Objectives. To study the safety, pharmacokinetics, biologic activity, and preliminary efficacy of the bispecific 5-alpha-reductase inhibitor (LY320236) in prostate cancer. Methods. Fifty-one patients with recurrent or metastatic prostate cancer were sequentially (nonrandomly) assigned in cohorts to receive one of five single daily oral doses of LY320236 (10, 50, 150, 250, and 500 mg). Serial evaluations included serum testosterone, dihydrotestosterone, androstenediol glucuronide, estradiol, and pharmacokinetics on days 1, 29, and 57. Toxicity assessments, x-rays/scans, and blood tests, including serum prostate-specific antigen (PSA) determination, were done at regular intervals. Results. Overall, treatment was well tolerated, with 3 of 51 patients developing reversible grade 3-4 toxicity (one diarrhea, two elevated liver enzymes). Peak blood levels (2 to 3 hours after drug administration) were greater for doses of 150 mg or greater compared with less than 150-mg doses with slow accumulation. Serum levels of testosterone, dihydrotestosterone, and androstenediol glucuronide did not change significantly during treatment; however, a statistically significant increase occurred in serum estradiol levels in both the castration and noncastration groups. One of 26 in the noncastration group and 4 (27%) of 15 in the castration group with baseline PSA levels of 5 ng/mL or greater had a 50% or greater PSA decline for 4 weeks or longer. Conclusions. LY320236 treatment is associated with modest reversible toxicity. An elevation of estradiol levels was seen in both castration and noncastration groups, although PSA declines were primarily seen in the castration group. The absence of cardiovascular toxicity suggests that this agent may be a promising alternative to exogenous estrogens in patients with prostate cancer who demonstrate evidence of disease progression after initial androgen deprivation treatment.
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