CHICAGO -- The novel anti-androgen orteronel delayed progression in chemotherapy-naive metastatic prostate cancer refractory to standard hormone therapy, but without a survival benefit.
The 8% relative difference in overall survival amounted to less than 2 months and wasn't significant , of Erasmus University Medical Center in Rotterdam, and colleagues found.
But radiographic progression-free survival (rPFS) remained 29% better with the drug than with prednisone alone in the pivotal ELM-PC 4 trial.
Orteronel delayed progression or death a median of 13.8 months compared with 8.7 months in the control group (P<0.00001), de Wit reported here at the American Society of Clinical Oncology meeting.
Nevertheless, "this is a positive study," declared study discussant , of Weill Cornell Medical College in New York City.
The study was designed to be positive if either of those primary endpoints was met, he pointed out.
"And we have relatively recently seen an rPFS benefit in absence of a statistically significant overall survival benefit has led to approval of drug, or at least expanded approval of drug," Tagawa said.
However, the sister pivotal trial, ELM-PC 5, with orteronel in docetaxel-treated patients was reported earlier this year negative for overall survival as the sole primary endpoint.
Again, rPFS was significantly extended, confirming that there is antitumor activity, Tagawa argued.
Orteronel targets 17,20-lyase, an enzyme involved in steroidal hormone biosynthesis and upregulated in metastatic castration-resistant prostate cancer.
That's the same mechanism as for abiraterone (Zytiga). But orteronel appears to have greater specificity and more potent inhibition, with some work suggesting that it may not have to be used with prednisone.
"Probably for our patients it is of benefit to have as many choices as possible," Tagawa said.
One of the reasons why these trials have been negative for overall survival may be crossover to subsequent therapies that muddies the impact of any one single drug, de Wit noted.
Also, the ELM-PC 4 trial had a relatively sick population -- 17% had visceral metastases -- and a number came off therapy even before the first assessment, Tagawa pointed out.
The trial included 1,560 patients with chemotherapy-naive, metastatic castration-resistant prostate cancer, who were asymptomatic and not on opioids at baseline.
They were randomized to either orteronel at 400 mg twice daily or placebo atop twice daily 5-mg prednisone.
As expected, the drug dramatically lowered testosterone levels from baseline (from a median 7.6 to 0.2 ng/dL). But prednisone didn't appear to be a true placebo in that regard, and lowered testosterone to 1.8 ng/dL as well, de Wit noted.
Regional differences as a surrogate for access to subsequent lines of therapy were not seen for either rPFS or overall survival.
Disclosures
The trial was sponsored by Millenium.
De Wit disclosed relationships with Millennium.
Tagawa disclosed relationships with Millenium, Dendreon, Janssen Pharmaceuticals, Medivation/Astellas, Sanofi, Amgen, Lilly, and Progenics.
Primary Source
American Society of Clinical Oncology
de Wit R, et al "Phase 3, randomized, placebo-controlled trial of orteronel (TAK-700) plus prednisone in patients (pts) with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) (ELM-PC 4 trial)" ASCO 2014; Abstract 5008.