Andrew Armstrong

BACKGROUND:In the PREVAIL study, enzalutamide significantly improved clinical outcomes versus placebo in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE:To evaluate long-term benefits and risks of enzalutamide in the final prespecified PREVAIL analysis. DESIGN, SETTING, AND PARTICIPANTS:We conducted a final 5-yr survival analysis of PREVAIL in men with chemotherapy-naïve mCRPC from the enzalutamide (n = 689) and placebo (n = 693) arms. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Predictors of the primary outcome of overall survival were estimated using the Kaplan-Meier method. Long-term adverse events over time were analyzed. RESULTS AND LIMITATIONS:At the 5-yr data cutoff, 1382 of 1717 (80%) men had died. Enzalutamide reduced the hazard of death by 17% (hazard ratio 0.83; 95% confidence interval [CI] 0.75-0.93; p < 0.001), despite 65%, 54%, and 43% of placebo-treated patients receiving subsequent docetaxel, abiraterone, and enzalutamide, respectively. Median overall survival was 36 mo (95% CI 34-38) in the enzalutamide arm versus 31 mo (95% CI 29-34) in the placebo arm, with a median follow-up of 69 mo. Prognostic modeling showed 5-yr survival rates of 42%, 24%, and 5% for low-, intermediate-, and high-risk groups, respectively. Greater degrees of confirmed prostate-specific antigen declines (≤3 mo) were associated with greater 5-yr survival. A higher incidence of fatal treatment-emergent adverse events was observed with enzalutamide (6.9% vs 3.8%), with an increase in fatal cardiovascular events (1.6% vs 0.4%). CONCLUSIONS:With >5 yr of follow-up, enzalutamide continued to demonstrate improved survival in patients with mCRPC despite crossover and multiple subsequent effective therapies, balanced against a slightly higher rate of fatal cardiovascular events. PREVAIL is registered on ClinicalTrials.gov as NCT01212991. PATIENT SUMMARY:We report a maintained long-term survival benefit with enzalutamide and risks with >5 yr of enzalutamide treatment and follow-up in men with metastatic prostate cancer, and identify groups of men with widely different outcomes based on clinical factors.

BACKGROUND: In the ARCHES study in metastatic hormone-sensitive prostate cancer (mHSPC), enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival (rPFS) versus ADT alone. OBJECTIVE: To evaluate patient-reported outcomes (PROs) to week 73. DESIGN, SETTING, AND PARTICIPANTS: ARCHES (NCT02677896) was a randomised, double-blind, placebo-controlled, phase 3 study in mHSPC patients. INTERVENTION: Enzalutamide (160 mg/day) plus ADT or placebo plus ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PROs were assessed at baseline, week 13, and every 12 wk until disease progression using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Prostate 25 (QLQ-PR25), Functional Assessment of Cancer Therapy-Prostate (FACT-P), Brief Pain Inventory Short Form, and EuroQoL 5-Dimensions, 5-Levels (EQ-5D-5 L) instruments. Endpoints included time to first (TTFD) and first confirmed (TTFCD) clinically meaningful deterioration (using predefined questionnaire thresholds) in health-related quality of life (HRQoL) and pain. RESULTS AND LIMITATIONS: A total of 1150 patients received ADT plus enzalutamide (n = 574) or placebo (n = 576). Baseline PRO scores indicated high HRQoL and low pain, which was generally maintained in both groups. There were no statistically significant (nominal p > 0.05) between-group differences that occurred in both TTFD and TTFCD together for QLQ-PR25 and FACT-P scores. Enzalutamide significantly delayed TTFD in worst pain (by ∼3 mo; nominal p = 0.032), pain severity (nominal p = 0.021), and EQ-5D-5 L visual analogue scale score (nominal p = 0.0070) versus placebo (not significant for confirmed deterioration for pain outcomes). Enzalutamide delays deterioration in several HRQoL subscales and pain severity in high-volume disease. CONCLUSIONS: Enzalutamide plus ADT enables men with mHSPC to maintain high-functioning HRQoL and low symptom burden. PATIENT SUMMARY: This study examined the effect on health-related quality of life and pain of adding enzalutamide or placebo to androgen deprivation therapy for patients with metastatic hormone-sensitive prostate cancer. Addition of enzalutamide allowed patients to maintain their health-related quality of life.