FDA Grants Apalutamide Priority Review for Nonmetastatic CRPC

The FDA has granted a priority review to a new drug application (NDA) for apalutamide (ARN-509) for the treatment of patients with nonmetastatic castration-resistant prostate cancer (CRPC), according to Janssen Biotech, the manufacturer of the next-generation oral androgen receptor inhibitor.

UPDATE 2/14/2018: FDA Approves Apalutamide for Nonmetastatic Castration-Resistant Prostate Cancer

The NDA is based on data from the phase III SPARTAN trial (ARN-509-003), which 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 primary endpoint of the study is metastasis-free survival.

Janssen reported in a press release that results from the trial will be presented in an oral session at the ASCO Genitourinary Cancers Symposium on Thursday, February 8, 2018. Under the Prescription Drug User Fee Act, the FDA is scheduled to make its decision on the NDA by April 2018.

"The prognosis for men with prostate cancer is significantly worse once the cancer has spread to other parts of the body. Accordingly, men with nonmetastatic castration-resistant prostate cancer need treatment options that can delay disease progression and improve long-term outcomes," Craig Tendler, MD, vice president, Late Development and Global Medical Affairs, Oncology, Janssen, said in a press release. "We are encouraged by the FDA's recognition, via the priority review designation, of the potential for apalutamide to provide such an option for these men."

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 its press release.

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

Researchers observed reductions in [18F]fluoro-α-dihydrotestosterone (FDHT) uptake at all levels, with a plateau in response at ≥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.