Can Dutasteride Be REDEEM-ed in Prostate Cancer?

Data interpreted very differently

Nick Mulcahy

February 17, 2011

February 17, 2011 — Dutasteride (Avodart, GlaxoSmithKline) might have a role to play in prostate cancer yet — as an adjunct treatment for men with low-risk disease on active surveillance, suggested the lead author of a new study on the subject. Men receiving dutasteride had a "delayed time to prostate cancer progression," compared with men receiving placebo, the study found.

However, an expert in the field called the study "a negative trial" and emphasized that the rate of disease progression in the 2 groups of men was "essentially the same" at 3 years, which was the end of the trial.

The study in question is the industry-sponsored Reduction with Dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial.

Dutasteride, a dual 5-alpha reductase inhibitor indicated for the treatment of benign prostatic hyperplasia, was recently rejected by the US Food and Drug Administration (FDA) as a chemopreventive agent for prostate cancer.

However, REDEEM indicates that dutasteride might be useful for "men with low-risk prostate cancer who want to have a period of observation," said lead investigator Neil Fleshner, MD, from the University Health Network in Toronto, Ontario, Canada. He was speaking at a press conference that preceded the start of the 2011 Genitourinary Cancers Symposium, where the study will be presented.

Primary End Point Data Questioned

All 302 men in REDEEM had biopsy-proven low-risk disease and were being managed with active surveillance — a program of monitoring disease markers in an attempt to avoid unnecessary treatment of indolent cancers. They were randomized to placebo or treatment with dutasteride (0.5 mg daily) and received follow-up biopsies at 1.5 and 3 years.

The primary end point of the study was "time to prostate cancer progression," which accounted for both the conventional measure of pathologic progression and a less familiar measure — "therapeutic progression" — the time to initiation of more aggressive therapy such as surgery.

Compared with placebo, dutasteride significantly delayed prostate cancer progression over the 3-year study period (relative risk reduction, 38.9%; 95% confidence interval [CI], 12.4 to 57.4%; P = .007), write Dr. Fleshner and his coauthors in an abstract made available by the American Society of Clinical Oncology at the time of the press conference.

However, Patrick Walsh, MD, from the James Buchanan Brady Urological Institute at Johns Hopkins Medical Institutions in Baltimore, Maryland, said that this claim requires scrutiny and does not mean that, at 3 years, dutasteride was significantly better than placebo.

Final data from REDEEM have been made public previously, said Dr. Walsh, including in a supplemental document that was part of the failed New Drug Application for dutasteride for prostate cancer chemoprevention.

By 3 years, the rate of progression in the 2 groups was essentially the same.

In that document, filed with FDA on December 1, 2010, GlaxoSmithKline indicated that in REDEEM the incidence of progression at 1.5 years favored dutasteride, with 23% of the 142 men in the dutasteride group progressing, compared with 35% of the 144 men in the placebo group. However, at 3 years, the 2 groups had nearly equal progression, with 24% of the placebo group (which by then comprised 86 men) progressing, compared with 21% of the dutasteride group (by then 106 men).

"It is my understanding of the data that there was a reduction in progression at 18 months, but by 3 years the rate of progression in the 2 groups was essentially the same," Dr. Walsh told Medscape Medical News.

"Because these patients will be on the drug for many years and because the effect was no longer present at 3 years, I would interpret this as a negative trial," summarized Dr. Walsh.

This is an important step forward.

The moderator of the press conference suggested that the study results are valuable. "This is an important step forward," said Nicholas Vogelzang, MD, from US Oncology, about the impact of the results on managing low-risk cancer. In the trial, low risk was defined as clinical stage T1c–T2a, a Gleason score of 6 or lower, and a serum prostate-specific antigen level of 10 ng/mL or less.

However, do not expect GlaxoSmithKline to file for an FDA indication for dutasteride in this setting, reported Dr. Fleshner.

"The FDA shot down the prevention model. I don't think we are going to see a formal indication for active surveillance," he said, adding that REDEEM is not a registration trial and that any use for prostate cancer would be off-label.

Another clinician approached by Medscape Medical News suggested that dutasteride has some value in men with low-risk prostate cancer.

"I do indeed use both finasteride and dutasteride for this purpose," said Richard Greenberg, MD, from the Fox Chase Cancer Center in Philadelphia, Pennsylvania, "although this is clearly beyond the FDA labeling."

"Whether we are treating the cancer or the patient and the patient's wife remains unclear," added Dr. Greenberg.

However, he also pointed to a potential clinical benefit of these drugs: They "can also be used to distinguish malignant growth (progression) [from] benign growth in many cases on the clinical level, thereby helping to determine appropriate timing for intervention."

Notes on High-Risk Disease

Dr. Fleshner and coauthors note that there was "no evidence of increased Gleason score upgrading with dutasteride" between the time of the baseline biopsy and final biopsy at 3 years. The dutasteride and placebo groups had comparable portions (around 15%) of patients progress to Gleason scores of 7 or 8 from a lower score.

However, the bigger issue is that, in earlier studies involving thousands of men, treatment with both dutasteride and finasteride was associated with a higher risk of being diagnosed with high-grade disease.

In the REDEEM trial, at final biopsy, only 3 men in the placebo group and 2 in the dutasteride group had a Gleason score of 8; none had a score of 9 or 10.

Dr. Fleshner acknowledged to Medscape Medical News that the 302-patient study was not powered to evaluate the significance of the incidence of high-grade disease.

But he also said that, in this setting, the risk for high-grade disease is "quite small" because the initial biopsy has eliminated patients with easily detectable high-grade tumors, and those patients do not qualify for active surveillance.

Dr. Fleshner also said that the association between dutasteride and finasteride and high-grade disease "might be a good thing."

"The drugs shrink the prostate, allowing for easier detection of high-grade cancers," he explained. "Dutasteride doesn't cause them, it just causes them to be detected."

REDEEM also found that 23% of men (n = 31) in the placebo group and 36% of men (n = 50) in the dutasteride group had no cancer detected on their final biopsy. On the basis of previous findings, the percentage in the placebo group was expected, said Dr. Fleshner. But the percentage in the dutasteride group indicates that the drug "seems to reduce the amount of cancer in the gland," said Dr. Vogelzang.

The investigators also found that prostate-cancer-related anxiety, measured with the Memorial Anxiety Scale for Prostate Cancer, was lower in the dutasteride group than in the placebo group (P = .036). This finding is an important part of the study because of the "increasing anxiety that men feel while under watchful waiting," said Dr. Vogelzang.

Dr. Vogelzang reports a leadership position at US Oncology; serving as a consultant for Amgen, Aveo, Bayer, Celgene, Dendreon, Eisai, GE Healthcare, Genentech, GlaxoSmithKline, Medscape, Novartis, Pfizer, Sanofi-Aventis, and Wilex; and receiving honoraria from Amgen, ArQule, Bayer, Clinical Care Options, Cougar Biotechnology, Genentech, Imedex, Lilly Lippincott, Williams and Wilkins, Medscape, Novartis, Onyx, Pfizer, and Veridex.

2011 Genitourinary Cancers Symposium (GUCS). To be presented February 17, 2011.


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