naive patients with Asymptomatic/Mildly symptomatic metastatic castration-resistant prostate cancer. Value Health: J Int Soc Pharmacoeconomics Outcomes Res. 2018;21:1259–68.
Pal SK, Sartor O. Prostate cancer: The best fit for enzalutamide in metastatic prostate cancer. Nat Rev Clin Oncol. 2014;11:504–6.
Chamie K, Daskivich TJ, Kwan L, Labo J, Dash A, Greenfield S, et al. Comorbidities, treatment and ensuing survival in men with prostate cancer. J Gen Intern Med. 2012;27:492–9.
Bennett CL, Greenfield S, Aronow H, Ganz P, Vogelzang NJ, Elashoff RM. Patterns of care related to age of men with prostate cancer. Cancer 1991;67:2633–41.
Matthes KL, Limam M, Pestoni G, Held L, Korol D, Rohrmann S. Impact of comorbidities at diagnosis on prostate cancer treatment and survival. J cancer Res Clin Oncol. 2018;144:707–15.
Lu-Yao G, Nikita N, Keith SW, Nightingale G, Gandhi K, Hegarty SE, et al. Mortality and hospitalization risk following oral androgen signaling inhibitors among men with advanced prostate cancer by pre-existing cardiovascular comorbidities. Eur Urol. 2020;77:158–66.
Soleimani M, Zou K, Sunderland K, Struss W, Eigl BJ, Nappi L, et al. Effectiveness of first-line abiraterone versus enzalutamide among patients >/=80 years of age with metastatic castration-resistant prostate cancer: A retrospective propensity score-weighted comparative cohort study. Eur J Cancer. 2021;152:215–22.
Hu J, Aprikian AG, Vanhuyse M, Dragomir A. Comparative cardiovascular safety of novel hormonal agents in metastatic castration-resistant prostate cancer using real-world data. Clin Genitourin Cancer. 2022;20:17–24.
Riekhof F, Luo S, Cheranda N, Govindan S, Sanfilippo KM, Schoen MW. Hospitalizations and common infections among veterans treated for metastatic prostate cancer. J Clin Oncol. 2022;40(6_suppl):92.
Scailteux LM, Despas F, Balusson F, Campillo-Gimenez B, Mathieu R, Vincendeau S, et al. Hospitalization for adverse events under abiraterone or enzalutamide exposure in real-world setting: A French population-based study on prostate cancer patients. Br J Clin Pharm. 2022;88:336–46.
Sun L, Parikh RB, Hubbard RA, Cashy J, Takvorian SU, Vaughn DJ, et al. Assessment and management of cardiovascular risk factors among US veterans with prostate cancer. JAMA Netw Open. 2021;4:e210070.
Tagawa ST, Ramaswamy K, Huang A, Mardekian J, Schultz NM, Wang L, et al. Survival outcomes in patients with chemotherapy-naive metastatic castration-resistant prostate cancer treated with enzalutamide or abiraterone acetate. Prostate Cancer Prostatic Dis. 2021;24:1032–40.
Scailteux LM, Campillo-Gimenez B, Kerbrat S, Despas F, Mathieu R, Vincendeau S, et al. Overall survival among chemotherapy-naive patients with castration-resistant prostate cancer under abiraterone versus enzalutamide: A Direct Comparison Based on a 2014-2018 French Population Study (the SPEAR Cohort). Am J Epidemiol. 2021;190:413–22.
Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377:352–60.
Romano PS, Roos LL, Jollis JG. Presentation adapting a clinical comorbidity index for use with ICD-9-CM administrative data: Differing perspectives. J Clin Epidemiol. 1993;46:1075–9.
Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi J-C, et al. Coding Algorithms for Defining Comorbidities in ICD-9-CM and ICD-10 Administrative Data. Med Care. 2005;43:1130–9.
Flaig TW, Potluri RC, Ng Y, Todd MB, Mehra M, Higano CS. Disease and treatment characteristics of men diagnosed with metastatic hormone-sensitive prostate cancer in real Life: Analysis from a commercial claims database. Clin Genitourin cancer. 2017;15:273–9.e1.
Riviere P, Luterstein E, Kumar A, Vitzthum LK, Deka R, Sarkar RR, et al. Survival of African American and non-Hispanic white men with prostate cancer in an equal-access health care system. Cancer 2020;126:1683–90.
Halabi S, Ou SS, Vogelzang NJ, Small EJ. Inverse correlation between body mass index and clinical outcomes in men with advanced castration-recurrent prostate cancer. Cancer 2007;110:1478–84.
Lee HY, Chen HL, Teoh JY, Chen TC, Hao SY, Tsai HY, et al. Abiraterone and enzalutamide had different adverse effects on the cardiovascular system: a systematic review with pairwise and network meta-analyses. Prostate Cancer Prostatic Dis. 2021;24:244–52.
