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Phase I-II Trial of Weekly Bicalutamide in Men with Elevated Prostate-Specific Antigen and Negative Prostate Biopsies

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Phase I-II Trial of Weekly Bicalutamide in Men with Elevated Prostate-Specific Antigen and Negative Prostate Biopsies Published OnlineFirst March 31, 2009; DOI: 10.1158/1940-6207.CAPR-08-0205 Cancer Prevention Research Phase I-II Trial of Weekly Bicalutamide in Men with Elevated Prostate-Specific Antigen and Negative Prostate Biopsies Silvia Zanardi,1 Matteo Puntoni,1,5 Massimo Maffezzini,2 Roberto Bandelloni,3 Marco Mori,4 Alessandra Argusti,1 Fabio Campodonico,2 Laura Turbino,3 Daniela Branchi,1 Rodolfo Montironi6 and Andrea Decensi1,7 Abstract Background: Men with elevated prostate-specific antigen (PSA) and negative prostate biopsies are at risk for prostate cancer. The antiandrogen bicalutamide has a prolonged half-life, thus potentially allowing an intermittent administration to retain activity while reducing toxicity. We conducted a phase I-II trial of weekly bicalutamide in men with PSA >4 ng/mL and negative biopsies. Methods: Eighty subjects were nonrandomly assigned to a three-arm trial to either bica- lutamide 50 mg/wk (n = 26) or 100 mg/wk (n = 28) or no treatment (n = 26) for 6 months. Blood samples were obtained at 0, 3, and 6 months, and prostate biopsies were repeated after 6 months. The outcome measures were 6-month changes of tissue Ki-67 (primary end point), high-grade prostatic intraepithelial neoplasia (HG-PIN), proliferative inflammatory at- rophy, circulating PSA, and sex hormones. Results: Ki-67 expression was higher in HG-PIN than in normal tissue (10% versus 3%; P < 0.01) but was not modulated by bicalutamide in normal luminal cells. A trend toward an improvement of HG-PIN status was found in treated subjects (26% improved, 60% had no change, 15% worsened) as compared with the no-treatment arm (4% improved, 83% had no change, 13% worsened; P = 0.07). Proliferative inflammatory atrophy prevalence was not reduced by bicalutamide. Bicalutamide reduced PSA by 50% in both arms and raised testosterone and estradiol levels. Asymptomatic breast swelling was noted in 40% of the treated cases. Conclusions: A weekly administration of bicalutamide seems to be reasonably safe and shows an encouraging signal of activity on HG-PIN prevalence, supporting further studies of this schedule in men at high risk despite the negative primary end-point findings on Ki-67. Chemoprevention may be a practical approach to reduce reduced sexual function (4), have so far lessened the attractive- prostate cancer incidence and mortality (1–3). Finasteride, a ness of finasteride as a preventive agent for prostate cancer. 5-α-reductase inhibitor, reduced prostate cancer by 25% in An alternative targeted approach for prostate cancer pre- average-riskmen (4), although the original finding of a higher vention is the use of androgen receptor antagonists. Bicaluta- proportion of high-grade cancers raised debate over its long- mide as a single agent at 150 mg/d is effective in locally term benefit (5). Recent bias-adjusted analyses of updated advanced prostate cancer (8), but its administration is associ- Prostate Cancer Prevention Trial results convincingly show ated with sexual side effects and grade 3 gynecomastia in that finasteride did not increase high-grade cancer rates most subjects (8), which have thus far prevented its assess- (6, 7), but treatment side effects, including gynecomastia and ment in chemoprevention. However, bicalutamide has a pro- longed absorption and half-life (∼7 days; ref. 9) and its serum concentration after a single 50 mg dose is nearly 0.8 μg/mL, a Authors' Affiliations: 1Medical Oncology Unit, 2Urology Unit, 3Pathology Unit, value in the range of inhibiting concentration for several pros- and 4Clinical Chemistry and Microbiology Laboratory, Galliera Hospital; tate cancer cell lines (10), thus providing the rationale for a 5Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, 6 weekly schedule in an attempt to retain activity while reduc- Italy; Section of Pathological Anatomy, Polytechnic University of the Marche Region, Ancona, Italy; and 7Division of Cancer Prevention and ing toxicity. Genetics, European Institute of Oncology, Milan, Italy Men with elevated serum prostate-specific antigen (PSA) Received 10/30/08; revised 1/27/09; accepted 2/9/09; published OnlineFirst 3/31/09. and negative prostate biopsies have a 20% to 25% riskof being Grant support: Italian League Against Cancer (Lega Italiana per la Lotta contro i Tumori), Italian Association for Cancer Research (Associazione Italiana diagnosed with cancer at subsequent biopsies (11, 12). Because per la Ricerca sul Cancro), and Cassa di Risparmio delle Province Lombarde. no standard treatment is available, chemoprevention repre- Requests for reprints: Andrea Decensi, Medical Oncology Unit, Galliera sents a promising approach for these high-riskindividuals Hospital, Mura delle Cappuccine 14, 16128 Genova, Italy. Phone: 39-010- (1, 13, 14). Whereas