The optimal patients for consideration of “dual intensification” or “triplet therapy” are best represented by the population enrolled in the following two completed trials – patients with de novo disease who are free of major comorbidities. Two recent phase III randomized trials have demonstrated improvement in OS in patients with de novo metastatic prostate cancer receiving either abiraterone acetate (with prednisone) or darolutamide in addition to ADT and docetaxel. The PEACE-1 trial100 enrolled 1,173 patients with de novo metastatic prostate cancer who were randomized to receive ADT plus docetaxel (considered the SOC) plus radiotherapy, SOC plus abiraterone/prednisone or SOC plus abiraterone/prednisone and radiotherapy. In the initial analysis of the study, patients treated with SOC plus abiraterone/prednisone had an improvement in both OS (HR=0.82; 95.1% CI: 0.69 to 0.98; p=0.030) and radiographic PFS (HR=0.54; 99.9% CI: 0.41 to 0.71; p<0.0001) with some increase in toxicity in the abiraterone group, primarily being more hypertension. The ARASENS phase III study101 enrolled 1,306 patients with mHSPC (86.1% of enrolled patients had de novo metastatic disease) and randomized them to receive either darolutamide or placebo in combination with ADT and docetaxel. The trial demonstrated that the combination of darolutamide plus ADT/docetaxel resulted in improved OS, with the risk of death reduced by 32.5% (HR=0.68; 95% CI: 0.57 to 0.80; p<0.001). The frequency of grade 3/4 events was similar between the treatment arms.102 As the majority of patients treated in both PEACE-1 and ARASENS had de novo metastatic disease, the role of “dual intensification” or “triplet therapy” in patients with mHSPC with progression following curative-intent local therapy remains undefined. Therapeutic Decision-Making in mHSPC  Unfortunately, no comparative data on efficacy exist between the previously discussed options. The clinician should consider factors like age and comorbidities when choosing chemotherapy, where toxicity might be more difficult for older patients than fit, younger patients. Enzalutamide, apalutamide, and darolutamide do present a small risk of seizures, so patients with a seizure disorder should be considered for a drug like abiraterone acetate plus prednisone. In terms of intermittent ADT, SWOG 9346103 evaluated intermittent ADT compared with continuous ADT and did not demonstrate non-inferiority in mHSPC. In fact, there was a non-significant benefit in OS with continuous ADT. Given all of the recent data suggesting that additional therapy added to continuous ADT significantly improves OS, the Panel generally advises against intermittent ADT.