San Francisco, CA (UroToday.co) The addition of bicalutamide to ongoing ADT has been approved for patients with hormone sensitive prostate cancer. This drug is also commonly used with ADT in the castrate resistant prostate cancer setting.
The TERRAIN study1 has shown that the use of enzalutamide rather than bicalutamide results in a greater benefit in patients with asymptomatic or mildly symptomatic metastatic castrate resistant prostate cancer. In the ENZAMET study,2 patients with hormone sensitive prostate cancer showed significantly longer overall survival with enzalutamide than bicalutamide.
The authors of the study aimed to evaluate real world overall survival in men with chemotherapy naive metastatic castration resistant prostate cancer treated with either first line enzalutamide or abiraterone or sequencing to these agents after treatment with bicalutamide for more than 90 days.
This was a retrospective analysis performed using the Veterans Health Administration database from 2013 to 2018. Chemotherapy-naïve men who either used enzalutamide or abiraterone following surgical and medical castration 12 months prior to the index date were identified. A Cox proportional hazards regression model examined the impact of treatment on overall survival and the impact of first using bicalutamide versus first line use of enzalutamide and abiraterone on overall survival. Adjusted Kaplan Meier analysis was also conducted to graphically depict overall survival.
The results demonstrated a total of 3174 patients with mCRPC in the final sample, who were identified with prescription for either enzalutamide or abiraterone. The enzalutamide cohort included 1229 patients with 161 of them receiving enzalutamide following bicalutamide. In the abiraterone cohort 1945 patients were identified with 317 of them receiving abiraterone following bicalutamide. However, when CRPC status was assessed with PSA data, only 45 of the 317 patients could be shown to have received bicalutamide after becoming castrate resistant. The two cohorts were well balanced although patients receiving enzalutamide were older had a more comorbidities (Table 1).
Table 1: 
Results demonstrated that after a median follow up of 18.27 months in the enzalutamide cohort and 19.07 months in the abiraterone cohort, median duration of first line treatment was longer with enzalutamide then with abiraterone (9.93 months vs. 8.47 months, p=0.0008).
When adjusting for baseline comorbidities, there was a 16% reduced risk of death in the enzalutamide cohort compared with the abiraterone cohort (HR 0.84, 95% CI 0.76-0.94), as shown in figure 2.
Median overall survival was 29.63 months in patients in the enzalutamide cohort compared with 25.87 months in the abiraterone cohort.
Figure 2:
The authors then compared the four subsets of patients with either first line enzalutamide, enzalutamide following bicalutamide, first line abiraterone or abiraterone following bicalutamide. The basic characteristics for these 4 subsets were generally well balanced. Compared to first line abiraterone, abiraterone following bicalutamide lead to shorter overall survival (HR 1.3, 95% CI 1.11-1.52), as shown in figure 3a. In contrast, compared with first line enzalutamide, enzalutamide following bicalutamide resulted in a non-significant effect on overall survival (HR 0.92, 95% CI 0.72-1.19).
Figure 3a: 
When comparing with first line abiraterone, abiraterone following bicalutamide led to shorter overall survival (HR 1.58, 95% CI 1.09-2.29), Figure 3b. Compared with first line abiraterone, enzalutamide following bicalutamide lead to a non-significant trend for shorter overall survival (HR 1.50, 95% CI 0.87-2.60).
Figure 3b:
The median duration of bicalutamide treatment prior to enzalutamide or abiraterone in patients with CRPC was 4.6 months overall, 4 months in patients with subsequent enzalutamide, and 5.2 months in patients with subsequent abiraterone. Interestingly, these results suggest that even if the time on bicalutamide for patients with CRPC was added for the calculation of median overall survival, from the CRPC date, we would find that patients who received bicalutamide first had actually a shorter median over survival as shown below for abiraterone and enzalutamide (figure 3c).
Figure 3c:
The results of overall survival in patients with first line abiraterone, first line enzalutamide and either enzalutamide or abiraterone following bicalutamide were assessed as well. The results showed that first line enzalutamide had longer overall survival, and agnostic enzalutamide or abiraterone following bicalutamide had a significantly shorter overall survival as shown in Figure 4.
Figure 4:
The authors concluded that improved overall survival benefit was apparent in those patients who started treatment with enzalutamide rather than abiraterone. Prescribing bicalutamide prior to abiraterone or enzalutamide had a deleterious effect on overall survival. A median duration of bicalutamide treatment of 4.6 months was associated with a 50% increase in mortality compared with first line abiraterone or enzalutamide.
These data support the hypothesis that delays in administration of life prolonging hormonal therapy in the CRPC state affects overall survival.
Speaker: Daniel George, MD, Professor of Medicine and Surgery, Divisions of Medical Oncology and Urology in the Duke University School of Medicine and leads the Duke Prostate and Urologic Cancer Center, Durham, North Carolina
Written By: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA, Twitter: @GoldbergHanan, at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California.
References:
- 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. The Lancet Oncology 2016; 17(2): 153-63.
- Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. New England Journal of Medicine 2019; 381(2): 121-31.