'Dramatic Response' Seen With New-Generation AR Antagonist

Roxanne Nelson

September 30, 2012

September 30, 2012 (Vienna, Austria) — A novel androgen receptor (AR) antagonist has demonstrated promising results in an early trial and could eventually emerge as a treatment for castration-resistant prostate cancer (CRPC).

Results with the new agent, ODM-201 (Orion and Endo Pharmaceuticals), from a phase1/11 dose-escalation trial show that 87% of 15 patients experienced a decrease in their prostate-specific antigen (PSA) levels, defined as ≥50% reduction, at 12 weeks.

Dr. Christophe Massard

These are very early results, but this shows "impressive antitumor activity" commented lead author Christophe Massard, MD, from Institute Gustave Roussy, Paris, France, who presented the results of the study here at the 2012 European Society for Medical Oncology (ESMO) Congress.

Dr. Massard noted that ODM-201 was active both in patients who had been previously treated with chemotherapy and those who were chemotherapy naïve. "It is a uniquely designed androgen receptor antagonist that showed good tolerability and high antitumor activity," he said.

ODM-201 is a novel agent with a different mechanism of action, note the authors. Unlike other antiandrogens, it did not enter the brain in nonclinical models and also lacks the partial agonist activity that has been observed with conventional antiandrogens such as bicalutamide (Casodex, AstraZeneca). Differing from bicalutamide, ODM-201 is able to inhibit AR function by blocking nuclear translocation, and it also has no agonist activity when AR is overexpressed.

Dramatic Response Seen

"Since 2010, there has been a plethora of trials with new agents that have shown benefit in CR," commented Joan Carles, MD, head of the Genitourinary, CNS and Sarcoma Tumors Program at Vall d'Hebron Institute Oncology, Barcelona, Spain, who led a discussion on the article. "New hormonal treatments are coming down through the pipeline."

Discussing the OD-201 results, he noted that most of the patients who received the lower dose had a very dramatic response and that the agent also has low toxicity.

The strengths of this study were the high efficacy, that it was well tolerated, and has linear pharmacokinetics, Dr. Carles noted. "Its weaknesses are that there are few patients, and we can't forget that this is a phase I study."

"What I would ask the researchers," he added, "is what dose should be used for the phase II and phase III trials."

Study Details

The multicenter ANDRADES trial began in March 2011 to assess the safety, pharmacokinetics, and antitumor effects of ODM-201 in men with CRPC who were both previously treatment with chemotherapy and chemotherapy naïve. The study was divided into 2 parts; phase I was dose escalation, and phase II was dose expansion.

ODM-201 is an oral agent and was administered twice daily with food. Between 3 to 6 men were enrolled in each dose-escalation cohort, in which the preplanned doses of 100, 200, 300, 500, 700, and 900 mg were administered. When the safety dose was established, patients received treatment at the next dosing level. Men with the previous dose level continued their treatment until disease progression occurred or they were unable to tolerate side effects.

Within the subgroup of 6 patients who had received previous treatment with docetaxel, all had a decrease in PSA levels at 12 weeks. A 50% decline in the PSA level was observed in 90% of prechemotherapy patients and in 75% of the postchemotherapy patients. One patient who had been pretreated with abiraterone experienced a 26% decrease in PSA levels.

In addition, partial response or stable disease in soft tissue was observed in all of the evaluable patients according to RECIST criteria, and there was stable disease in the bone of 90% of evaluable patients, at 12 weeks.

The pharmacokinetics is linear in dose range 100 to 300 mg x 2, and the steady state was reached at day 8.

Among the 21 patients who have undergone treatment, the drug has been well tolerated without any significant adverse events related to the treatment. The most common adverse events were asthenia, nausea, and diarrhea. There were no dose-limiting toxicities or treatment-related deaths.

The dose-escalation segment of the trial is currently in progress, at 900 mg twice daily, and enrollment in a phase II study has begun

The trial is sponsored by Orion Corporation Orion Pharma and Endo Pharmaceuticals. Dr. Massard and coauthors are investigators in Orion Corporation sponsored clinical trial NCT01317641. Coauthor Dr. Fizazi is a member of ODM-201 Advisory Board of Orion Corporation Orion Pharma and Endo Pharmaceuticals.

2012 European Society for Medical Oncology (ESMO) Congress. Presented September 30, 2012: Abstract LBA25.