In an analysis of the final results of two STAMPEDE platform phase III trials reported in The Lancet Oncology, Gerhardt Attard, PhD, and colleagues found that the addition of enzalutamide to abiraterone plus prednisolone did not appear to improve survival outcomes and was associated with worse toxicity among patients with metastatic prostate cancer initiating androgen-deprivation therapy (ADT).
Gerhardt Attard, PhD
As stated by the investigators, “Abiraterone acetate plus prednisolone or enzalutamide added at the start of [ADT] improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and [ADT] improves survival.”
Study Details
In the two open-label trials—conducted at sites in the UK and Switzerland—patients were randomly assigned:
- Between November 2011 and January 2014 to receive standard of care (ADT, docetaxel at 75 mg/m² for six cycles with prednisolone at 10 mg per day) or standard of care plus abiraterone at 1,000 mg and prednisolone at 5 mg (abiraterone trial; standard-of-care group = 502, abiraterone group = 501); or
- Between July 2014 and March 2016 to receive standard of care (n = 454) or abiraterone and prednisolone plus enzalutamide at 160 mg once a day (n = 462; abiraterone/enzalutamide trial).
The primary outcome measure was overall survival in the intention-to-treat population.
Key Findings
Median follow-up was 96 months (interquartile range [IQR] = 86–107 months) in the abiraterone trial and 72 months (IQR = 61–74 moths) in the abiraterone/enzalutamide trial.
In the abiraterone trial, median overall survival was 76.6 months (95% confidence interval [CI] = 67.8–86.9 months) in the abiraterone group vs 45.7 months (95% CI = 41.6–52.0 months) in the standard-of-care group (hazard ratio [HR] = 0.62, 95% CI = 0.53–0.73, P < .0001). In the abiraterone/enzalutamide trial, median overall survival was 73.1 months (95% CI = 61.9–81.3 months) in the abiraterone/enzalutamide group vs 51.8 months (95% CI = 45.3–59.0 months) in the standard-of-care group (HR = 0.65, 95% CI = 0.55–0.77, P < .0001).
In a fixed-effect meta-analysis of individual patient data, no difference in treatment effect between the two trials was observed (interaction HR = 1.05, 95% CI = 0.83–1.32, P = 0.71 for interaction) and no evidence of between-trial heterogeneity (P = .70 for I²) was identified.
In the first 5 years of treatment, grade ≥ 3 adverse events occurred in 54% of patients in the abiraterone group vs 38% of the standard-of-care group in the abiraterone trial and in 68% of patients in the abiraterone/enzalutamide group vs 45% of the standard-of-care group in the abiraterone/enzalutamide trial. The most common cause of death due to adverse events was cardiac events, occurring in five patients in the abiraterone/enzalutamide group (treatment-related in two) and one patient receiving the standard-of-care regimen in the abiraterone trial.
The investigators concluded, “Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term [ADT]. Clinically important improvements in survival from [the] addition of abiraterone to [ADT] are maintained for longer than 7 years.”
Dr. Attard, of the Cancer Institute, University College London, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas. For full disclosures of the study authors, visit thelancet.com.
