Prostate cancer agent fails to extend survival in phase III trial

San Francisco-The investigational 17,20 lyase inhibitor orteronel failed to significantly extend overall survival (OS) in an international phase III study of patients with metastatic castration-resistant prostate cancer (mCRPC).

Orteronel did improve radiographic progression-free survival (rPFS), time to progression of PSA level, and PSA response, however, indicating “clinically meaningful activity,” reported first author Robert Dreicer, MD, at the Genitourinary Cancers Symposium in San Francisco.

17,20 lyase is a key enzyme in the production of steroidal hormones. In the study presented here, orteronel plus prednisone was compared with placebo plus prednisone in 1,099 patients with mCRPC. Patients were randomized in a 2:1 ratio to orteronel, 400 mg/day, plus prednisone, 5 mg, or placebo plus prednisone twice daily, without food restrictions, in 28-day treatment cycles.

Patients randomized to orteronel plus prednisone received a median of 6.2 treatment cycles compared with five cycles in those randomized to placebo plus prednisone. The median treatment duration was 5.7 months and 4.6 months in the two groups, respectively. Median follow-up was 10.7 months.

Median OS, the primary endpoint, was 17.0 months versus 15.2 months (p=.1898) in patients randomized to orteronel/prednisone versus placebo/prednisone, respectively.

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‘Striking’ regional differences in OS

There were striking regional differences in OS. In the non-European/North American population, median OS was significantly superior in patients randomized to orteronel/prednisone compared with placebo/prednisone, with a hazard ratio of 0.709 (15.3 months vs. 10.1 months; p=.019).

Availability of other effective therapies such as abiraterone acetate (ZYTIGA) and enzalutamide (XTANDI) in the United States and Europe may have masked a survival advantage with orteronel in the overall study population, as early PSA failures may have been switched to these other agents, said Dr. Dreicer, chair of solid tumor oncology at Cleveland Clinic’s Taussig Cancer Institute.

“That’s speculation, but it’s one way of interpreting the trial,” Dr. Dreicer told Urology Times.

An improvement in rPFS, from a median of 5.7 months to a median of 8.3 months, was observed in the orteronel group (p=.00038). A PSA response of a 50% decrease at 12 weeks occurred in 25% and 10% of the orteronel/prednisone and placebo/prednisone groups, respectively (p<.0001). The median time to PSA progression was 5.5 months and 2.9 months, respectively (p<.001).

Dr. Dreicer has a consultant or advisory role with Abbvie, Dendreon Corp., Endo Pharmaceuticals, Janssen Pharmaceuticals, and Millennium Pharmaceuticals. He has received research funding from Endo, Millennium, and Progenics Pharmaceuticals.UT

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