New Agent Misses the Mark in Advanced Prostate Cancer

Roxanne Nelson

February 04, 2014

SAN FRANCISCO — A promising investigational agent for metastatic castration-resistant prostate cancer has failed to meet its primary end point in a phase 3 trial.

There was no significant improvement in overall survival when orteronel (Takeda) was added to prednisone. Median overall survival with orteronel plus prednisone was similar to that with placebo plus prednisone.

The study was terminated for failing to meet its primary end point.

However, orteronel "did lead to a notable improvement in radiographic progression-free survival," reported lead author Robert Dreicer, MD, MS, professor of medicine at the Cleveland Clinic Lerner College of Medicine, and chair of the Department of Solid Tumor Oncology at the Cleveland Clinic Foundation. That was a secondary end point of the trial.

Dr. Dreicer presented the findings here at the 2014 Genitourinary Cancers Symposium.

In addition, he noted that there were regional differences in overall survival, and that a subgroup of patients did achieve a benefit. For patients treated outside Europe and North American, survival was better in the orteronel group than in the placebo group.

"This represented a little over a third of patients in the trial," Dr. Dreicer said.

Orteronel is an investigational oral, nonsteroidal, selective inhibitor of 17,20-lyase, a key enzyme in the production of steroidal hormones, including androgens. Early-phase trials showed efficacy and safety, Dr. Dreicer pointed out. Phase 2 trials showed that the agent led to significant and durable declines in prostate-specific antigen (PSA) levels in patients with nonmetastatic castration-resistant prostate cancer.

Phase 3 Trial Results

The phase 3 Evaluation of the Lyase Inhibitor Orteronel in Metastatic Prostate Cancer (ELM-PC) 5 trial was conducted in 1099 men with metastatic castration-resistant prostate cancer that had progressed during or after docetaxel-based therapy. The manufacturer unblended the study last July after a prespecified interim analysis indicated that orteronel plus prednisone would likely not meet its primary end point, but this is the first time that the full results of the trial have been reported.

The trial was conducted in 260 centers in 42 countries. Patients were randomized to 28-day cycles of oral orteronel 400 mg twice daily plus prednisone 5 mg twice daily or to placebo plus prednisone, without regard to food. Men who had received previous orteronel, abiraterone, or ketoconazole were excluded from the analysis.

For the entire cohort, median overall survival was similar in the orteronel and placebo groups (17.0 vs 15.2 months; hazard ratio [HR], 0.886; P = .1898).

However, geography had an effect. There was a difference in median overall survival between the orteronel and placebo groups in the 112 patients treated in North America (20.9 vs. 16.9 months; HR, 0.889), the 590 patients treated in Europe (18.3 vs. 17.8 months; HR, 1.048), and the 397 patients treated in the rest of the world (15.3 vs 10.1 months; HR, 0.709).

The secondary end point of median radiographic progression-free survival was significantly better in the orteronel group than in the placebo group (8.3 vs. 5.7 months; HR, 0.76; P = .00038).

Table. Common Adverse Events

Event Orteronel Group, % Placebo Group, %
Nausea 30 16
Vomiting 23 8
Fatigue 17 11
Diarrhea 16 9
Grade 3 or higher    
   Increased lipase 12 <1
   Increased amylase 8 <1
   Amylase and fatigue 3 3


Reasons for Regional Differences

One reason for the regional difference is that only "38% of the non-European, non–North American population received subsequent therapy," Dr. Dreicer explained, whereas a higher percentage of patients treated in Europe and North America did.

In addition, while orteronel was being investigated in this trial, abiraterone (Zytiga) and enzalutamide (Xtandi) became available. "Abiraterone was available in the United States and Canada through an expanded-access program at the time of the study initiation," Dr. Dreicer noted.

Another explanation could lie in the overall differences in disease burden. In an interview with GU Daily News, the official publication of the symposium, Jeff Michael Michalski, MD, MBA, professor of radiation oncology at the Washington University School of Medicine in St. Louis, Missouri, noted that patients treated in North America had very early stages of metastatic disease (average PSA, 50 ng/mL), compared with patients treated elsewhere (average PSA, 150 ng/mL).

Also, patients from other countries were "more often heavily treated and had worse performance status, just worse overall disease," he said. "It may appear that patients with earlier stages of [metastatic] disease do not benefit from these newer agents, compared with patients who have a greater burden of illness."

A High Hurdle

The trial did demonstrate that orteronel has activity, as evidenced by the radiographic progression-free survival, Dr. Michalski said. "Also, the PSA progression rate was improved with the use of orteronel."

Although this probably isn't going to be the trial that leads to approval by the US Food and Drug Administration, "we are encouraged to continue the existing/ongoing trials that are using orteronel," he added.

Dr. Michalski believes that the end point of overall survival is "a very high hurdle to cross in the investigation of prostate cancer." With more agents being investigated, "knowing in advance that there are other agents that might be made available to those patients will make overall survival end points very difficult to cross," he said.

The improvements in clinical disease-free survival and radiographic progression-free survival seen in the ELM-PC 5 trial could be important end points to consider for patients and, ultimately, for drug approval, he concluded.

Dr. Dreicer reports relationships with AbbVie, Dendreon, Endo Pharmaceuticals, Janssen, Millennium, and Progenics.

2014 Genitourinary Cancers Symposium (GUCS): Abstract 7. Presented January 30, 2014.


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