An Available Phase III Trial of ODM-201 in Men with High Risk, Non-Metastatic, Hormone Resistant Prostate Cancer

ODM-201 (also known as BAY-1841788) is a non-steroidal, oral anti-androgen (specifically a full and high-affinity antagonist of the androgen receptor (AR), that is under development by Orion and Bayer Healthcare for the treatment of advanced, hormone-resistant prostate cancer. [An antagonist is a drug (blocking agent) that binds to the cellular receptor for a hormone (e.g. testosterone) thus blocking the effect of the hormone without producing any physiologic effect itself.]  Bayer HealthCare and Orion Corporation have begun to enroll patients in a Phase III trial with ODM-201. The study, called ARAMIS, evaluates ODM-201 in men with hormone-resistant prostate cancer (CRPC) who have rising Prostate-Specific Antigen (PSA) levels and no detectable metastases. The trial is designed to determine the effects of the treatment on metastasis-free survival (MFS). The trial is being conducted at 502 locations in the US. For enrollment and location information see the following clinicaltrials.gov link.

The ARAMIS trial is a randomized, Phase III, multicenter, double-blind, placebo-controlled trial evaluating the safety and efficacy of oral ODM-201 in patients with non-metastatic CRPC who are at high risk for developing metastatic disease. About 1,500 patients are planned to be randomized in a 2:1 ratio to receive 600mg of ODM-201 twice a day or matching placebo. Randomization will be stratified by PSA doubling time (PSADT < 6 months vs. > 6 months) and use of osteoclast-targeted therapy (yes vs. no). In men with progressive non-metastatic CRPC, a short PSA doubling time has been consistently associated with reduced time to first metastasis and death.

The primary endpoint of this study is metastasis-free survival (MFS), defined as time between randomization and evidence of metastasis or death from any cause. The secondary objectives of this study are overall survival (OS), time to first symptomatic skeletal event (SSE), time to initiation of first cytotoxic chemotherapy (such as taxotere), time to pain progression, and characterization of the safety and tolerability of ODM-201.

A Phase II clinical trial conducted in patients with progressive metastatic castration-resistant prostate cancer assessed the efficacy and safety of three dose levels of ODM-201 (100mg, 200mg and 700mg given twice a day) in 124 patients. The study included patients who were treated previously with abiraterone and/or chemotherapy as well as patients who were chemotherapy-naïve. The results showed that ODM-201 provided disease suppression and had a favorable safety profile. The results were presented at the international ECCO oncology congress at the end of September 2013 and published in June 2014 in The Lancet Oncology.

Relative to enzalutamide (MDV3100 or Xtandi) and apalutamide (ARN-509), two other recent non-steroidal antiandrogens, ODM-201 shows some advantages. ODM-201 appears to negligibly cross the blood-brain barrier. This is beneficial due to the reduced risk of seizures and other central side effects that tends to occur in non-steroidal antiandrogens that are structurally similar to enzalutamide.  Moreover, in accordance with its lack of central penetration, ODM-201 does not seem to increase testosterone  levels in mice or humans, unlike other non-steroidal antiandrogens. Another advantage is that ODM-201 has been found to block the activity of all tested/well-known mutant ARs in prostate cancer, including the recently-identified clinically-relevant F876L mutation that produces resistance to enzalutamide and ARN-509.  ODM-201 has been studied in phase I and II clinical trials and has thus far been found to be effective and well-tolerated with the most commonly reported side effects including fatigue, nausea and diarrhea.  No seizures have been observed.  As of July 2015, ODM-201 is in phase III trials for CRPC. For more specific information, see the following link.