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ZD1839 (gefitinib) and hormone resistant (HR) prostate cancer - final results of a double blind randomized placebo-controlled phase II study.

4698 Background: The epidermal growth factor receptor (EGFR) is expressed in most prostate cancers. We investigated the effect of gefitinib (ZD1839), an orally active EGFR tyrosine kinase inhibitor, on the slope of changing prostate specific antigen (PSA) levels.


METHODS
We conducted a placebo-controlled, double blind, randomized Phase II study of gefitinib (500 mg/day) in patients with prostate cancer and hormone-independent PSA progression. To calculate sample size, the method of Schlesselman (J Chron Dis 1973; 26: 561-70) was applied; 24 patients per group were necessary to detect a change in slope of 0.25 (ie to zero slope) with 90% power using a two-sided significance level of alpha = 0.05. Asymptomatic patients with PSA progression after castration or under luteinizing hormone-releasing hormone treatment (excluding antiandrogens and recent radiotherapy) were eligible. Unblinding took place after 6 months or in the case of medical emergencies. Secondary endpoints included PSA response rate at 6 months, time to response, PSA progression, time to progression (TTP), overall survival (OS), and safety. The study was approved by regional and institutional ethical review boards.


RESULTS
All 58 patients randomized (28 to placebo and 30 to gefitinib) were evaluable for comparison of PSA slopes. Both slopes differed significantly from zero (placebo: p<0.0001; gefitinib: p<0.0023). The slopes amounted to 0.2569 for placebo and 0.2001 for gefitinib per month, translating into doubling times of 3.9 and 5.0 months (p=0.25), respectively. This study was not powered to compare changes in slope between treatment arms however, no relevant differences in progression rates, TTP, and OS were seen between arms in intention-to-treat and treatment-received analysis. Adverse events (AEs) were usually mild; CTC grade 3/4 AEs occurred in 2 patients receiving placebo and 5 receiving gefitinib (liver toxicity, diarrhea).


CONCLUSIONS
Gefitinib showed modest activity in delaying PSA rise. Differences in clinical progression rates were not seen. Gefitinib was generally well tolerated. [Table: see text].