Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study

Abstract

Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naïve metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated the longer-term efficacy and safety of enzalutamide up to the prespecified number of deaths in the final analysis, which included an additional 20 mo of follow-up for investigator-assessed rPFS, 9 mo of follow-up for OS, and 4 mo of follow-up for safety. Enzalutamide reduced the risk of radiographic progression or death by 68% (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.28–0.37; p < 0.0001) and the risk of death by 23% (HR 0.77, 95% CI 0.67–0.88; p = 0.0002). Median investigator-assessed rPFS was 20.0 mo (95% CI 18.9–22.1) in the enzalutamide arm and 5.4 mo (95% CI 4.1–5.6) in the placebo arm. Median OS was 35.3 mo (95% CI 32.2–not yet reached) in the enzalutamide arm and 31.3 mo (95% CI 28.8–34.2) in the placebo arm. At the time of the OS analysis, 167 patients in the placebo arm had crossed over to receive enzalutamide. The most common adverse events in the enzalutamide arm were fatigue, back pain, constipation, and arthralgia. This final analysis of PREVAIL provides more complete assessment of the clinical benefit of enzalutamide.

LuCaP Prostate Cancer Patient-Derived Xenografts Reflect the Molecular Heterogeneity of Advanced Disease an­­d Serve as Models for Evaluating Cancer Therapeutics

“…We observed a wide‐range of responses to these modalities, as also occurs in men with PC. Notably, results of studies using LuCaP PDXs identified AR amplification/activity as an important mechanism of resistance to ADT , supporting the use of enzalutamide (now FDA‐approved for men with mCRPC) , and also identified AR splice variants as an important mechanism of resistance to ADT which supported the development of new AR N‐terminal antagonists .…”

Non-Genomic Actions of the Androgen Receptor in Prostate Cancer

“…Androgen deprivation therapy, both surgical and biochemical castration, is the main treatment for relapsed patients and provides temporary relief to tumor burden; however, all patients will acquire lethal, castration-resistant prostate cancer (CRPC). Androgen receptor (AR)-targeted therapies for blocking the androgen signaling axis have improved, with more potent, second-generation antiandrogens such as enzalutamide, and 17-hydroxylase/17,20-lyase (CYP17) inhibitors, but these agents only increase median overall survival by approximately 4 months in chemotherapy-naïve patients (2, 3). …”

Pharmacoeconomic analysis of enzalutamide and abiraterone for treatment of chemotherapy naive patients with metastatic castration resistant prostate cancer

“…На сегодняшний день в рандомизированных исследованиях не проводилось прямого сравнения абиратерона и энзалутамида, одна-ко доступны результаты работ, в которых изучалось применение абиратерона в комбинации с преднизоло-ном (COU-AA-302) [8][9][10] и энзалутамида (PREVAIL) [11,12] по сравнению с плацебо у пациентов, ранее не получавших химиотерапии. Оба исследования яв-лялись рандомизированными двойными слепыми пла-цебоконтролируемыми, при этом различия в исходных характеристиках пациентов были минимальными.…”

“…Однако при трактовке результатов необходимо учиты-вать разницу в подходах, которые применялись при формировании отчетов о нежелательных явлениях (НЯ). В исследовании PREVAIL отражались НЯ, про-явившиеся более чем у 10 % пациентов, и различия в частоте которых превышали 2 процентных пункта по сравнению с контрольной группой [11], в то время как в работе COU-AA-302 были отражены НЯ, часто-та возникновения которых превышала 15 % в хотя бы одной из групп [8]. Кроме того, даже в контрольных группах частота возникновения НЯ близка к 100 %, а частота возникновения НЯ III-IV степеней состав-ляет 37-44 %.…”