PCTC Study Ended Early on Finding Proscar Significantly Reduces Prostate Cancer Risk

WASHINGTON— Researchers have closed the Prostate Cancer Prevention Trial (PCPT) 15 months early after finding that men who took Proscar (finasteride) had a 25% lower risk of developing the disease, compared with men given placebo. "This trial proves that prostate cancer, at least in part, is preventable. It is a huge step forward for cancer research," Peter Greenwald, MD, DrPH, director of the National Cancer Institute’s Division of Cancer Prevention, said at a press conference announcing the results.

The study also found that men taking finasteride had a significantly greater number of high-grade tumors than those in the placebo arm. This noted, "98% of all cancers diagnosed in the entire PCPT were localized to the prostate at the time of diagnosis," said principal investigator Ian M. Thompson, MD, of the University of Texas Health Science Center in San Antonio.

The 10-year PCPT was scheduled to end in May 2004. However, the study’s independent data and safety monitoring committee concluded on Feb. 21, 2003, that the data already collected were sound and unlikely to change with the addition of more data, and on March 3, it recommended closing the trial. The committee based its recommendation on findings from 9,060 trial participants who had developed prostate cancer or completed the study’s 7-year follow-up process.

The Food and Drug Administration initially approved Proscar in 1992 as a 5-mg/d treatment for benign prostatic hyperplasia (BPH), and later approved its sale in a 1-mg daily dose, marketed as Propecia, to treat male-pattern hair loss.

The drug inhibits the steroid 5a-reductase, an enzyme that converts testosterone to androgen dihydrotestosterone (DHT). Because strong evidence supports the influence of androgens on the development of prostate cancer, researchers decided to test finasteride as a possible means of reducing the disease prevalence.

The PCPT was funded by the NCI, coordinated by the Southwest Oncology Group (SWOG), and carried out at 219 sites. Researchers originally considered using mortality as an endpoint for PCPT but found that would require a 15-year trial involving 50,000 men. "It was just too big a bite," said SWOG chair Charles E. Coltman, MD.

Between January 1994 and May 1997, the controlled, double-blind study enrolled 18,882 men ages 55 or older with normal digital rectal examinations and PSA levels of 3 ng/mL or lower. The men were randomized to either 5 mg of finasteride daily or placebo. Participants underwent a yearly digital rectal exam and PSA test. They also agreed to an end-of-study biopsy after 7 years if they had not been diagnosed with prostate cancer during the trial.

Among the 9,060 men included in the data analysis, 803 (18.4%) of the 4,368 randomized to the Proscar group and 1,147 (24.4%) of the 4,692 participants in the placebo arm were diagnosed with prostate cancer, a relative risk reduction of 24.8% (P < .001). "The reduction in prostate cancer was noted at 1 year and continued over the 7 years of the study," Dr. Thompson said.

Prostate cancer was diagnosed due to biopsy for cause in 435 of the finasteride group and 571 of the placebo group. Prostate cancer was diagnosed as a result of the end-of-study biopsy in 368 of the men taking finasteride and 576 of those in the placebo group.

The tumors detected by biopsy performed for cause were clinically similar to those found in clinical practice due to biopsy based on PSA screening and digital rectal examination. The clinical significance of cancers found in the end-of-study biopsies is unknown, the researchers said.

High-Grade Tumors

The study’s central pathology laboratory reported that among the men in the study who developed prostate cancer, those in the finasteride arm had a larger proportion of tumors with high Gleason scores than those who received placebo. In the finasteride arm, 280 (37%) of 757 graded tumors had Gleason scores of 7 to 10, compared with 237 (22.2%) of 1,068 graded tumors from the placebo group. Thus, tumors with high Gleason scores were found in 6.4% of the men treated with finasteride vs 5.1% of the placebo group.

"There are several hypotheses about these tumors and whether they are real or just an artifact," Dr. Ford commented. "Only time and continued follow-up will tell us whether these tumors behave like traditional tumors or are, in fact, more like the low-grade tumors." [See box on page 6.]

Adverse Events

An analysis of adverse events reported by all participants—9,423 men receiving finasteride and 9,437 on placebo—found sexual side effects were significantly more common in the treatment arm, and urinary problems were significantly more common in the control group.

Sexual side effects included reduced volume of ejaculate (60.4% in the treatment arm vs 47.3% in the placebo group), erectile dysfunction (67.4% vs 61.5%), loss of libido (65.4% vs 59.6%), and gynecomastia (4.5% vs 2.8%). One man in each arm developed breast cancer.

Genitourinary side effects included BPH (5.2% in the finasteride arm vs 8.7% in the placebo group), increased urinary urgency or frequency (12.9% vs 15.6%), urinary incontinence (1.9% vs 2.2%), urinary retention (4.2% vs 6.3%), transurethral resection of the prostate performed (1.0% vs 1.9%), prostatitis (4.4% vs 6.1%), and urinary tract infection (1.0% vs 1.3%).

Both Dr. Ford and Dr. Thompson noted that the PCPT has yielded a trove of blood samples, prostate tissue, and tumor specimens that will provide the basis for further studies related to prostate cancer.

The full PCPT report appears in the July 17, 2003, issue of The New England Journal of Medicine.