mHSPC remains an incurable manifestation of the disease. While ADT, with or without non-steroidal antiandrogens, has been the backbone of mHSPC treatment for many decades, ADT alone is no longer considered sufficient treatment for mHSPC. Multiple studies have shown that additional therapy significantly extends OS and PFS in mHSPC patients. Abiraterone Acetate Abiraterone acetate, an androgen biosynthesis inhibitor, is a non-steroidal irreversible inhibitor of CYP17A1, which catalyzes the conversion of C21 progesterone precursors to C19 adrenal androgens, DHEA, and androstenedione.88 In essence, abiraterone acetate is similar to ADT, but it is more potent, inhibiting gonadal and extragonadal androgen synthesis. In the double-blind, placebo-controlled, phase III LATITUDE trial, 1,199 patients were randomly assigned to receive either ADT plus abiraterone acetate (1,000mg given once daily as four 250mg tablets) plus prednisone (5mg daily) or ADT plus placebo. The primary endpoints were OS and radiographic PFS. After a median follow-up of 30.4 months at a planned interim analysis, the median OS was significantly longer in the abiraterone acetate group than in the placebo group (not reached versus 34.7 months) (HR=0.62; 95% CI: 0.51 to 0.76; p<0.001). The median length of radiographic PFS was 33.0 months in the abiraterone acetate group and 14.8 months in the placebo group (HR=0.47; 95% CI: 0.39 to 0.55; p<0.001). Updated results continue to confirm benefit in this trial. The final analysis of this trial, at a median follow-up of 51.8 months, OS was significantly longer in the abiraterone acetate plus prednisone group (median 53.3 months [95% CI: 48.2 to not reached]) compared to the placebo group (36.5 months [33.5 to 40.0]), with an HR of 0.66 (95% CI: 0.56 to 0.78; p<0.0001).89 In the STAMPEDE trial,90 1,917 patients were randomized in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1,000mg daily) and prednisolone (5mg daily). A total of 52% of patients had metastatic disease. The primary outcome was OS. The median follow-up was 40 months. There were 184 deaths in the abiraterone acetate group compared with 262 in the ADT group (HR=0.63; 95% CI: 0.52 to 0.76; p<0.001); the HR was 0.61 in those with metastatic disease. Abiraterone acetate can elevate liver enzyme levels, and should be avoided in patients where liver toxicity is a concern. As such, clinicians should monitor liver enzymes as well as potassium levels. Adverse events in the LATITUDE trial included mineralocorticoid-related hypertension (20%) and hypokalemia (10%). Further, the use of a steroid in combination with treatments for metastatic disease may require additional considerations for patients with comorbid conditions, such as diabetes or significant osteoporosis. Apalutamide Apalutamide is an ARPI. This oral agent acts as an AR inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription.91 In the double-blind, phase III TITAN study,92 525 patients were assigned to receive apalutamide (240mg daily) with ADT compared to 527 patients receiving placebo plus ADT. Primary endpoints included radiographic PFS and OS. At a median of 22.7 months follow-up, the percentage of patients with radiographic PFS at 24 months was 68.2% in the apalutamide group compared to 47.5% in the placebo group (HR=0.48; 95% CI: 0.39 to 0.60; p<0.001). OS at 24 months was greater with apalutamide compared to placebo (82.4% versus 73.5%; HR=0.67; 95% CI: 0.51 to 0.89; p=0.005). At the time of final analysis (44.0 months median follow-up), a total of 405 deaths had occurred (170 in the apalutamide arm, 235 in the placebo arm). An improvement in median OS was observed: not reached in the apalutamide group versus 52.2 months in the placebo group (HR=0.65; 95% CI: 0.53 to 0.79; p<0.0001), with a 35% reduction in risk of death.93 Rash of any grade was more common among patients who received apalutamide compared to those who received placebo (27.1% versus 8.5%) including the risk of Stevens-Johnson syndrome/toxic epidermal necrolysis.94 Enzalutamide Enzalutamide is an ARPI. It is a competitive inhibitor of androgen binding and also inhibits nuclear translocation of the AR, DNA-binding and coactivator recruitment.95 In the open-label, randomized, phase III ENZAMET trial,96 1,125 men were randomized to receive testosterone suppression plus either open-label enzalutamide (160mg daily) or a standard non-steroidal antiandrogen therapy (bicalutamide, nilutamide, or flutamide—standard care). The primary end point was OS. With a median follow-up of 34 months, there were 102 deaths in the enzalutamide group compared to 143 deaths in the standard care group (HR=0.67; 95% CI: 0.52 to 0.86; p=0.002). Kaplan-Meier estimates of OS at 3 years were 80% in the enzalutamide group and 72% in the standard care group. Discontinuation of treatment due to adverse events was more frequent in the enzalutamide group (33 events versus 