Investigational treatment increased radiologic PFS, did not improve OS in mCRPC

Issue: July 25, 2014

CHICAGO — Men with metastatic castration-resistant prostate cancer previously treated with docetaxel experienced improved radiographic PFS after a regimen of orteronel plus prednisone, according to results of the phase 3 ELM-PC 4 trial.

Perspectives from Bruce Roth, MD; Scott T. Tagawa, MD

The combination did not, however, improve OS, researcher Ronald de Wit, MD, PhD, of Erasmus Medical Center, reported during his presentation here at the ASCO Annual Meeting.

Approximately 1,500 asymptomatic or mildly symptomatic patients (n=1,560) were randomly assigned twice-daily orteronel 400 mg — an investigational, non-steroidal, selective 17, 20-lyase inhibitor — plus prednisone 5 mg (n=781) or prednisone plus placebo (n=779). Progressive disease was evidenced by rising PSA and/or radiography, and all participants had testosterone levels <50 ng/dL and no history of opioid use. Primary endpoints were OS, which was assessed at 600 deaths, and radiographic PFS (rPFS), examined at the OS interim analysis. Secondary endpoints included PSA response, change in circulating tumor cells (CTCs), time-to-pain progression and subsequent chemotherapy.

The primary endpoint for OS was not met. However, at interim OS analysis, median rPFS was longer in the orteronel and prednisone group vs. the prednisone and placebo group (11 vs. 8.3 months; HR=0.7; 95% CI, 0.5-0.8). At the time of OS analysis, median rPFS improved by an additional 5.1 months in the orteronel and prednisone group (13.8 vs. 8.7 months; HR=0.7; 95% CI, 0.6-0.8).

At 12 weeks, PSA decreased by ≥50% in a greater number of patients assigned to orteronel plus prednisone compared with those assigned to prednisone plus placebo (43% vs. 25%; P<.00001), and de Wit reported satisfactory levels of CTCs.

Fewer patients in the orteronel group compared with placebo (45% vs. 51%) went on to receive subsequent chemotherapy, including docetaxel (31% vs. 33%), abiraterone (Zytiga, Janssen Biotech; 14% vs. 20%) and enzalutamide (Xtandi, Astellas; 6% in both).

Thirty percent of participants in the orteronel group discontinued due to adverse events, compared with 18% of those in the prednisone and placebo group. The most common adverse events were fatigue, nausea, diarrhea and constipation. – by Stacey L. Adams

For more information:

de Wit R. Abstract #5008. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago.

Disclosure: de Wit reports holding a consultant or advisory role and receiving honoraria from Millennium.

Perspective

Bruce Roth, MD

We have an androgen synthesis inhibitor, abiraterone (Zytiga, Janssen Biotech), that was approved first in post-chemotherapy patients, and then the label was extended to pre-chemotherapy. We have enzalutamide (Xtandi, Astellas), which is approved for use post-chemotherapy and is in the process of being advanced in the pre-chemotherapy setting [with the PREVAIL trial]. Now we have another androgen synthesis inhibitor, orteronel, that had already been shown not to prolong survival in the post-docetaxel setting, and now it is being used in the pre-chemotherapy setting.
Once again, it has been shown to have a PFS benefit but not an OS benefit, which is disappointing. I thought targeting a specific enzyme might preclude the use of prednisone in the long run and that it might be an attractive option compared with abiraterone, but in the end it didn’t show the same type of results. That could be due to one of several reasons. It is possible that more specific targeting of an enzyme may cause loss of benefit. The other possibility is that now we have so many agents that provide survival benefit, you dilute the results and maybe never demonstrate a survival benefit again.
The disturbing thing was that they tried to check for that and see if there was a difference in the two groups related to receipt of abiraterone or enzalutamide or docetaxel. However, the percentage of people who got those drugs in the two arms is about the same, so that argues a bit against the idea that this is all dilution effect, and it’s more a matter of saying that if orteronel had come along first, it would be approved and abiraterone wouldn’t look so good.

Bruce Roth, MD

Professor of medicine

Division of Oncology, Section of Medical Oncology

Siteman Cancer Center

Washington University in St. Louis

Disclosures: Roth reports no relevant financial disclosures.

Perspective

Scott T. Tagawa, MD

The ELM-PC 5 study was a well-performed study in the post-docetaxel setting with a primary endpoint of OS that was negative. In subset analysis looking at the non-Europe/North American population, it was not likely a pharmacogenetic or pharmacodynamic change, but it likely reflected less availability of other drugs. When we look at these two studies together, the two large randomized trials in this dose of 400 [mg] twice a day with prednisone for mCRPC really confirmed that there is anti-tumor activity. There is a need for continued research and for all future researchers to continue to collect biospecimens. We need to continue to collaborate among academic, pharma, philanthropy and patients. We need to get advocates in the trial design early, as well as advocate for additional funding. As a final comment, I think we really need to complete studies. I think it’s in the interest of our patients and it’s ethical that we complete the studies that we start.

Scott T. Tagawa, MD

Medical oncologist

Weill Cornell Medical College

Disclosures: Tagawa reports holding a consultant or advisory role with Dendreon, Janssen Pharmaceuticals, Medivation/Astellas and Sanofi. He also receives honoraria from Amgen, Janssen Pharmaceuticals and Medivation/Astellas. He receives research funding from Astellas, Janssen Pharmaceuticals, Lilly, Millennium, Progenics and Sanofi.