Enzalutamide Improves Overall Survival In Nonmetastatic CRPC

Author: By Laura Cowen, medwireNews Reporter 

medwireNews: Enzalutamide significantly reduces the risk of death, relative to placebo, in men with nonmetastatic, castration-resistant prostate cancer (CRPC) and rapidly increasing prostate-specific antigen (PSA) levels who are receiving androgen deprivation therapy (ADT), PROSPER trial data show. 

The results from the final overall survival (OS) analysis of the phase III study were presented at the virtual 2020 ASCO Annual Meeting and simultaneously published in The New England Journal of Medicine. 

Cora Sternberg, from Weill Cornell Medicine in New York, USA, and co-authors say: “In line with recent studies, these results add to the growing body of evidence that androgen-receptor inhibitors not only delay the time to metastasis but also improve overall survival among men with nonmetastatic, castration-resistant prostate cancer.” 

The preliminary analysis of the trial data, with a median 23 months of follow-up, showed that enzalutamide plus ADT lowered the risk of metastasis or death without radiographic progression by a significant 71% compared with placebo plus ADT, leading to FDA approval of the combination in this setting. 

The current analysis, at a median 48 months of follow-up, showed that the mortality rate was 31% among the 933 men with a median PSA doubling time of 3.8 months who were randomly assigned to receive enzalutamide 160 mg/day while continuing with ADT. 

By comparison, the mortality rate was 38% among the 468 men with a median PSA doubling time of 3.6 months who were randomly assigned to receive placebo plus ADT. The corresponding rates of prostate cancer-related deaths were 19% and 29%. 

The researchers report that the risk of death was a significant 27% lower in the enzalutamide group than in the placebo group, with median OS times of 67.0 months and 56.3 months, respectively. 

Cora Sternberg and team note that “[t]he treatment effect of enzalutamide was generally consistent across prespecified subgroups, with the possible exception of patients receiving bone-sparing agents”, but they say that small numbers mean this potential anomaly needs further study. 

The median treatment duration was 33.9 months in the enzalutamide group and 14.2 months in the placebo group. 

During treatment, there were no unexpected adverse events (AEs), with exposure-adjusted rates of grade 3 or higher AEs at 17 and 20 cases per 100 patient–years in the enzalutamide and placebo groups, respectively. 

The most commonly reported AEs were fatigue, musculoskeletal events, fracture, hypertension and falls. Of these, falls and fractures were considered events of special interest and both occurred at an exposure-adjusted rate of nine cases per 100 patient–years in the enzalutamide group. The corresponding rates in the placebo group were four and five cases per 100 patient–years. 

Discussing their findings, the investigators say: “As treatments are evaluated at earlier stages of disease and more life-prolonging therapies are available, it is increasingly difficult to show improvements in overall survival in clinical trials. 

“Metastasis-free survival has been shown to be a surrogate for overall survival among patients with intermediate-risk, high-risk, clinically localized prostate cancer.”  

Cora Sternberg et al therefore believe that their results “provide clinical validation for the use of metastasis-free survival as a meaningful end point and as a potential surrogate for overall survival among patients with nonmetastatic, castration-resistant prostate cancer.” 

References 

Sternberg CN, Fizazi K, Saad F, et al. Final overall survival (OS) from PROSPER: A phase III, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol 38: 2020 (suppl; abstr 5515).  

Sternberg C, Fizazi K, Saad F, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med; Advance online publication 29 May 2020. doi: 10.1056/NEJMoa2003892.