Combination Therapy for Metastatic Prostate Cancer

The management of newly diagnosed metastatic prostate cancer had changed little from the days of the seminal work of Huggins and Hodges in the early 1940s until the recent publication of the CHAARTED study (Ann Oncol 2016; 27:243) and the STAMPEDE study (Lancet 2016; 387:1163). Both of these trials provided compelling level-1 evidence that combining standard androgen-deprivation therapy (ADT) with docetaxel significantly improved survival. Now, two groups of investigators have evaluated the efficacy and safety of combining ADT with abiraterone, which blocks androgen synthesis, and prednisolone or prednisone.

In the first study, James and STAMPEDE colleagues compared the use of ADT alone or with abiraterone and prednisolone in 1917 patients with newly diagnosed, locally advanced, or metastatic disease who were starting ADT. Of these patients, 52% had metastatic disease. For those with locally advanced disease, radiotherapy was mandated, and ADT was continued for 2 years or until disease progression.

At a median follow-up of 40 months, 3-year overall survival was improved with combination therapy versus ADT alone (83% vs. 76%; hazard ratio, 0.63; P<0.001), as were treatment-failure–free survival (75% vs. 45%; HR, 0.29; P<0.001) and absence of symptomatic skeletal events (88% vs. 62%; HR, 0.46; P<0.001). More patients in the abiraterone arm had grade 3–5 treatment-related adverse events (47% and 33%, respectively) and cardiovascular events (10% and 4%).

In the second study (LATITUDE), Fizazi and colleagues randomized 1199 patients with newly diagnosed, metastatic, castration-sensitive prostate cancer to receive ADT plus placebo or abiraterone and prednisone.

At a median follow-up of 30.4 months, median OS was longer in the abiraterone group than in the placebo group (not yet reached vs. 34.7 months; hazard ratio, 0.62; P<0.001). At 3-years, OS was 66% in the abiraterone group and 49% in the placebo group, and median radiologic progression-free survival was longer with abiraterone (33.0 vs. 14.8 months; HR 0.47; P<0.001). More placebo recipients received subsequent therapy (52% vs. 40%). The toxicity profile was typical of abiraterone, with an increased rate of hypertension and hypokalemia.