Dataset Information

Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer.

ABSTRACT:

Purpose

ARN-509 is a novel androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (CRPC). ARN-509 inhibits AR nuclear translocation and AR binding to androgen response elements and, unlike bicalutamide, does not exhibit agonist properties in the context of AR overexpression. This first-in-human phase I study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ARN-509 in men with metastatic CRPC.

Patients and methods

Thirty patients with progressive CRPC received continuous daily oral ARN-509 at doses between 30 and 480 mg, preceded by administration of a single dose followed by a 1-week observation period with pharmacokinetic sampling. Positron emission tomography/computed tomography imaging was conducted to monitor [(18)F]fluoro-α-dihydrotestosterone (FDHT) binding to AR in tumors before and during treatment. Primary objective was to determine pharmacokinetics, safety, and recommended phase II dose.

Results

Pharmacokinetics were linear and dose proportional. Prostate-specific antigen declines at 12 weeks (≥ 50% reduction from baseline) were observed in 46.7% of patients. Reduction in FDHT uptake was observed at all doses, with a plateau in response at ≥ 120-mg dose, consistent with saturation of AR binding. The most frequently reported adverse event was grade 1/2 fatigue (47%). One dose-limiting toxicity event (grade 3 abdominal pain) occurred at the 300-mg dose. Dose escalation to 480 mg did not identify a maximum-tolerated dose.

Conclusion

ARN-509 was safe and well tolerated, displayed dose-proportional pharmacokinetics, and demonstrated pharmacodynamic and antitumor activity across all dose levels tested. A maximum efficacious dose of 240 mg daily was selected for phase II exploration based on integration of preclinical and clinical data.

SUBMITTER: Rathkopf DE

PROVIDER: S-EPMC3782148 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Publications

Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer.

Rathkopf Dana E DE Morris Michael J MJ Fox Josef J JJ Danila Daniel C DC Slovin Susan F SF Hager Jeffrey H JH Rix Peter J PJ Chow Maneval Edna E Chen Isan I Gönen Mithat M Fleisher Martin M Larson Steven M SM Sawyers Charles L CL Scher Howard I HI

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20130903 28

<h4>Purpose</h4>ARN-509 is a novel androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (CRPC). ARN-509 inhibits AR nuclear translocation and AR binding to androgen response elements and, unlike bicalutamide, does not exhibit agonist properties in the context of AR overexpression. This first-in-human phase I study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ARN-509 in men with metastatic CRPC.<h4>Patients and ...[more]

PMID: 24002508

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Project description:BackgroundApalutamide is a potent androgen receptor (AR) antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets.ObjectiveTo evaluate the activity and safety of apalutamide in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC).Design, setting, and participantsWe conducted a multicenter phase 2 study of nmCRPC patients with a high risk for progression (prostate-specific antigen [PSA] ≥8 ng/ml or PSA doubling time [PSA DT] ≤10 mo).InterventionPatients received 240mg/d apalutamide while continuing on androgen-deprivation therapy.Outcome measurements and statistical analysisPrimary end point was 12-wk PSA response (Prostate Cancer Working Group 2 criteria). Secondary end points included safety, time to PSA progression (TTPP), and metastasis-free survival (MFS).Results and limitationsA total of 51 patients were enrolled; four patients with metastatic disease were excluded from the efficacy analysis. Patient characteristics included median age, 71 yr; Eastern Cooperative Oncology Group performance status 0 (76%); Gleason score ≤7 (57%); median PSA 10.7 ng/ml; and PSA DT ≤10 mo (45%). At median follow-up of 28.0 mo, 18 patients (35%) remained in the study. Overall, 89% of patients had ≥50% PSA decline at 12 wk. Median TTPP was 24.0 mo (95% confidence interval [CI], 16.3 mo-not reached [NR]); median MFS was NR (95% CI, 33.4 mo-NR). Most of the patients discontinued study treatment (n=33) due to disease progression (n=11 [22%]) or adverse events (AEs) (n=9 [18%]). The most common AE was fatigue (any grade, n=31 [61%]) although grade ≥3 fatigue was uncommon (n=2 [4%]). These represent the first apalutamide nmCRPC patient clinical data.ConclusionsIn high-risk nmCRPC patients, apalutamide was safe with robust activity based on durable PSA responses and disease control.Patient summaryAntitumor activity and the safety of apalutamide in patients with nonmetastatic castration-resistant prostate cancer support continued development in this setting.Trial registrationClinicalTrials.gov identifier NCT01171898.

Project description:BackgroundAntagonizing the androgen-receptor (AR) pathway is an effective treatment strategy for patients with metastatic castration-resistant prostate cancer (CRPC). Here, we report the results of a first-in-human phase 1/2 study which assessed the safety, pharmacokinetics, and activity of SHR3680 (a novel AR antagonist) in patients with metastatic CRPC.MethodsThis phase 1/2 study enrolled patients with progressive metastatic CRPC who had not been previously treated with novel AR-targeted agents. In the phase 1 dose-escalation portion, patients received oral SHR3680 at a starting daily dose of 40 mg, which was subsequently escalated to 80 mg, 160 mg, 240 mg, 360 mg, and 480 mg per day. In phase 2 dose-expansion portion, patients were randomized to receive daily dose of 80 mg, 160 mg, or 240 mg of SHR3680. The primary endpoint in phase 1 was safety and tolerability and in phase 2 was the proportion of patients with a prostate-specific antigen (PSA) response (≥ 50% decrease of PSA level) at week 12.ResultsA total of 197 eligible patients were enrolled and received SHR3680 treatment, including 18 patients in phase 1 and 179 patients in phase 2. No dose-limiting toxicities were reported and the maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 116 (58.9%) patients, with the most common one being proteinuria (13.7%). TRAEs of grade ≥ 3 occurred in only 23 (11.7%) patients, and no treatment-related deaths occurred. Antitumor activities were evident at all doses, including PSA response at week 12 in 134 (68.0%; 95% CI, 61.0-74.5) patients, stabilized bone disease at week 12 in 174 (88.3%; 95% CI, 87.2-95.5) patients, and responses in soft tissue lesions in 21 (34.4%, 95% CI, 22.7-47.7) of 61 patients.ConclusionSHR3680 was well tolerated and safe, with promising anti-tumor activity across all doses tested in patients with metastatic CRPC. The dose of 240 mg daily was recommended for further phase 3 study.Trial registrationClinical trials.gov NCT02691975; registered February 25, 2016.

Dataset Information

Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer.

Purpose

Patients and methods

Results

Conclusion

Publications

Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer.

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