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NCI MAY ASSIST MERCK IN DEVELOPING PROSCAR FOR PROSTATE CANCER

Executive Summary

NCI MAY ASSIST MERCK IN DEVELOPING PROSCAR FOR PROSTATE CANCER, National Cancer Institute Cancer Therapy Evaluation Program Associate Director Michael Friedman, MD, indicated at the Oct. 21 meeting of NCI's Division of Cancer Treatment Board of Scientific Counselors. Friedman said NCI would like to work with Merck on the development of the 5-alpha reductase inhibitor finasteride for prostate cancer but acknowledged that there was a "dilemma" with the drug since it is unclear if finasteride's reduction of dihydrotestosterone (DHT) levels has a clinical impact on prostate cancer versus testosterone or other androgens. Friedman said that NCI is "supportive of the idea of having a true prevention trial with Proscar in a high risk group." He noted that some populations, such as black men, have a 10-fold or greater incidence of prostate cancer compared to white men in the United States. He said NCI would like to see three to five years of safety demonstrated and noted that Merck is developing this data. Friedman made his comments following the presentation of data on two Phase III trials of Proscar for benign prostatic hyperplasia by Merck Sharp & Dohme researcher Glenn Gormley. The two trials, a North American trial involving 895 BPH patients and an international trial of 750 patients, were the pivotal clinicals in Merck's April NDA filing for Proscar 5 mg for prostate enlargement. Merck discussed the trials at the American Urological Association annual meeting in June ("The Pink Sheet" June 10, p. 6). In both of the 12-month placebo-controlled studies, Proscar reduced levels of the hormone DHT by 75%-85% and over six months reduced prostate gland size by 20%. Treatment with Proscar also reduced serum prostate specific antigen (PSA) levels about 50%. Patients in the trials received either 1 mg or 5 mg of Proscar. Gormley reported similar results in a pilot study of 28 asymptomatic men with stage D prostate cancer who received 10 mg doses of Proscar. Thirteen patients received Proscar and 15 placebo; 28 patients were treated for six weeks and nine for 24 weeks. The study found a 70%-75% reduction in serum DHT at weeks three and six and a 15%-20% reduction in serum PSA. Gormley commented that one could get a much greater reduction (50%-70% from baseline) in serum PSA with orchiectomy or an LHRH analog. "So we don't think the data here support a significant role for monotherapy in the latter stages" of prostate cancer, he stated. NCI's Friedman noted that a study published in the New England Journal of Medicine last year found that men with "PSA levels above four have about a two- to three-fold increased risk of prostate cancer and those with PSA levels above 10 have a 10-fold increase in risk." He added that this is complicated by the fact that glandular epithelial tissue in BPH also secretes PSA "so there are men with PSAs of 12 who have nothing but alot of glandular BPH." Friedman cited the advantages and disadvantages of studying Proscar in A1 prostate cancer patients and in patients with more advanced cancer -- A2, B1 and B2 patients. He said the latter trial could involve three arms -- placebo, Proscar and a retinoid. While Friedman expressed his backing of an NCI/Merck Proscar prostate cancer study, board member William Hryniuk, Ontario Cancer Foundation, asserted that he has seen no evidence that Proscar is active against prostate cancer, or that it "interdicts the malignant process." Without such evidence, he said he could not "account for such expenditure of time and energy" studying the drug. Board member Paul Carbone, University of Wisconsin Clinical Cancer Center, suggested that some basic studies should be done. "There is evidence that the epithelial cells do decrease in number and volume and that is what causes the decrease in prostate volume," Carbone commented. He said studies should look at proliferative rates of the cells and the DNA index of the prostate. DCT Director Bruce Chabner commented that he thought a "true prevention study would be best" but said such a trial would be large and costly. He said NCI is looking at other alternatives and noted that it would be "relatively inexpensive" to do a trial in advanced prostate cancer. Gormley indicated that Merck may also study Proscar for the prevention of prostate cancer. He commented that after radical prostatectomy, PSA levels should drop to zero but that this does not always happen and some patients have a rise in PSA after a few years, which is usually the first sign of a relapse. He said Merck initiated a placebo-controlled study this year in men with elevated PSAs after radical prostatectomy to test the hypothesis that if Proscar can prevent PSA levels from rising, it may prevent or delay relapse.
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