14 events, respectively). Fatigue was more common in the enzalutamide group, and seizures occurred in 7 patients in the enzalutamide group (1%) compared to 0 patients in the standard care group. In this trial, approximately 16% of patients also received docetaxel and this study did not impact the observed benefit of enzalutamide. This trial did not address the role of early intensification by adding docetaxel to enzalutamide. In the double-blind, phase III ARCHES trial, Armstrong et al. randomly assigned 1,150 men with mHSPC in a 1:1 ratio to receive either enzalutamide (160mg per day) or placebo. All patients also received ADT. The primary endpoint was radiographic PFS. As of October 2018, the risk of radiographic PFS or death was significantly reduced with enzalutamide plus ADT versus placebo plus ADT (median not reached versus 19.0 months; HR=0.39; 95% CI: 0.30 to 0.50; p<0.001). Similar improvements were also seen in risk of PSA progression, initiation of new antineoplastic therapy, first symptomatic skeletal event, castration-resistance, and reduced risk of pain progression. In an update on this trial, the final pre-specified analysis of OS, which was a key secondary end point, and an update on radiographic PFS was reported. Following unblinding, 180 (31.3%) progression-free patients randomly assigned to placebo plus ADT crossed over to open-label enzalutamide plus ADT. At a median follow-up of 44.6 months, 154 of 574 patients randomly assigned to enzalutamide plus ADT and 202 of 576 patients randomly assigned to placebo plus ADT had died. Enzalutamide plus ADT reduced risk of death by 34% versus placebo plus ADT (median not reached in either group; HR=0.66; 95% CI: 0.53 to 0.81; p<0.001).97 Darolutamide Darolutamide is an ARPI. The ARANOTE trial98 was a global, phase III trial that randomized 669 patients with mHSPC to ADT with darolutamide versus ADT with placebo in a 2:1 ratio. Darolutamide 600mg was given twice daily. Primary endpoint was radiographic PFS. After median follow-up of 25 months, rate of radiographic progression was 28.7% in the darolutamide groups versus 42.2% in the placebo group. Darolutamide plus ADT significantly improved rPFS (HR=0.54; 95% CI: 0.41 to 0.71; p<0.0001). There was also delayed time to mCRPC (HR=0.40; 95% CI: 0.32 to 0.51) and time to pain progression (HR=0.72; 95% CI: 0.54 to 0.96). At the primary cutoff date, difference in OS was not significant but favored darolutamide. Tolerability was similar between groups and rates of fatigue was lower in patients who received darolutamide versus placebo (5.6% versus 8.1%).    Docetaxel Docetaxel is a potent inhibitor of microtubule assembly and disassembly. Two clinical trials demonstrated the benefits of adding docetaxel chemotherapy to ADT for mHSPC patients. In the phase III CHAARTED study,99 790 patients with mHSPC were equally randomized to receive either ADT in combination with docetaxel (75mg/m2) for up to 6 cycles or ADT alone. In an updated reporting on the trials, at a median follow-up of 53.7 months, the median OS was 57.6 months for the chemo-hormonal therapy arm versus 47.2 months for ADT alone (HR=0.72; 95% CI: 0.59 to 0.89; p=0.0018). The median time to clinical progression was 33.0 months for the combination arm versus 19.8 months in the ADT alone arm (HR in the combination arm=0.62; 95% CI: 0.51 to 0.75; p<0.001). Similarly, in the STAMPEDE trial, ADT plus docetaxel significantly improved median OS compared with ADT alone. The study randomly assigned 2,962 men 2:1:1:1 to receive SOC defined as hormone therapy for at least 2 years, SOC plus zoledronic acid, SOC plus docetaxel, or SOC with zoledronic acid and docetaxel. Docetaxel (75mg/m2) was given for six 3-week cycles with prednisolone (10mg) daily. Patients were followed up 6-weekly to 6 months, 12-weekly to 2 years, 6-monthly to 5 years, then annually. At a median follow-up of 43 months, median OS was 71 months for SOC compared to 81 months for SOC plus docetaxel (HR=0.78; 95% CI: 0.66 to 0.93; p=0.006). SOC plus docetaxel also improved median failure-free survival at 37 months compared 20 months with SOC alone. The durability of these results was supported in an update of this trial. At a median follow-up of 78.2 months, there were 494 deaths on SOC. There was good evidence of benefit in docetaxel over SOC on OS (HR=0.81; 95% CI: 0.69 to 0.95; p=0.009). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR=0.66; 95% CI: 0.57 to 0.76; p<0.001) and PFS (HR=0.69; 95% CI: 0.59 to 0.81; p<0.001).97 Since the publication of these two studies, additional trials (PEACE-1 and ARASENS) demonstrated that the addition of abiraterone or darolutamide to ADT and docetaxel improved OS.100, 101 Therefore, doublet therapy with ADT and docetaxel alone is not advised unless patient cannot receive ARPI. Patients with high-volume disease should be considered for triplet therapy (see Guideline Statement 16).