Dutasteride Enhances Predictive Usefulness of PSA Test

Roxanne Nelson

December 21, 2010

December 21, 2010 — The prostate-specific antigen (PSA) test remains the most widely validated marker of prostate cancer risk. However, it is an imperfect screening tool, and in many cases it has led to unnecessary biopsy and overtreatment. In addition, its effect on prostate cancer mortality is also uncertain.

A new study published in the January 2011 issue of the Journal of Urology suggests that the PSA test is more reliable in men taking dutasteride (Avodart; GlaxoSmithKline). Researchers found that even a slight increase in PSA levels in men receiving dutasteride was a better indicator of clinically significant cancer compared with those men in the placebo group.

In particular, the researchers found that found that a rise in PSA levels during the study period was more likely to be linked to aggressive, high-grade tumors (Gleason score, 7 - 10). Participants using dutasteride were almost twice as likely to be diagnosed with aggressive prostate cancer if their PSA levels increased compared with PSA level elevation in the placebo group.

Among men with any PSA elevation, aggressive, high-grade tumors were diagnosed in 13.2% of those using dutasteride and 7.7% in the placebo group. The authors noted that even a slight elevation in PSA of 1 point or less was a more accurate predictor of aggressive tumors in men using dutasteride; 10.3% had aggressive cancer compared with 5.4% using placebo.

The same held true for greater rises in PSA levels. For men with levels that increased 2 or more points, nearly 20.9% of the participants in the dutasteride group had aggressive cancer compared with 9.8% in the placebo group.

Conversely, PSA levels generally declined or remained stable in men using dutasteride who had either no cancer or low-grade tumors.

Take-Home Points

Dutasteride may make the PSA a more effective screening tool for prostate cancer, according to lead author Gerald Andriole, MD, the Robert Killian Royce Distinguished Professor and chief of urologic surgery at Washington University School of Medicine, St. Louis, Missouri.

"Overall, I think it will improve PSA screening, as it will tend to reduce the number of negative biopsies which are often triggered by the slow rise of PSA, due to benign growth of the prostate," said Dr. Andriole. "Clinicians need to be aware that they should interpret PSA differently for men on dutasteride and finasteride than for men not taking those medicines."

He pointed out that there are 2 main points that physicians should be aware of when interpreting these results. "First, PSA levels generally will fall by about 50% within 6 months of starting dutasteride," he told Medscape Medical News. "But the magnitude of fall does not predict whether that man harbors prostate cancer. In the REDUCE [Dutasteride of Prostate Cancer Events] study, men who were never found to have cancer had the same initial PSA drop as men who were later found to have cancer — even high-grade cancer.

"The second point is that any PSA rise off nadir is a worrisome finding that should mandate consideration of a biopsy since the patient has a higher chance of a high-grade, or any grade, cancer than men on placebo whose PSA is rising," he said. "This is because most men on placebo, or not taking these medications, will have ongoing growth of their prostate, and their PSA will generally rise, irrespective of whether they have a cancer or not."

Use as Chemopreventive?

The REDUCE study was initially conducted to evaluate the efficacy and safety of 0.5 mg dutasteride daily as a means of reducing prostate cancer risk. The study involved 8122 men between the ages of 50 and 75 years with a PSA of 2.5 to 10.0 ng/mL who had 1 negative prostate biopsy (6 - 12 cores) within 6 months before inclusion in the cohort.

As previously reported by Medscape Medical News, earlier results of this study found that during the 4-year study period, there were significantly fewer prostate cancers detected in men taking dutasteride than in the placebo group. This represented a relative risk reduction of 22.8% (P < .001).

Patrick Walsh, MD, a professor of urology at the James Buchanan Brady Urological Institute at Johns Hopkins Medical Institutions in Baltimore, Maryland, commented that the new findings with dutasteride were similar to what has been observed with finasteride (Proscar; Merck). However, he told Medscape Medical News at that time that he believes neither drug should be prescribed for the chemoprevention of prostate cancer.

He explained that these agents suppress PSA levels and that this was "worrisome," because a decline in PSA levels might convince men that the drug was preventing cancer, giving them a false sense of security.

In new guidelines issued in February 2009, the American Society of Clinical Oncology and the American Urological Association jointly recommended the use of both dutasteride and finasteride in asymptomatic men to reduce the risk for prostate cancer.

Enhances PSA as a Predictor

In the current analysis, Dr. Andriole and colleagues evaluated whether dutasteride use enhanced the usefulness of total PSA for diagnosing clinically significant prostate cancer. Participants were randomly assigned to receive either dutasteride or placebo, and total serum PSA was assessed every 6 months. In addition, participants underwent 10-core transrectal ultrasound guided biopsy at 2 and 4 years; unscheduled biopsies were also performed if there was a clinical indication for one.

Among those who underwent at least 1 biopsy, prostate cancer was detected in 659 men (19.9%) in the dutasteride group and 858 (25.1%) in the placebo group (P < .0001). Of these cancers, 220 (6.7%) were Gleason score 7 to 10 in the dutasteride group and 233 (6.8%) in the placebo group (P = .81).

At 6 months, the PSA of dustasteride users was reduced by a mean of 46.9% in men without cancer, by 45.4% in men with Gleason score 5 to 6 cancer and 46.3% in men found to have Gleason score 7 to 10 cancer. In both groups, the mean PSA was highest in men who were eventually diagnosed with Gleason score 7 to 10 cancer and was similar in those who were eventually diagnosed with low-grade cancer or no cancer.

The authors note that baseline PSA was a "poor predictor of the future diagnosis of any prostate cancer" (area under the curve, 0.530 for placebo vs 0.514 for dutasteride; P = .42) or Gleason score 7 to 10 prostate cancer (area under the curve, 0.543 for placebo vs 0.552 for dutasteride; P = .79).

The final PSA was also a relatively poor predictor of prostate cancer of any Gleason score, but better predicted disease with Gleason score 7 to 10 in both treatment groups. Significantly higher area-under-the-curve values were seen in the dutasteride group compared with placebo (any Gleason score, P = .0020; Gleason score 7 - 10, P = .0491).

PSA levels rose during the study period in 72% of men receiving placebo, but only 29% of those receiving dutasteride. As compared with no increase in PSA from month 6 to the final PSA in men who received dutasteride, the authors write, "an increase in PSA was associated with a higher likelihood of biopsy detectable prostate cancer (any grade and Gleason score 7–10) and greater likelihood of a clinically significant tumor."

In contrast, increases in PSA in the placebo group were less predictive of cancer overall, or of high-grade tumors.

"Dutasteride has the benefit of decreasing the overall number of false-positive PSA signals, reducing the risk for diagnosis of low grade cancers that are less likely to cause harm if left untreated, and enhancing the diagnosis of high grade cancers or those cancers not responding to dutasteride therapy that may benefit from early diagnosis and treatment," they conclude.

The REDUCE study was supported by GlaxoSmithKline, the manufacturer of dutasteride. Dr. Andriole is a consultant for GlaxoSmithKline. Several coauthors report financial interest and/or other relationships with Aeterna Zentaris, Amgen, Cambridge Endo, EMD Serono, Envisioneering Medical, Ferring Pharmaceuticals, GenProbe, GlaxoSmithKline, Myriad Genetics, Nema Steba, Onconome, Veridex, and Viking Medical.

J Urol. 2011;185:126-131. Abstract

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