Kim N. Chi, MD
In a Canadian phase II crossover trial reported in The Lancet Oncology, Kim N. Chi, MD, and colleagues found that time to second prostate-specific antigen (PSA) progression from start of treatment was longer with crossover from abiraterone acetate/prednisone to enzalutamide vs the reverse sequence in patients with newly diagnosed metastatic castration-resistant prostate cancer.
In the open-label multicenter trial, 202 newly diagnosed patients were randomly assigned between October 2014 and December 2016 to receive abiraterone acetate at 1,000 mg once daily plus prednisone at 5 mg twice daily followed after PSA progression by enzalutamide at 160 mg once daily (abiraterone-to-enzalutamide group, n = 101) or the reverse sequence (enzalutamide-to-abiraterone group, n = 101). PSA response was defined as ≥ 30% PSA decline from baseline confirmed by repeat measurement at least 28 days later. PSA progression was defined as an increase of 2 µg/L and 25% from nadir confirmed by subsequent rising PSA at least 28 days later. In case of no PSA decline, PSA progression was defined as an increase of 2 µg/L and 25% from baseline after 12 or more weeks of treatment.
The primary endpoints were time to second PSA progression (time from start of first-line therapy to PSA progression on second-line therapy or death from prostate cancer before crossover) and PSA response on second-line therapy.
Time to Second Progression
At data cutoff in May 2018, 73 (72%) patients in the abiraterone-to-enzalutamide group and 75 (74%) in the enzalutamide-to-abiraterone group had crossed over to second-line treatment. On intention-to-treat analysis at a median follow-up of 22.8 months, median time to second PSA progression was 19.3 months vs 15.2 months (hazard ratio [HR] = 0.66, P = .036). PSA response was observed in 36% of 73 patients receiving enzalutamide and 4% of 75 receiving abiraterone as second-line treatment (P < .0001).
Among patients who crossed over to second-line treatment, median time to PSA progression on second-line treatment was 3.5 months in those receiving enzalutamide vs 1.7 months in those receiving abiraterone (HR = 0.42, P < .0001), and median time on second-line treatment was 4.6 months vs 3.6 months (HR = 0.66, P = .023).
In first-line therapy, PSA response was observed in 68% of patients receiving abiraterone/prednisone vs 82% of those receiving enzalutamide (P = .023). However, no significant difference was observed in median time to first progression (11.2 months vs 10.2 months, HR = 0.95, P = .78).
The most common grade 3 or 4 adverse events were hypertension (27% of abiraterone-to-enzalutamide group vs 18% of enzalutamide-to-abiraterone group) and fatigue (10% vs 4%). Serious adverse events were reported in 15% vs 20% of patients. No treatment-related deaths were observed.
The investigators concluded, “Enzalutamide showed activity as a second-line novel androgen receptor pathway inhibitor, whereas abiraterone acetate did not, leading to a longer time to second PSA progression for the sequence of abiraterone followed by enzalutamide than with the opposite treatment sequence. Our data suggest that using a sequencing strategy of abiraterone acetate followed by enzalutamide provides the greatest clinical benefit.”