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.

Kim N. Chi, MD

Study Details

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).

Adverse Events

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.”

Dr. Chi, of the Division of Medical Oncology, BC Cancer, Vancouver, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the Canadian Cancer Society Research Institute, Prostate Cancer Canada, Movember Foundation, Prostate Cancer Foundation, Janssen, Astellas, and others. For full disclosures of the study authors, visit thelancet.com.