Apalutamide Submitted for FDA Approval in Prostate Cancer

Janssen Biotech has submitted a new drug application to the FDA for apalutamide (ARN-509) for the treatment of non-metastatic castration-resistant prostate cancer, the manufacturer of the next-generation oral androgen receptor inhibitor announced today.

Peter F. Lebowitz, MD, PhD

Peter F. Lebowitz, MD, PhD

Janssen Biotech has submitted a new drug application to the FDA for apalutamide (ARN-509) for the treatment of non-metastatic castration-resistant prostate cancer (CRPC), the manufacturer of the next-generation oral androgen receptor inhibitor announced today.

Apalutamide inhibits the action of testosterone in prostate cancer cells and prevents androgen from binding to the androgen receptor. Currently, there are no FDA-approved treatments for patients with nonmetastatic CRPC, Janssen noted in a press release.

In support of the NDA, Janssen submitted data from the pivotal phase III SPARTAN trial (ARN-509-003). That trial evaluated the safety and efficacy of apalutamide versus placebo in patients with a rapidly rising prostate specific antigen (PSA) level despite receiving continuous androgen deprivation therapy (ADT). The company plans to release results at a future medical meeting.

"The SPARTAN data lead the path towards a new approach to treating men with prostate cancer earlier in the disease course. We have demonstrated that treating patients before the disease has metastasized improves outcomes," Peter Lebowitz, MD, PhD, Janssen’s global therapeutic area head of oncology, said in a press release. "We are thrilled to have completed our submission of the SPARTAN data to the FDA and we look forward to a promising treatment that can provide new hope and expectations for men facing this disease."

Phase I results were published in 2013 for a study assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of apalutamide in patients with CRPC.

Thirty men with progressive CRPC treated at Memorial Sloan-Kettering Cancer Center from July 2010 to May 2012 were assigned to a single dose of apalutamide across 9 daily dose levels ranging from 30 mg to 480 mg, followed by a 1-week observation period with pharmacokinetic sampling.

Eligible patients had histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small-cell features, and progressive disease based on a minimum of 3 rising PSA levels at least 1 week apart, and final PSA had to be &ge;2 ng/mL. Patients with new or progressive soft tissue and/or bone disease confirmed on CT/MRI or bone scans, excluding brain metastases, were also eligible. Patients who had not undergone orchiectomy were required to maintain castrate levels of testosterone <50 ng/dL with ADT.

At 12 weeks, 46.7% of patients had a &ge;50% reduction from baseline in PSA. Eighteen patients (60%) had a &ge;50% decline in PSA from baseline, and of those, 6 (20%) had a &ge;90% decline. The median PSA change from baseline at 12 weeks was —43.2% (range, &ndash;98.6 to 120.6), and the maximum median decline on study was &ndash;62.7% (range, &ndash;99.8 to 16.7).

Researchers observed reductions in [18F]fluoro-&alpha;-dihydrotestosterone (FDHT) uptake at all levels, with a plateau in response at &ge;120-mg dose.

Ten patients had measurable soft tissue disease at baseline. Of those, half maintained stable disease responses for at least 6 months. One patient (10%) experienced disease progression based on the appearance of new lesions, and 4 (40%) had indeterminate responses.

Sixteen patients left the study due to disease progression and 1 withdrew consent. No patient discontinued because of toxicity. Median duration of study participation was 9.5 months.

Fatigue (47%) was most the frequently reported adverse event (AE), but the severity did not rise above grade 2. Four patients experienced grade 3 AEs, 3 of which were considered unrelated to study treatment.

There was 1 dose-limiting toxicity (DLT), grade 3 abdominal pain in patient with history of irritable bowel syndrome, at the 300-mg dose level. Researchers said the condition resolved with dose interruption and subsequent dose reduction to 240 mg. Three other patients treated at the 300-mg dose level did not experience DLTs, and there were no seizures were reported at any dose level.

Researchers chose 240 mg of daily apalutamide as the maximum effective dose, which was the regimen used in the SPARTAN trial.


Rathkopf DE, Morris MJ, Fox JJ, et al. Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer.J Clin Oncol.2013;31:3525-3530.

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