Novel Drug Shows Activity in Prostate Cancer

Authors: MedPage Today

By Charles Bankhead, Staff Writer, MedPage Today
Published: October 02, 2012
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston

VIENNA -- An investigational androgen receptor antagonist achieved partial response or stable disease after 12 weeks of therapy in almost all evaluable patients with castration-resistant prostate cancer (CRPC), an initial clinical study showed.

Treatment with ODM-201 led to a decline in PSA level of 50% or more in 15 of 18 evaluable patients, including six of eight patients treated in the postchemotherapy setting, researchers reported here at the European Society for Medical Oncology.

The drug was generally well tolerated across a range of doses from 100 to 900 mg BID, according to Christophe Massard, MD, PhD, of Gustave Roussy Institute in Villejuif, France.

"It is really rare to see a drug so beneficial to most patients in such an early phase of development," Massard said at a press briefing. "These results are better than the historical data with enzalutamide or abiraterone."

Unlike other anti-androgens, ODM-201 does not cross the blood-brain barrier or lead to increases in testosterone in animal models of prostate cancer, he added.

In addition, unlike conventional androgen-receptor antagonists such as bicalutamide, ODM-201 does not exhibit agonist activity in the setting of androgen-receptor overexpression. Also unlike conventional anti-androgens, the drug inhibits androgen-receptor function by blocking nuclear translocation.

Massard presented findings from the first-in-man evaluation of ODM-201, an ongoing study that has accrued a total of 21 patients, 18 of whom were evaluable for response. From three to six patients were treated at preplanned doses. Patients treated at doses up to 700 mg BID were included in the analysis.

The primary objectives of the study were to identify the dose for evaluation in a phase II trial and to assess the safety, pharmacokinetics, antitumor activity, and effects of the drug on bone markers and androgen-receptor gene expression. The clinical activity assessment included change in PSA level, soft-tissue lesions, bone lesions, and circulating tumor cells.

The response group comprised 10 patients in the prechemotherapy setting and eight who had progressed after treatment with docetaxel. The entire 21 patients had a median treatment duration of 168 days.

PSA levels declined by 50% or more in nine of 10 patients with no prior exposure to chemotherapy and in six of the eight previously treated with docetaxel. PSA responses were observed at all doses evaluated.

Analysis of soft-tissue response at 12 weeks showed that all 18 patients had achieved partial responses or stable disease. Bone lesions remained stable in all but two patients.

The most common adverse events were asthenia, diarrhea, and nausea. No grade 3+ adverse events were reported.

Invited discussant Joan Carles, MD, PhD, of Vall d'Hebron University Hospital in Barcelona, said the development of ODM-201 follows the recent "plethora" of new therapies for CRPC, which previously had few options. The growing list of therapies and therapeutic candidates reflects the improved understanding of the role that androgen receptor signaling plays in the evolution of CRPC.

"Even the patients who received the lower doses of the drug had very dramatic responses, and it is important that the ODM-201 is active in pre- and postchemotherapy patients," said Carles. "More exciting was the toxicity, which is really low.

"If we compare these results with the results of a phase I/II study of enzalutamide, published 2 years ago, we see that ODM-201 has higher activity in terms of PSA response, soft-tissue disease, and bone disease," he added.

"The primary limitation of the study is the small number of patients. Obviously, more patients must be treated before the activity and safety can be assessed thoroughly."

Orion Pharma and Endo Pharmaceuticals sponsored the study, and investigators included one or more employees of Orion and Endo.

Massard disclosed relationships with Orion and Endo. One or more co-investigators disclosed relationships with Orion.

Primary source: European Society for Medical Oncology
Source reference:
Massard C, et al "ARADES trial: A first-in-man, open-label, phase I/II safety, pharmacokinetic, and proof-of-concept study of ODM-201 in patients with progressive metastatic castration resistant prostate cancer" ESMO 2012; Abstract LBA25.

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