In the past clinicians used bicalutamide in the nmCRPC patient population as a method to reduce PSA in the absence of trials demonstrating a clinical benefit. In 2018, apalutamide became the first FDA-approved treatment for patients with non-metastatic disease; shortly thereafter, enzalutamide and darolutamide were also approved in this patient population. There are now three FDA approved agents that demonstrate superiority in terms of prolonging MFS by nearly two years. Bicalutamide is no longer a viable strategy for treatment of this patient population. It should also be noted that there are no head-to-head clinical trials demonstrating superiority of any one of these agents (apalutamide, darolutamide, enzalutamide) over the other two. Apalutamide In the double-blind, placebo-controlled, phase III SPARTAN trial, Smith et al. randomly assigned 1,207 men in a 2:1 ratio to receive apalutamide (240mg per day) or placebo.16 All patients had a diagnosis of nmCRPC with a PSADT ≤10 months and continued on ADT. At the time of planned primary analysis, median MFS was 40.5 months in the apalutamide group compared to 16.2 months in the placebo group (HR=0.28; 95% CI: 0.23 to 0.35; p<0.001), representing a 72% reduction in the risk of distant metastasis or death. Median OS was not reached in the apalutamide group versus 39.0 months in the placebo group (HR=0.70; 95% CI: 0.47 to 1.04; p=0.07). Secondary endpoints including time to symptomatic progression (HR=0.45; 95% CI: 0.32 to 0.63; p<0.001) and time to metastasis (HR=0.27; 95% CI: 0.22 to 0.34, p<0.001) were significantly longer in the apalutamide arm compared to placebo. Median PFS was 40.5 months in the apalutamide group versus 14.7 months in the placebo group (HR=0.29; 95% CI: 0.24 to 0.36; p<0.001). Overall, 10.6% of patients receiving apalutamide discontinued treatment due to adverse events compared to 7.0% of patients receiving placebo. The adverse events that occurred in ≥15% of patients in either group (apalutamide versus placebo) included fatigue, hypertension, rash, diarrhea, nausea, weight loss, arthralgia, and falls. Darolutamide ARAMIS is a randomized, double-blind, placebo-controlled, phase III study assessing the safety and efficacy of darolutamide in men with nmCRPC.17 All patients had nmCRPC with a PSADT ≤10 months and PSA ≥2ng/mL (median 9.0 and 9.7ng/mL in the darolutamide versus placebo arms, respectively). The study enrolled 1,509 patients who were randomized in a 2:1 fashion to ADT with darolutamide or ADT with placebo, with a primary endpoint of MFS survival. The median MFS was 22 months longer with darolutamide compared to placebo (40.4 months with darolutamide versus 18.4 months with placebo, HR=0.41; 95% CI: 0.34 to 0.50; p<0.001). Median OS was not reached in either group, but there was a lower risk of death with darolutamide than placebo (HR=0.71; 95% CI: 0.50 to 0.99; p=0.045). The median time to PSA progression was 33.2 months versus 7.3 months in the darolutamide versus placebo groups, respectively (HR=0.13; 95% CI: 0.11 to 0.16; p<0.001). Treatment discontinuation due to adverse events occurred in 8.9% of patients receiving darolutamide compared to 8.7% receiving placebo. Enzalutamide PROSPER is a randomized, double-blind, placebo-controlled, phase III study evaluating the efficacy and tolerability of enzalutamide in nmCRPC patients.15 All patients had nmCRPC with a PSADT ≤10 months. The 1,401 patients were randomized (2:1) to enzalutamide 160mg per day or placebo. Both arms continued ADT. During the first interim analysis of OS, 103 patients (11%) in the enzalutamide group and 62 (13%) in the placebo group had died. Median OS was not reached in either group. As of June 2017, a total of 219 patients (23%) in the enzalutamide group had metastases or had died, as compared with 228 (49%) in the placebo group. Median MFS was approximately 22 months longer in the enzalutamide arm at 36.6 months compared to 14.7 months in the placebo group (HR=0.29; 95% CI: 0.24 to 0.35; p<0.001). Additionally, median time to PSA progression was approximately 33 months longer in patients receiving enzalutamide compared to those receiving placebo (37.2 months in the enzalutamide group compared to 3.9 months in the placebo group; HR=0.07; p<0.001). Following completion of the systematic review for this guideline, additional data were released on OS as of October 2019. In the enzalutamide group, the median OS was 67.0 months (95% CI: 64.0 to not reached) and 56.3 months (95% CI: 54.4 to 63.0) in the placebo group. Treatment with enzalutamide plus ADT was associated with a 27% lower risk of death versus placebo plus ADT (HR=0.73; 95% CI: 0.61 to 0.89; p=0.001).109 Adverse events as the primary reason for treatment discontinuation occurred in 87 patients (9%) receiving enzalutamide compared to 28 (6%) receiving placebo. Deaths due to adverse events on trial irrespective of attribution occurred in 32 patients (3%) receiving enzalutamide and 3 patients (1%) receiving placebo. Adverse events noted to occur more frequently with enzalutamide included convulsion, hypertension, neutropenia, memory impairment disorders, and major cardiovascular events. Data from the STRIVE and TERRAIN trials110, 111 suggest that bicalutamide is not a reasonable option for treatment of men with nmCRPC. In STRIVE, Penson et al. randomized (1:1) a mixed population of men diagnosed with non-metastatic (n=139) or metastatic (n=257) CRPC to receive enzalutamide 160mg per day or bicalutamide 50mg per day. Both arms remained on ADT. The treatment effect of enzalutamide on PFS was consistently favorable across all patient populations, and median PFS was not reached with enzalutamide in the non-metastatic population compared with 8.6 months with bicalutamide (HR=0.24; 95% CI: 0.14 to 0.42; p<0.001). PSA decline, defined as ≥50% and ≥90% decline from baseline, favored enzalutamide (enzalutamide: 91% versus bicalutamide: 42% and enzalutamide: 76% versus bicalutamide: 12%, respectively). Analysis of other secondary endpoints, such as decreased risk of radiographic progression or death, favored enzalutamide with a 76% risk reduction (HR=0.24; 95% CI: 0.10 to 0.56). In TERRAIN, men with mCRPC were randomized to treatment with ADT plus enzalutamide 160mg per day or bicalutamide 50mg per day, and were followed to assess the primary endpoint of PFS. Median PFS was significantly prolonged in men treated with enzalutamide when compared with bicalutamide (15.7 months versus 5.8 months for enzalutamide versus bicalutamide, respectively, HR = 0.44; 95% CI: 0.34 to 0.57; p<0.0001).111 The Panel does not recommend the use of abiraterone acetate plus prednisone for men with nmCRPC because of other options and lack of an FDA-approved indication for this clinical space. However, in a single arm study of 131 men with nmCRPC at high risk of developing metastatic disease as identified by a PSADT of ≤10 months, patients treated with abiraterone acetate plus prednisone had a PSA significantly reduced by ≥ 50% in 86.9% of cases (p<0.0001).112 Additionally, median time to PSA progression was 28.7 months (95% CI: 21.2 to 38.2). The data are not considered sufficient to confirm clinical benefit in the nmCRPC population, particularly in the setting of three FDA-approved alternative treatment options.