US study examines dutasteride's benefit in men with high PCa risk

Monday, 4 May 2009- Prostate cancer incidence decreased by 23% in high-risk men treated with dutasteride (Avodart), according to results of an international clinical trial.

"There was a consistent effect across time and key baseline subgroups," said Dr. Gerald Andriole. "Dutasteride enhanced the utility of PSA as a diagnostic test for prostate cancer -- overall and for high-grade disease; it had beneficial effects on benign prostatic hypertrophy outcomes and was well tolerated."

The benefit accrued throughout the four years of follow-up, resulting in almost 200 fewer cases of prostate cancer in patients treated with dutasteride versus placebo, according to Andriole (Washington University in St. Louis), who reported his findings at the American Urological Association annual meeting recently held in Chicago.

The benefits add to those demonstrated with finasteride in the Prostate Cancer Prevention Trial (PCPT), although the two trials had different designs. PCPT involved healthy men with an average risk for prostate cancer, whereas the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial focused on men with an increased risk of prostate cancer by virtue of elevated PSA levels. REDUCE included 8,200 men ages 50 to 75 from 250 sites in 42 countries.

The trial had PSA-based entry criteria: baseline values of 2.5 to 10 ng/mL for men younger than 60, or 3.0 to 10 ng/mL for older men. Participants had a negative prostate biopsy in the six months prior to enrollment and no evidence of prostate cancer, high-grade prostatic intraepithelial neoplasia (PIN), or atypical small acinar proliferation (ASAP). The men were randomised to dutasteride 0.5 mg/day or to placebo and followed for four years. All study participants had prostate biopsies after two years and at the end of the study.

The primary endpoint was biopsy-detectable prostate cancer. Secondary endpoints included Gleason score at diagnosis, occurrence of high-grade PIN or ASAP, number of positive biopsy cores, percentage of core with cancer involvement, and volume of cancer in cores. Investigators also assessed the diagnostic utility of PSA, BPH endpoints, and the safety and tolerability of dutasteride.

During the trial, prostate cancer was diagnosed in 1,516 (22.5%) study participants and high-grade PIN or ASAP in 621 (9.2%). Cancer was diagnosed by protocol-mandated biopsy in 1,419 of the cases (93.6%), and by for-cause biopsy in 97 cases (6.4%).

Andriole reported that placebo-treated patients had 857 cases of prostate cancer compared with 659 in the dutasteride group, representing a 23% risk reduction (P<0.0001). During the first two years of REDUCE, the placebo group had a prostate cancer incidence of 17.2% versus 13.4% in the dutasteride group, a difference of 22.5%.

In the final two years of the trial, prostate cancer incidence was 11.8% in the placebo group and 9.1% in the dutasteride arm, representing a relative risk reduction of 23.5%. Subgroup analysis consistently favored dutasteride regardless of patient age, family history of prostate cancer, or baseline prostate symptom score, prostate volume, or PSA level.

The risk reduction in the PCPT was overshadowed by the occurrence of significantly more high-grade cancers in the finasteride group, a finding subsequently attributed to an artifact of trial design. In REDUCE, the two patient groups had similar rates of high-grade cancer, whether high grade was defined as Gleason 7 to 10 or Gleason 8 to 10.

An analysis of area under the receiver operating characteristic curve (AUC) showed that treatment with dutasteride improved the diagnostic utility of PSA. The AUC was significantly greater with dutasteride for all tumors that were diagnosed (P<0.0001) and for diagnosis of high-grade cancer (P<0.02).

Treatment with dutasteride significantly reduced all major BPH-related endpoints, including acute urinary retention, need for BPH-related surgery, and the composite of the two endpoints (P<0.0001 for all comparisons). The frequency of any adverse events, serious adverse events, and fatal adverse events was similar in the two groups.

Patients in the dutasteride arm had a significantly higher rate of drug-related adverse events (22% versus 15%, P<0.0001) and drug-related adverse events leading to permanent discontinuation (4.3% versus 2.0%, P<0.0001). The most common adverse events were decreased libido, loss of libido, erectile dysfunction, decreased semen volume, and gynecomastia, all of which occurred more often in the dutasteride group (P<0.05).

At a press briefing that followed his presentation, Andriole said he would feel comfortable recommending chemoprevention for high-risk men on the basis of the REDUCE findings, adding that he would take it himself, if indicated.  He defined high risk as 30% over four years, resulting from factors such as high body mass index, elevated PSA, and positive family history.

Source: Andriole G, et al., “Further analyses from the REDUCE prostate cancer risk reduction trial," AUA 2009; Abstract LBA1. American Urological Association Annual Meeting, Chicago, USA.



Edited by: JV

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