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Enzalutamide prolonged survival in castration-resistant prostate cancer after chemotherapy
Men with castration-resistant prostate cancer who underwent chemotherapy experienced significantly longer OS when assigned to enzalutamide compared with placebo, according to results of a phase 3 study.
Howard I. Scher, MD, chief of the Genitourinary Oncology Service at the Sidney Kimmel Center for Urologic and Prostate Cancers at Memorial Sloan-Kettering Cancer Center, and colleagues conducted the double blind, placebo-controlled trial to determine whether enzalutamide (Medivation) — an oral androgen receptor signaling inhibitor formerly called MDV3100 — prolonged survival in this patient population.
Scher and colleagues stratified 1,199 patients according to ECOG performance status score and pain intensity.
The researchers randomly assigned the patients to oral enzalutamide 160 mg per day (n=800) or placebo (n=399).
The primary endpoint was OS.
The researchers halted the study after a planned interim analysis when 520 deaths had occurred.
Median OS among patients assigned to enzalutamide was 18.4 months (95% CI, 17.3 to not yet reached) compared with 13.6 months (95% CI, 11.3-15.8) among patients assigned to placebo (HR for death in the enzalutamide group=0.63; 95% CI, 0.53-0.75; P<.001).
“The survival benefit in this study substantiates preclinical work showing that androgen receptor signaling contributes to disease progression despite castrate levels of testosterone and previous conventional antiandrogen therapy,” Scher and colleagues wrote. “This result … establishes that these tumors are not refractory to hormones, even after chemotherapy has been administered.”
Enzalutamide demonstrated superiority over placebo in all secondary endpoints, including: proportion of patients with a 50% or greater reduction in PSA level (54% vs. 2%, P<.001); soft tissue response rate (29% vs. 4%, P<.001); quality-of-life response rate (43% vs. 18%); time to PSA progression (8.3 months vs. 3 months; HR=0.25; P<.001); radiographic PFS (8.3 months vs. 2.9 months; HR=0.40; P<.001); and time to first skeletal-related event (16.7 months vs. 13.3 months; HR=0.69; P<.001).
Enzalutamide was linked to increased rates of fatigue, diarrhea and hot flashes compared with placebo. Five patients assigned enzalutamide experienced seizures.
“This novel agent is anticipated to join the therapeutic armamentarium of anticancer drugs with diverse mechanisms of action that confer a survival benefit in men with castration-resistant prostate cancer,” Scher and colleagues wrote. “These results validate androgen receptor signaling as a key therapeutic target throughout the clinical spectrum of prostate cancer, including in men who have received previous chemotherapy.”
Disclosure: The study was supported by Medivation, the maker of enzalutamide, and Astellas Global Development. The researchers report financial relationships with Amgen, AstraZeneca, Bristol-Myers Squibb, Johnson & Johnson, Medivation, Novartis, Sanofi-Aventis and other pharmaceutical companies.
Perspective
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The recognition that androgen receptor (AR) remains the most important therapeutic target in castration-resistant prostate cancer has revolutionized the contemporary management of prostate cancer. From changes in the definition of resistant disease (ie, androgen independent vs. hormone refractory vs. castration-resistant) to more sophisticated consensus guidelines for drug development, the past 4 years in prostate cancer have marked a major shift in drug development. Three new agents have been FDA approved: sipuleucel-T (Provenge, Dendreon), cabazitaxel (Jevtana, Sanofi Aventis) and, more recently, the adrenal inhibitor abiraterone acetate (Zytiga, Janssen). Although heterogeneous in their mechanism of action, these agents share a common theme: OS improvement in men with metastatic castration-resistant prostate cancer.
The results from the AFFIRM trial will likely add another novel and powerful therapy for men with metastatic castration-resistant prostate cancer who have failed prior docetaxel-based chemotherapy. The development of this agent exemplifies the collaboration between basic scientists and clinicians. Enzalutamide — formerly known as MDV3100 — is a diarylthiohydantoin, a compound optimized from a screen for nonsteroidal antiandrogens that retained activity in the setting of increased AR expression. Enzalutamide binds to AR with greater relative affinity than existing antiandrogens, reduces the efficiency of its nuclear translocation, and impairs both DNA binding to androgen response elements and recruitment of coactivators. These molecular events are thought to be responsible for the clinical benefits observed in the initial phase 1 and phase 2 studies and, more recently, in the AFFIRM trial. These include improvement in OS coupled with a positive impact on traditional endpoints used in routine clinical practice, such as quality of life, PSA reduction and objective response.
With the availability of this compound, new questions — such as cost-effectiveness, appropriate patient selection, utility of combination strategies, timing of therapy and proper treatment sequence — have emerged. Although this agent was tested in the docetaxel-resistant setting, there is no biologic rationale for its use this late in the disease process. The lack of need for prednisone makes this compound an attractive treatment strategy earlier in the disease state. This, in fact, is the aim of several ongoing clinical trials. Additional AR-directed strategies are also undergoing early clinical development and should improve our understanding of alternative pathways linked to AR signaling. The future of prostate cancer drug development promises to be a very exciting time for patients, their families and the entire prostate cancer community. The development of agents such as enzalutamide is just the beginning of a difficult and complex task of unfolding and better understanding the biology of castration-resistant prostate cancer.
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