Abstract
The next-generation antiandrogen ARN-509 has antitumor activity in metastatic CRPC.
Major finding: The next-generation antiandrogen ARN-509 has antitumor activity in metastatic CRPC.
Approach: Preclinical and clinical efficacy data were integrated to determine the maximum efficacious dose.
Impact: Further study of ARN-509 is warranted based on its high therapeutic index and favorable safety profile.
Drugs targeting androgen receptor (AR) signaling have significant activity in many patients with metastatic castration-resistant prostate cancer (CRPC), but intrinsic and acquired resistance to these agents remains a clinical challenge. ARN-509 is a second-generation AR antagonist that has shown greater potency than first-generation AR inhibitors in preclinical models and, unlike some first-generation AR inhibitors, does not act as an AR agonist when AR is overexpressed. Rathkopf and colleagues report findings from a first-in-human phase I dose-escalation study in patients with metastatic CRPC that assessed the safety, tolerability, and pharmacokinetics of ARN-509 as well as a recommended phase II dose. The secondary objective of the trial was to evaluate antitumor activity. ARN-509 was rapidly absorbed, had linear and dose-proportional pharmacokinetics, and showed evidence of antitumor activity at all doses tested. Of 30 patients enrolled in the trial, 18 (60%) had a greater than 50% decline in prostate-specific antigen levels after ARN-509 treatment, and 4 of 7 patients with unfavorable circulating tumor cell counts converted to favorable status after receiving ARN-509. Uptake of 16β-[18F]fluoro-α-dihydrotestosterone (FDHT), an indicator of AR binding capacity, declined in all patients tested in a dose-dependent manner, indicating that ARN-509 effectively bound and inhibited AR in patients. The most common adverse event caused by ARN-509 was grade 1 or 2 fatigue, and only 1 grade 3 adverse event related to treatment was reported. Because of the lack of dose-limiting toxicity, a maximum tolerated dose was not defined. Instead, a maximum efficacious dose was chosen for the recommended phase II dose based on the doses that elicited the best clinical responses and produced steady-state plasma levels in the range that led to tumor regressions in mice. These findings suggest that ARN-509 is safe and effective and provide support for its further clinical development for treatment of CRPC.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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