Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial.

Background: ODM-201 is a novel androgen receptor (AR) inhibitor designed to block the growth of prostate cancer cells through high-affinity binding to the AR and inhibition of AR nuclear translocation. This trial assessed ODM-201's safety, pharmacokinetics, and activity in men with metastatic castration-resistant prostate cancer.

Methods: The ARADES trial is an open-label phase 1-2 trial undertaken in 23 hospitals across Europe and USA with ongoing long-term follow-up. Men with progressive metastatic castration-resistant prostate cancer, who had castrate concentrations of testosterone and an Eastern Cooperative Oncology Group score of 0-1 were enrolled. In the phase 1 part of the trial, patients were given oral ODM-201 at a starting daily dose of 200 mg, which was increased to 400 mg, 600 mg, 1000 mg, 1400 mg, and 1800 mg. In phase 2, patients were randomly assigned centrally and stratified by previous chemotherapy and treatment with CPY17 inhibitors, to receive one of three daily doses of ODM-201 (200 mg, 400 mg, and 1400 mg). The primary endpoint in phase 1 was safety and tolerability, whereas in phase 2 it was the proportion of patients with a PSA response (50% or greater decrease in serum PSA) at week 12. All analyses included patients who had received at least one dose of ODM-201. This trial is registered with ClinicalTrials.gov, number NCT01317641, and NCT01429064 for the follow-up after 12 weeks.

Findings: We enrolled patients between April 5, 2011, and March 12, 2013. In phase 1, 24 patients were enrolled to six sequential cohorts of three to six patients and received a daily dose of ODM-201, 200-1800 mg. No dose-limiting toxic effects were reported and the maximum tolerated dose was not reached. In phase 1, three patients reported eight adverse events of grade 3 (fracture, muscle injury, laceration, paralytic ileus, pain, presyncope, urinary retention, and vomiting) and one patient had a grade 4 adverse event (lymphoedema). None of the grade 3-4 adverse events were deemed to be related to ODM-201. Of the phase 1 patients, the four who received 200 mg, seven who received 400 mg, and three who received 1400 mg entered the phase 2 part of the trial. In addition to these patients, 110 were randomly assigned to three groups: 200 mg (n=38), 400 mg (n=37), and 1400 mg (n=35). For these patients, the most common treatment-emergent adverse events were fatigue or asthenia (15 [12%] of 124 patients), hot flush (six [5%]), and decreased appetite (five [4%]). One patient (<1%) had a grade 3 treatment-emergent adverse event (fatigue); no patients had a treatment-emergent grade 4 adverse event. 38 patients who received 200 mg, 39 who received 400 mg, and 33 who received 1400 mg were assessable for PSA response at 12 weeks. 11 (29%) patients in the 200 mg group, 13 (33%) in the 400 mg group, and 11 (33%) in the 1400 mg group had a PSA response at 12 weeks.

Interpretation: Our results suggest that ODM-201 monotherapy in men with progressive metastatic castration-resistant prostate cancer provides disease suppression and that ODM-201 has a favourable safety profile. These findings support further investigation of clinical responses with ODM-201 in men with castration-resistant prostate cancer.

Funding: Orion Corporation Orion Pharma, Endo Pharmaceuticals Inc.