The investigational oral androgen receptor drug ODM-201 has significant antitumor activity with a favorable safety profile in men with metastatic castration-resistant prostate cancer, according to a pooled analysis of 2 early-phase clinical trials.
In these studies, the median time to progression of serum prostate-specific antigen (PSA) was slightly longer than 1 year in men who were naïve to chemotherapy or to CYP17 inhibitors, said Neal D. Shore, MD, Medical Director, CPI, Carolina Urologic Research Center, Myrtle Beach, SC, at the 2016 American Urological Association annual meeting.
ODM-201 is an oral androgen receptor antagonist that binds with high affinity and selectivity to the androgen receptor; it inhibits testosterone-induced nuclear translocation of the androgen receptor, and blocks the activity of mutant androgen receptors to overcome resistance to androgen receptor–targeted therapies, such as enzalutamide (Xtandi).
Blood–brain barrier penetration was negligible in preclinical studies of ODM-201. This property may enhance neurocognitive tolerability, “which we have typically not seen in earlier generation lutamides, some that haven’t come to market,” said Dr Shore.
He reported on the long-term safety and antitumor activity of ODM-201 in the ARADES and ARAFOR clinical trials in chemotherapy- and CYP17-inhibitor–naïve patients with metastatic castration-resistant prostate cancer.
“Overall, we demonstrated very good tolerability in a chemotherapy-, abiraterone [Zytiga]-naïve group [and] significant PSA declines,” Dr Shore said.
ODM-201 in Clinical Trials
ARADES was a nonrandomized dose-escalation study in which 24 patients with metastatic prostate cancer received ODM-201 at 100 mg to 900 mg twice daily, with an additional randomized extension study that included 110 patients. There were no dose-limiting toxicities, “and we saw a very significant PSA decline at dosages of 1000 mg daily dose,” reported Dr Shore.
ARAFOR was an open-label pharmacokinetic study (N = 30) and an open-label extension study (N = 30) of ODM-201 dosed at 600 mg twice daily in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer. A PSA response, defined as a ≥50% decrease in the PSA level at week 12, was observed in 25 of 30 (83%) patients.
The median PSA level in the entire cohort was 28 ng/mL, and the median Gleason score at diagnosis was 2 to 6 in 7 patients, 7 in 16 patients, and 8 to 10 in 17 patients. Overall, 36 patients had bone lesions, and 3 patients had visceral metastases.
The median duration of treatment with ODM-201 was 13.5 months (range, 2.5-25.2 months). ODM-201 was well-tolerated, with the majority of adverse events being grade 1 or 2 in severity. The most frequent adverse events were fatigue (7%) and hot flashes (5%).
In the pooled analysis of 41 patients from the 2 clinical trials, 30 patients discontinued treatment—27 for disease progression, 2 for adverse events, and 1 for other reasons; 8 patients continue to receive treatment.
The median time to PSA progression was 12.4 months, and the median time to radiologic progression was 15.3 months.
“We ultimately settled on the 1200 mg daily dose, 600 mg twice a day. It’s at that dose that we saw very effective PSA declines,” said Dr Shore. The patients who received ODM-201 experienced “rather marked PSA declinations in this group of patients, chemotherapy- and abiraterone-naïve…with the majority of patients having rather extended suppressive PSAs,” he added.
The data support the ongoing, global, phase 3 clinical trial of ODM-201, called ARAMIS, in men with nonmetastatic castration-resistant prostate cancer.