Enzalutamide Improves Survival in Nonmetastatic CRPC

Enzalutamide (Xtandi) plus androgen deprivation therapy (ADT) demonstrated a statistically significant improvement in overall survival (OS) compared with placebo/ADT in patients with nonmetastatic castration-resistant prostate cancer (CRPC), according to results of the final OS analysis of the phase III PROSPER trial.¹

Full efficacy and safety findings will be presented at a later date. Preliminary data also showed that the trial met its primary endpoint of metastasis-free survival (MFS) favoring the enzalutamide/ADT regimen; OS was a key secondary endpoint of the trial. Here, the combination of enzalutamide and ADT led to a median MFS of 36.6 months versus 14.7 months with ADT alone, leading to a 71% reduction in the risk of metastases or death (HR, 0.29; 95% CI, 0.24-0.35; P <.001).^2,3

Based on these MFS results, the FDA approved enzalutamide in July 2018 for the treatment of patients with nonmetastatic CRPC.

In the double-blind, placebo-controlled, international phase III PROSPER study, 1401 patients with asymptomatic M0 CRPC were randomized to receive ADT plus enzalutamide at 160 mg daily (n = 933) or placebo (n = 468). ADT consisted of a gonadotropin-releasing hormone agonist/antagonist. All patients in the study had testosterone levels of ≤50 ng/dL, a prostate-specific antigen (PSA) doubling time of ≤10 months, and a PSA of ≥2 ng/mL.

The primary endpoint was MFS within 112 days of treatment discontinuation, while secondary endpoints beyond OS included time to PSA progression and time to next antineoplastic therapy. Median duration of treatment with enzalutamide was 18.4 months compared with 11.1 months for the placebo group.

Additional results showed that there was a 93% reduction in the risk of PSA progression in the enzalutamide arm versus ADT alone (HR, 0.07; 95% CI, 0.05-0.08; P <.001). The median time to PSA progression in the enzalutamide group was 37.2 months compared with 3.9 months for the placebo/ADT arm.

The time to first subsequent antineoplastic therapy was extended by a median of 21.9 months with enzalutamide versus ADT alone. Patients who were on enzalutamide arm required a new therapy after a median of 39.6 months compared with 17.7 months in the placebo group, leading to a 79% reduction in the risk of requiring a new therapy (HR, 0.21; 95% CI, 0.17-0.26; P <.001).

The initial results from the PROSPER trial were available 2 years earlier than estimates, which predicted data maturation in 2020. At the time of the analysis, OS data were not yet mature, with medians unavailable for each arm. However, there was a trend toward improvement in OS with the addition of enzalutamide (HR, 0.80; 95% CI, 0.58-1.09; P = .15).

Moreover, a preliminary analysis showed that the safety profile was consistent with what has been reported previously from the PROSPER trial. In the earlier analysis, there were significantly more adverse events (AEs) in the enzalutamide group compared with placebo, at 87% versus 77%, respectively. Grade ≥3 AEs were reported in 31% of men on enzalutamide/ADT compared with 23% of those in the placebo group; these included hypertension (5% vs 2%, respectively) and fatigue (3% vs 1%).

The treatment discontinuation rate due to AEs occurred in 9% of patients on enzalutamide compared with 6% of those in the placebo group.

The most common AEs that led to death were cardiac events on the enzalutamide arm (n = 9) and placebo (n = 2). Six patients on enzalutamide had acute myocardial infarction; cardiac failure, cardiorespiratory arrest, and ventricular arrhythmia also occurred on this arm (n = 1 each). In the placebo group, cardiac arrest, and left ventricular failure occurred in 1 patient each.

Patient-reported outcomes from the PROSPER trial were reported in Lancet Oncology.⁴ Results showed that patients with nonmetastatic CRPC who received enzalutamide had the MFS benefit versus placebo while maintaining low pain levels, low prostate cancer symptom burden, and high health-related quality of life. The antiandrogen also delayed pain progression, symptom worsening, and decrease in functional status compared with placebo.

Enzalutamide was initially approved in 2012 as a treatment for men with metastatic CRPC following prior docetaxel therapy, and it was later expanded to be used prior to chemotherapy.

References

1. Xtandi (enzalutamide) demonstrates significant improvement in overall survival in phase 3 prosper trial of patients with NMCRPC [news release]: Tokyo, Japan and New York NY. Astellas Pharma, Inc., and Pfizer. Published February 11, 2020. Accessed February 12, 2020.
2. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Eng J Med. 2018;378(26):2465-2474. doi: 10.1056/NEJMoa1800536.
3. Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol. 2018;36(suppl 6S; abstr 3).
4. Tombal B, Saad F, Penson D, et al. Patient-reported outcomes following enzalutamide or placebo in men with non-metastatic, castration-resistant prostate cancer (PROSPER): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2019;20(4):556-569. doi: 10.1016/S1470-2045(18)30898-2.