Study Summary: Use of Enzalutamide for High-Risk, Nonmetastatic, Castration-Resistant Prostate Cancer (PROSPER)

Background

Median survival in men with metastatic, castration-resistant prostate cancer is approximately 3 years. Enzalutamide is an antiandrogen drug used in the treatment of prostate cancer that works by binding directly to the androgen receptor and inhibiting the binding of androgens, thereby preventing androgen-receptor nuclear translocation and androgen-receptor—mediated DNA binding. The results of 2 phase 3 clinical trials have demonstrated that enzalutamide prolonged survival when used in men with metastatic, castration-resistant prostate cancer, regardless of whether enzalutamide was given before or after chemotherapy (docetaxel).¹

In 1 phase 2 trial, enzalutamide prolonged radiographic progression-free survival (PFS) in a subgroup of patients having nonmetastatic, castration-resistant prostate cancer. The PROSPER trial further evaluated the use of enzalutamide in men with nonmetastatic, castration-resistant prostate cancer and rapid PSA doubling times to determine if treatment could delay the development of metastases and ultimately prolong survival.¹

Study Design

The phase 3, international, double-blind, randomized, placebo-controlled PROSPER trial evaluated whether enzalutamide could delay the development of metastases in men with nonmetastatic, castration-resistant prostate cancer and rapid PSA doubling times. Eligible patients had pathologically-confirmed prostate cancer and rising PSA levels (PSA level of ≥2 ng/mL and PSA doubling time of ≤10 months) despite castration-associated testosterone levels. Patients were required to have received androgen-deprivation therapy with a gonadotropin-releasing hormone agonist or antagonist or to have undergone a bilateral orchiectomy. Stratification was based on PSA doubling time (<6 months vs ≥6 months) and use of bone-targeting agents at baseline (previous vs current). Patients were randomized 2:1 to either enzalutamide (160 mg once daily) or placebo.¹

The primary end point was metastasis-free survival (time from randomization to radiographic progression) or time to death from any cause during the period from randomization to 112 days after the discontinuation of treatment without evidence of radiographic progression, whichever occurred first. Secondary end points included time to PSA progression, PSA response rate, time to the first use of subsequent chemotherapy agent, quality of life, overall survival, and safety/tolerability.¹

ResultsBaseline Characteristics

Overall, 1401 patients were randomized (enzalutamide, n = 933; placebo, n = 468). Baseline demographics were generally well balanced between the 2 groups. Among all patients, median PSA doubling time was 3.7 months.¹

Efficacy

Enrollment was stopped after the occurrence of 447 primary end point events. The median duration of treatment was 18.4 months in the enzalutamide group and 11.1 months in the placebo group. At data cutoff, 810 patients were still receiving treatment (enzalutamide, n = 634; placebo, n = 176). The most commonly reported reasons for treatment discontinuation were disease progression (enzalutamide, 15%; placebo, 44%) and adverse events (AEs) (enzalutamide, 10%; placebo, 6%).¹

At data cutoff, a primary end point event was significantly less likely with enzalutamide compared with placebo (23% vs 49%; P <.001); this represented a 71% lower risk of radiographic progression or death with enzalutamide compared with placebo. Median metastasis-free survival was significantly improved with enzalutamide compared with placebo (P <.001). Median metastasis-free survival was 36.6 months with enzalutamide and 14.7 months with placebo.¹

The time to first use of a subsequent chemotherapy agent was significantly longer with enzalutamide compared with placebo (39.6 months vs 17.7 months; P <.001). Fifteen percent of enzalutamide-treated patients and 48% of placebo-treated patients required subsequent chemotherapy. The time to PSA progression was also significantly improved with enzalutamide compared with placebo (37.2 months vs 3.9 months; P <.001). Twenty-two percent of enzalutamide-treated patients and 69% of placebo-treated patients experienced disease progression. At the first interim analysis of overall survival, 11% of enzalutamide-treated patients and 13% of placebo-treated patients had died. Median overall survival was not reached for either group. The percentage of patients who achieved a PSA response (reduction of at least 50% from baseline) was higher with enzalutamide compared with placebo. Quality of life measures were similar among the 2 treatment groups.¹

Safety

Eighty-seven percent of enzalutamide-treated patients experienced an AE, with 31% being grade ≥3 events. Seventy-seven percent of placebo-treated patients experienced an AE, with 23% being grade ≥3. Serious AEs were reported in 24% of enzalutamide-treated patients and in 18% of placebo-treated patients. AEs leading to treatment discontinuation occurred in 9% of enzalutamide-treated patients and in 6% of placebo-treated patients. AEs leading to death occurred in 3% of enzalutamide-treated patients and 1% of placebo-treated patients.¹

The most commonly reported AE in both groups was fatigue (enzalutamide, 33%; placebo, 14%). AEs of special interest (occurring at a frequency ≥2 percentage points higher with enzalutamide vs placebo) were hypertension (12% vs 5%), major adverse cardiovascular events (5% vs 3%), and mental impairment disorders (5% vs 2%).¹

Conclusion

Treatment with enzalutamide decreased metastases or death by 71% in men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level.¹

Reference

1. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465-2474. doi: 10.1056/NEJMoa1800536.