Nick Mulcahy

June 06, 2011

June 6, 2011 (Chicago, Illinois) — Abiraterone acetate (Zytiga, Cougar Biotechnology), which was approved recently in the United States, significantly improves survival in men with metastatic castration-resistant prostate cancer. The survival data, which were recently published, have been now been updated; they were reported here at the American Society of Clinical Oncology ASCO®) 2011 Annual Meeting.

The survival benefit is even better with more follow-up.

Dr. Howard Scher

Overall survival in the phase 3 trial was 15.8 months in the abiraterone group and 11.2 months in the placebo group (P < .0001); median follow-up was 20.2 months, said investigator Howard I. Scher, MD, from Memorial Sloan-Kettering Cancer Center in New York City, at a press conference.

This data from the study's final analysis are a clear improvement over the interim results, which were published last month in the New England Journal of Medicine (2011;364:1995-2005). The interim data indicated that overall survival in the abiraterone group was 14.8 months, compared with 10.9 months in the group that received placebo plus prednisone (P < .001). The median follow-up was about 12 months at that time.

Thus, the difference in median overall survival between the 2 groups increased from 3.9 to 4.6 months from the interim to the final analysis in the trial known as COU-AA-301.

Abiraterone represents a first in the treatment of men whose disease has progressed while on androgen-deprivation therapy, Dr. Scher said at the time the study was published.

"This trial establishes a new category of treatment for men who have progressed on conventional hormone therapies, as well as chemotherapy. It proves that these previously treated patients have tumors that are still hormonally responsive. Previously, this was the point in the illness where hormonal agents were typically not considered," he said.

In Search of a Survival Surrogate

The new survival data on abiraterone were actually not the primary focus of the press conference. Instead, another facet of the pivotal 1195-patient trial of the new agent — the use of circulating tumor cells (CTCs) as a potential biomarker for measuring a drug's effectiveness in prostate cancer and as a possible surrogate for survival in treated men — was explored and explained.

Dr. Sonali Smith

The past year has been "absolutely incredible" in the treatment of advanced prostate cancer, with 3 new therapies being approved, said Sonali Smith, MD, from the University of Chicago Medical Center in Illinois, who moderated the press conference. "What we don't have is a way to predict who is going to do well or not," she added.

CTCs are a good choice to be a biomarker, or part of a biomarker panel, because they are not affected by androgen, prostate-specific antigen (PSA), or other factors that may drive the disease, Dr. Scher explained. Thus, any change in their count is probably the result of a drug effect, he said.

In the trial, investigators evaluated CTC counts as one of the end points in the trial at screening, baseline, and at weeks 4, 8, and 12. They used a validated instrument to do so — the Veridex CellSearch technology, which is the only CTC enumeration assay approved by the US Food and Drug Administration (FDA).

The researchers found that treatment with abiraterone reduced the number of CTCs, changing levels from unfavorable (5/7.5 mL whole blood or more) to favorable (below 5/7.5 mL whole blood) counts in "about 40% of patients," said Dr. Scher.

This conversion was predictive of a better prognosis and of overall survival as early as 4 weeks after treatment, said Dr. Scher, who is the D. Wayne Calloway Chair in Urologic Oncology and chief of the genitourinary oncology service at Memorial Sloan-Kettering.

"The presence of CTCs in the blood is prognostic for survival pre- and posttreatment — the higher the number, the worse the prognosis," he said. Another measure in the biomarker panel used in the study, lactate dehydrogenase (LDH), was also prognostic of survival. However, the other measures — PSA, mercury, and alkaline phosphatase — were not.

An initial biomarker panel with CTC and LDH was "strongly associated" with overall survival, and after adjustment for the panel, the treatment affect was no longer apparent, said Dr. Scher, which suggests that the 2 measures indicate efficacy and could be valid biomarkers.

The "Ultimate Goal"

In a press statement, Dr. Scher placed the new findings about CTCs, which are cancer cells that have broken off from a tumor and have entered the bloodstream, in the context of other research on the subject in prostate cancer.

Other studies have linked declining numbers of CTCs with improved overall survival in metastatic castration-resistant prostate cancer. Also, CTCs have been shown to be a more powerful early predictor of survival than PSA in men with prostate cancer.

But CTCs have not been shown to be indicators of an effective response to a drug. A biomarker or panel of markers that could provide early insight into whether or not a drug can prolong life would be highly beneficial, said Dr. Scher at the press conference. Such markers or surrogates could be used instead of a survival end point in clinical trials, allowing drugs to be tested in smaller, less costly trials that could potentially enable faster approval by the FDA. Changes in PSA have not been shown to be surrogates for survival in prospective trials and cannot be used for regulatory approval.

"The ultimate goal of these studies is to develop a biomarker panel that includes CTCs that can be used in phase 3 trials instead of a survival end point," said Dr. Scher in an ASCO press statement. "This trial was the first to show a survival benefit with the CTC question embedded, which is part of a formal collaboration with the FDA," he explained.

The clinical trial was funded by Cougar Biotechnology. The CTC analyses were independently conducted at Memorial Sloan-Kettering Cancer Center and the Institute for Cancer Research, with funding support from the Prostate Cancer Foundation and the Prostate Cancer Clinical Trials Consortium; The Medical Research Council, United Kingdom; the Experimental Cancer Medical Centre, United Kingdom; and an NIHR Biomedical Research Center Grant. Dr. Scher reports serving as a consultant/advisor for Veridex and Cougar Biotechnology, and receiving honoraria from Cougar. A number of coauthors disclosed financial relationships with Cougar and its parent company, Johnson & Johnson.

American Society of Clinical Oncology ASCO®) 2011 Annual Meeting: Abstract LBA4517. Presented June 6, 2011.

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