Tsao PA, Estes JP, Griggs JJ, Smith DC, Caram MEV. Cardiovascular and Metabolic Toxicity of Abiraterone in Castration-resistant Prostate Cancer: Post-marketing Experience. Clin Genitourin cancer. 2019;17:e592–e601.
Kulkarni AA, Rubin N, Tholkes A, Shah S, Ryan CJ, Lutsey PL, et al. Risk for stroke and myocardial infarction with abiraterone versus enzalutamide in metastatic prostate cancer patients. ESMO Open. 2021;6:100261.
Cone EB, Reese S, Marchese M, Nabi J, Kilbridge KL, Trinh Q-D. Association of abiraterone and higher odds of cardiac complications compared to enzalutamide. J Clin Oncol. 2020;38:70.
Karantanos T, Karanika S, Gignac G. Uncontrolled diabetes predicts poor response to novel antiandrogens. Endocr Relat Cancer. 2016;23:691–8.
George DJ, Ramaswamy K, Huang A, Russell D, Mardekian J, Schultz NM, et al. Survival by race in men with chemotherapy-naive enzalutamide- or abiraterone-treated metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2022;25:524–30.
Alvarado LC. Do evolutionary life-history trade-offs influence prostate cancer risk? a review of population variation in testosterone levels and prostate cancer disparities. Evol Appl. 2013;6:117–33.
Halabi S, Dutta S, Tangen CM, Rosenthal M, Petrylak DP, Thompson IM Jr, et al. Overall Survival of Black and White Men With Metastatic Castration-Resistant Prostate Cancer Treated With Docetaxel. J Clin Oncol. 2019;37:403–10.
Heiden BT, Eaton DB, Jr., Chang SH, Yan Y, Baumann AA, Schoen MW, et al. Racial Disparities in the Surgical Treatment of Clinical Stage I Non-Small Cell Lung Cancer Among Veterans. Chest. 2022.
Schoen MW, Luo S, Carson KR, Sanfilippo KM. Survival and Treatment of Black Patients with Chronic Lymphocytic Leukemia in the Veterans Health Affairs. Blood 2018;132:4847.
Fillmore NR, Yellapragada SV, Ifeorah C, Mehta A, Cirstea D, White PS, et al. With equal access, African American patients have superior survival compared to white patients with multiple myeloma: a VA study. Blood 2019;133:2615–8.
Martini A, Shah QN, Waingankar N, Sfakianos JP, Tsao CK, Necchi A, et al. The obesity paradox in metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2022;25:472–8.
Vidal AC, Howard LE, de Hoedt A, Kane CJ, Terris MK, Aronson WJ, et al. Obese patients with castration-resistant prostate cancer may be at a lower risk of all-cause mortality: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. BJU Int. 2018;122:76–82.
Vidal AC, Oyekunle T, Howard LE, De Hoedt AM, Kane CJ, Terris MK, et al. Obesity, race, and long-term prostate cancer outcomes. Cancer 2020;126:3733–41.
George DJ, Sartor O, Miller K, Saad F, Tombal B, Kalinovsky J, et al. Treatment Patterns and Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer in a Real-world Clinical Practice Setting in the United States. Clin Genitourin cancer. 2020;18:284–94.
Leuva H, Sigel K, Zhou M, Wilkerson J, Aggen DH, Park YA, et al. A novel approach to assess real-world efficacy of cancer therapy in metastatic prostate cancer. Analysis of national data on Veterans treated with abiraterone and enzalutamide. Semin Oncol. 2019;46:351–61.
de Wit R, de Bono J, Sternberg CN, Fizazi K, Tombal B, Wulfing C, et al. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N. Engl J Med. 2019;381:2506–18.
Fizazi K, Tran N, Fein LE, Matsubara N, Rodríguez Antolín A, Alekseev BY, et al. LATITUDE: A phase III, double-blind, randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naive prostate cancer. Journal of Clinical Oncology. 2017;35 (18_suppl):LBA3-LBA.
We would like to thank Kelley Chadwick-Mansker for her efforts to shepherd this project and maintain compliance. We also appreciate the support of the VA St. Louis Health System Research and Development Service including Dr. Ziyad Al-Aly, Carolyn Williams and the St. Louis VA PREP Team including Amy Garner and Rebecca Kammer. This work was supported by a seed grant to Martin Schoen from the Saint Louis Veterans Affairs Medical Center.
All authors declare no competing financial interests or conflicts of interest related to this manuscript. Dr. Whitmer contributed to this work as an employee of the Saint Louis Veterans Affairs Medical Center prior to her joining Pfizer in 2022.
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Schoen, M.W., Carson, K.R., Eisen, S.A. et al. Survival of veterans treated with enzalutamide and abiraterone for metastatic castrate resistant prostate cancer based on comorbid diseases. Prostate Cancer Prostatic Dis (2022). https://doi.org/10.1038/s41391-022-00588-5