July 22, 2018
Advances in Treatment of Nonmetastatic Prostate Cancer: In 2018, the FDA approved the antiandrogens apalutamide (Erleada®) and enzalutamide (Xtandi®) for treatment of men with nonmetastatic, castration-resistant prostate cancer. These are the first agents approved for this indication. The results of two Phase 3 trials showed that men with nonmetastatic castration-resistant prostate cancer who were at high risk for developing metastases (defined as a PSA doubling time of 10 months or less) had significantly improved metastasis-free survival when treated with one of the antiandrogens vs. placebo. These results suggest that starting antiandrogen therapy earlier in the course of disease is better than waiting until the appearance of metastases. Longer follow-up is needed to determine the effect of antiandrogen therapy on overall survival.
Advances in Treatment of Nonmetastatic Prostate Cancer
Author: Gary C. Yee, PharmD, FCCP, BCOP, Professor and Associate Dean, University of Nebraska Medical Center, Omaha, Nebraska
Topic: In 2018, the FDA approved two antiandrogens, apalutamide (Erleada®) and enzalutamide (Xtandi®), for the treatment of men with nonmetastatic, castration-resistant prostate cancer. These drugs represent the first drugs approved for this indication.
Background: Despite high initial response rates, nearly all men with advanced prostate cancer eventually develop progressive disease following androgen deprivation therapy. In these patients with nonmetastatic disease, the first sign of progressive disease is often an increase in prostate-specific antigen (PSA) level. Systemic treatment is usually not initiated until the patient has evidence of distant metastases.
Apalutamide and enzalutamide are nonsteroidal antiandrogens. Enzalutamide was FDA-approved in 2012 for the treatment of castration-resistant prostate cancer. Researchers hypothesized that apalutamide or enzalutamide treatment in men with nonmetastatic, castration-resistant prostate cancer and a rapidly increasing PSA level would delay the development of metastases.
New Information: The results of two randomized double-blind phase 3 trials led to the FDA approval of apalutamide and enzalutamide for treatment of men with nonmetastatic, castration-resistant prostate cancer.1,2 Both trials had a similar study design, patient eligibility criteria, and study methods. In both trials, men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastases, as defined as a PSA doubling time of 10 months or less, were randomized to receive study drug (either apalutamide 240 mg/day or enzalutamide 160 mg/day) or placebo. All patients continued on their androgen-deprivation therapy. Patients in both trials were assessed at regular intervals for the development of distant metastases. The primary study endpoint in both trials was metastasis-free survival, defined as the time from randomization to either distant metastases or death.
The results of both trials showed that the antiandrogen significantly improved metastasis-free survival. In the SPARTAN trial, median metastasis-free survival was 40.5 months in the apalutamide group versus 16.2 months in the placebo group (hazard ratio 0.28; 95% CI: 0.23-0.35, P<0.001).1 The results of the PROSPER trial were similar; median metastasis-free survival was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group (hazard ratio 0.29; 95% CI: 0.24-0.35, P<0.001).2 Overall survival, a secondary endpoint, was not significantly different in both trials.
In each trial, the incidence of grade 3 or 4 adverse events and rate of discontinuation due to adverse events were more frequent in patients receiving the active study drug. In the apalutamide trial, the adverse events reported more frequently in the apalutamide group were fatigue, hypertension, rash, hypothyroidism, falls, fracture, and seizure.1 In the enzalutamide trial, the most commonly reported adverse event was fatigue. Other adverse events that occurred more frequently in the enzalutamide group were hot flush, hypertension, dizziness, falls, and convulsions.2 Major cardiovascular events were also more common in the enzalutamide group.
Interpretation and Application: The FDA approval of apalutamide and enzalutamide for nonmetastatic castration-resistant prostate cancer represents an important advance in the management of prostate cancer and suggests that starting antiandrogen therapy earlier is better than waiting until the appearance of metastases.3 Furthermore, the use of metastasis-free survival represents a new endpoint in prostate cancer trials.4 Longer follow-up is required to determine the effect, if any, of antiandrogen therapy on overall survival.
Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018; 378:1408–1418.
Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018; 378:2465–2474.
Smith MR. Progress in nonmetastatic prostate cancer. N Engl J Med. 2018; 378:2531–2532.
Beaver JA, Kluetz PG, Pazdur R. Metastasis-free survival – a new end point in prostate cancer trials. N Engl J Med. 2018; 378:2458–2460.