no surrogate end-point biomarkers have 5634501; Fax: 39-010-57481090; E-mail: [email protected]. ©2009 American Association for Cancer Research. been validated for prostate cancer, a number of tissue-based doi:10.1158/1940-6207.CAPR-08-0205 and non–tissue-based markers may be potential targets for www.aacrjournals.org 377 Cancer Prev Res 2009;2(4) April 2009 Downloaded from cancerpreventionresearch.aacrjournals.org on September 24, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst March 31, 2009; DOI: 10.1158/1940-6207.CAPR-08-0205 Cancer Prevention Research Fig. 1. Participant flow diagram. chemoprevention, including high-grade prostatic intraepithe- ref. 8). Having checked the safety of 50 mg/wk, a second phase in- lial neoplasia (HG-PIN); Ki-67, an immunohistochemically cluding a 100 mg/wkarm and a no-treatment arm was implemen- detectable antigen of proliferation; and proliferative inflam- ted. Inclusion in either arm was based on patient preference after matory atrophy (PIA), another putative biomarker in prostate discussion of potential risks and benefits. The primary end point cancer prevention (1, 15, 16). Among circulating biomarkers, was the change of Ki-67 expression in normal prostate luminal cells. Secondary end points were the changes of HG-PIN and PIA preva- PSA is also being used to assess the activity of chemopreven- lence and of circulating PSA and sex hormone levels. The study was tive agents in at-riskcohorts (13, 14). approved by the hospital review board and a written informed con- The present phase I-II trial evaluated the feasibility and toxic- sent was obtained by each subject. ity and explored the activity of a weekly administration of bica- lutamide in subjects with PSA levels >4 ng/mL and noncancer Treatment plan and study procedures findings on prostate biopsies using immunohistochemical, mor- The study started on June 1, 2004 and the accrual was completed phologic, and biochemical parameters as activity end points. on June 22, 2006. Subjects received bicalutamide (Casodex, Astra- Zeneca) at the dose of 50 mg (1 tablet) or 100 mg (2 tablets at once) Subjects and Methods at lunchtime on every Sunday for 6 mo. The drug was purchased through the hospital Pharmacy, then packaged and labeled for the Eligibility criteria and study design study. A third group of subjects did not receive any treatment and Men ages 50 to 80 y and with PSA levels >4 ng/mL and at least one served as controls. Fasting blood samples were taken between 8 and negative biopsy (8-10 cores) within 90 d from study entry were eligi- 10 a.m. at baseline and at 3 and 6 mo visits for blood hematology, ble. Exclusion criteria were prior malignancy within 5 y; grade >2 al- total and free PSA, gonadotropins, sex hormones, and sex hormone terations of liver, renal, metabolic, and cardiac functions; and use of binding globulin. After 6 mo, an end-of-study prostate biopsy (8-10 antiandrogens or 5-α-reductase inhibitors within 3 mo. cores) was done to assess changes in tissue biomarkers and morphol- This study was a two-step, nonrandomized, open-label, dose-esca- ogy. Compliance was assessed by pill count. Toxicity was evaluated lation trial. The first 25 subjects were treated with a single 50 mg using the National Cancer Institute-Common Terminology Criteria bicalutamide dose once a weekwith a stopping rule of 30% in the for Adverse Events (NCI-CTCAE; ref. 17), except for gynecomastia, upper confidence interval (exact method) of G3 gynecomastia inci- which in the NCI-CTCAE is not graded quantitatively and does not dence (i.e., less than one half the incidence reported with 150 mg/d; include minimal asymptomatic breast gland enlargements. Thus, we Cancer Prev Res 2009;2(4) April 2009 378 www.aacrjournals.org Downloaded from cancerpreventionresearch.aacrjournals.org on September 24, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst March 31, 2009; DOI: 10.1158/1940-6207.CAPR-08-0205 Weekly Bicalutamide in Men at Risk for Prostate Cancer Table 1. Baseline subject characteristics by treatment arm Control group Bicalutamide 50 mg/wk Bicalutamide 100 mg/wk (n = 26) (n = 26) (n = 28) Age, y (mean ± SD) 66 ± 7.6 64 ± 7.0 64 ± 6.8 Body mass index, kg/m2 (mean ± SD) 25.8 ± 2.5 25.5 ± 3.1 25.9 ± 4.1 Smoking habit (smoker/nonsmoker/former) 5/10/11 4/15/7 7/14/7 Alcohol consumption (0/1-14/15+ glasses/wk) 7/10/9 11/10/5 6/16/6 No. of subjects with 1st/2nd degree 75 1 family history for prostate cancer No. of cores per biopsy before entry biopsy 8 (6-10) 6 (5-10) 6 (5-8) (median, range) Total PSA, ng/mL (median, IQR) 7.2 (6.2-9.9) 8.8 (5.4-13.5) 9.6 (7.6-12.0) Free PSA, ng/mL (median, IQR) 1.1 (0.7-1.7) 1.8 (0.8-2.3) 1.4 (1.1-2.0) LH, mIU/mL (median, IQR) 4.5 (3.4-6.1) 4.6 (3.3-5.6) 4.1 (3.6-7.0) Testosterone, ng/mL (median, IQR) 3.9 (3.1-5.2) 3.8 (3.4-4.8) 4.1 (3.3-5.3) Free testosterone, % (median, IQR) 33.3 (29.1-46.1) 32.1 (28.9-36.2) 35.8 (29.8-40.6) 17β-Estradiol, pg/mL (median, IQR)* 28.9 (22.4-32.7) 20.5 (17.5-26.5) 22.5 (18.7-29.8) Abbreviations: LH, luteinizing hormone; IQR, interquartile range.
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