Striving Toward a Cure for Prostate Cancer.

Androgen receptor (AR) signaling is essential for cancer cell proliferation throughout much, if not all, of the course of a patient’s journey through prostate cancer. Discovery of the AR in the late 1960s prompted development of antiandrogen drugs that competitively inhibit binding of androgens to the AR ligandbinding domain (LBD), leading to conformational changes in AR that disrupt its function. Between 1989 and 1996, flutamide, bicalutamide, and nilutamide were approved by the US Food and Drug Administration (FDA) to be used in combination with chemical or surgical castration. Of these three first-generation nonsteroidal antiandrogens, bicalutamide is the most commonly used because of its once-per-day pharmacokinetics, tolerability, and efficacy. Bicalutamide binds the LBD, recruits corepressors to the AR, and interferes with recruitment of coactivators. Despite the use of these agents, drug resistance and disease progression remain a challenge in diseasemanagement. Commonmechanisms of resistance to bicalutamide include induction of wild-type AR expression, which leads to increased nuclear AR protein levels that cause bicalutamide to act as an AR agonist, increased AR coactivator expression, and development of mutations in the AR LBD-conferring antagonist-toagonist switch on bicalutamide. In an effort to develop next-generation AR-targeted therapy, a drug screen was used to evaluate agents that inhibit AR activity in the setting of AR receptor overexpression. In preclinical studies, enzalutamide, an AR inhibitor, demonstrated favorable pharmacokinetics and significantly higher affinity for the AR than bicalutamide. Unlike bicalutamide, enzalutamide lacked agonist activity for the wild-type AR, did not recruit AR coactivators, and inhibited AR binding to DNA, which leads to reduced expression of androgen-dependent genes. On the basis of findings from the AFFIRM (Safety and Efficacy Study of MDV3100 in Patients With Castration-Resistant Prostate Cancer Who Have Been Previously Treated With Docetaxel-Based Chemotherapy) trial showing a significant improvement in overall survival (OS) compared with placebo in patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel (hazard ratio [HR], 0.63; 95% CI, 0.53 to 0.75), the FDA approved enzalutamide for menwithmetastatic CRPC who had received prior chemotherapy. A subsequent phase III trial of enzalutamide versus placebo in patients with metastatic CRPC who have not previously been treated with docetaxel, the PREVAIL (A Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer) trial, demonstrated that enzalutamide resulted in an 81% reduction in risk of radiographic progression and a 29% reduction in the risk of death. To illustrate the natural history of prostate cancer relative to various treatments and to assess the response status to different therapies (ie, antiandrogens), a conceptual description of the natural history of prostate cancer referred to as the “clinical states model” has been proposed (Fig 1). In this model, the history of a patient’s prostate cancer is described as progression through a series of states from diagnosis to death. Each state represents a clinically significant category, and progression from one state to another reflects a change in prognosis generally prompting a change in therapy. In the article accompanying this editorial, Penson et al present results of the STRIVE (Safety and Efficacy Study of Enzalutamide Versus Bicalutamide in Men With Prostate Cancer) trial, a study in chemotherapy-naı̈ve men with metastatic CRPC or nonmetastatic CRPC comparing progression-free survival (PFS) with enzalutamide 160 mg/d versus bicalutamide 50 mg/d administered as secondary hormonal therapy. Data from this trial clearly validate the preclinical studies noted earlier that demonstrate the superiority of enzalutamide over bicalutamide as an antiandrogen. With respect to the primary end point, enzalutamide, when compared with bicalutamide, reduced the risk of death or progression, which was defined as prostate-specific antigen (PSA) progression or investigator assessed radiographic progression by 76% (HR, 0.24; 95% CI, 0.18 to 0.32). In addition, the secondary end points of PSA progression, proportion of patients with a significant (. 50%) PSA decrease, and radiographic PFS, strongly favored enzalutamide. In the 139 patients with nonmetastatic CRPC, the median radiographic PFS was not yet reached in either arm. However, enzalutamide reduced risk of radiographic progression by 76% (HR, 0.24; 95%CI, 0.10 to 0.56) compared with bicalutamide. In the 257 patients with metastatic CRPC, enzalutamide reduced the risk of radiographic progression by 68%.Median radiographic PFS was not reached with enzalutamide and was 8.3 months with bicalutamide (HR, 0.32; 95%CI, 0.21 to 0.50; P, .001). One should consider the 50 mg/d bicalutamide dosing that was chosen for the study when interpreting these findings. Bicalutamide has been FDA-approved for men with nonmetastatic CRPC at this dose and when used conjunction with androgen deprivation therapy (ADT). It is possible that bicalutamide 50 mg/d may be insufficient to block the AR amplification observed in CRPC, and a higher dose of 150 mg/d may have resulted in improved efficacy of the bicalutamide control arm. These results are compelling, but how can these data be used in clinical practice and howmight these results influence the future