© 2007 THE AUTHORS JOURNAL COMPILATION © 2 0 0 7 B J U I N T E R N A T I O N A L | 1 0 0 , 7 6 5 – 7 6 9 | doi:10.1111/j.1464-410X.2007.07121.x 765 Urological Oncology GEFITINIB FOR NON-METASTATIC HORMONE-REFRACTORY PROSTATE CANCER SMALL et al. A phase II trial of gefitinib in patients with non-metastatic hormone-refractory prostate cancer Eric J. Small, Joseph Fontana*, Nizar Tannir†, Robert S. DiPaola‡, George Wilding¶, Mark Rubin§, Renee Bailey Iacona∞ and Fairooz F. Kabbinavar** University of California San Francisco Comprehensive Cancer Center, San Francisco, CA, *John D Dingell Veterans Affairs Medical Center, Detroit, MI, †University of Texas MD Anderson Cancer Center, Houston, TX, ‡The Cancer Institute of New Jersey, New Brunswick, NJ, ¶University of Wisconsin Comprehensive Cancer Center, Madison, WI, §Florida Cancer Specialists, Bonita Springs, FL, °AstraZeneca, Wilmington, DE, and **Division of Hematology-Oncology, University of California Los Angeles, School of Medicine, CA, USA Accepted for publication 27 April 2007 evidence of metastatic disease were enrolled into this open-label, multicentre study of monotherapy with gefitinib 500 mg/day. The primary endpoint of the study was biochemical response, defined as a ≥ 50% decrease in serum prostate-specific antigen (PSA) level. RESULTS Fifty-eight men were enrolled across 10 centres in the USA; none of the 40 evaluable patients had a PSA response. Gefitinib was generally well tolerated, with diarrhoea being the most common treatment- related adverse event, in 71% of patients. There was treatment-related grade 3 diarrhoea in 5% of patients, with no grade 4 adverse events or deaths during the course of the study. CONCLUSIONS Gefitinib has no single-agent activity in non- metastatic HRPC, as assessed by decreases in serum PSA level. This phase II study also confirmed the well-established favourable tolerability profile of gefitinib monotherapy. KEYWORDS epidermal growth factor receptor, EGFR, gefitinib, prostate cancer, PSA Type of Study – Therapy (case series) Level of Evidence 4 OBJECTIVE To investigate, in a phase II trial, the use of the epidermal growth factor receptor (EGFR) inhibitor gefitinib as monotherapy in patients with non-metastatic hormone refractory prostate cancer (HRPC), as current treatment options for this disease are limited, and agents which target the EGFR should be assessed because EGFR is highly expressed in prostate cancer and associated with a poor prognosis. PATIENTS AND METHODS Patients with histologically or cytologically confirmed cancer of the prostate with no INTRODUCTION Prostate cancer is the sixth most common cause of cancer-related death in men worldwide [1]. Advanced prostate cancer is initially treated with androgen ablation, by surgical or medical castration [2]; although effective, androgen ablation controls metastatic prostate cancer for a mean of ≈ 18 months, and thereafter, progressive prostate cancer develops in the face of anorchid levels of testosterone, and is termed hormone-refractory prostate cancer (HRPC). The earlier use of androgen-deprivation therapy has resulted in a growing cohort of patients who develop HRPC but who do not yet have radiographic evidence of metastatic disease. While docetaxel-based chemotherapy has been shown to provide a modest survival benefit in patients with metastatic HRPC, all patients ultimately progress, and the use of docetaxel is associated with potential toxicity [3–4]. Furthermore, the utility of docetaxel in patients with non-metastatic HRPC has not yet been evaluated. Novel agents for the treatment of HRPC are therefore needed. Gefitinib is an orally active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Preclinical studies of gefitinib showed antitumour activity, with 70–80% growth inhibition of human prostate tumour cell line xenografts in nude mice [5]. Subsequent phase I studies of gefitinib monotherapy in patients with a range of solid tumours, including prostate cancer, showed promising antitumour activity [6–8]. Of the 19 patients with HRPC who were enrolled onto these phase I trials, one had an objective soft- tissue partial response, with a > 50% decline in PSA level lasting 6.5 months, and another had a > 50% decline in PSA level that lasted 2.5 months. Furthermore, several patients had pain relief with a concurrent decreased need for pain medication. These studies also showed that gefitinib is generally well tolerated, and was not associated with the typical cytotoxic side-effects common with chemotherapy [6–8]. Prostate cancer is an epithelial malignancy, in which aberrant EGFR expression has been described [9]. In addition, the EGFR