FINASTERIDE AND FLUTAMIDE THERAPY IN PATIENTS WITH ADVANCED PROSTATE CANCER: RESPONSE TO SUBSEQUENT CASTRATION AND LONG-TERM FOLLOW-UP WILLIAM K. OH, JUDITH MANOLA, LAURIE BITTMANN, ADAM BRUFSKY,IRVING D. KAPLAN, MATTHEW R. SMITH, DONALD S.KAUFMAN, AND PHILIP W. KANTOFF ABSTRACT Objectives. To report the efficacy of castration after progression on finasteride and flutamide. Standard androgen deprivation strategies for prostate cancer typically lead to castrate levels of testosterone. One alternative is the use of finasteride and flutamide. Methods. A Phase II trial evaluated the combination of finasteride (5 mg/day) and flutamide (250 mg three times daily) in patients with rising prostate-specific antigen levels after local treatment for prostate cancer or with newly discovered metastatic disease. Patients were followed up for subsequent events, including castration-free, androgen-independent prostate cancer (AIPC)-free, and overall survival. Results. With a median follow-up of 88 months, 5 patients (25%) continued on finasteride and flutamide, and 12 had stopped this combination and subsequently underwentmedical or surgical castration. No patients experienced a flutamide withdrawal effect. All patients experienced more than a 50% decline in prostate-specific antigen after castration (mean 89%). The median protocol treatment failure-free survival was 29.9 months, the median castration-free survival was 37 months, and the median AIPC-free survival was 48.6 months. At 5 years, the overall survival rate was 65% (95% confidence interval 47% to 90%); 29% were alive and have not required castration, and 35% were alive and free of AIPC. Conclusions. Finasteride and flutamide have a durable effectin suppressing prostate-specific antigen progression in some men with advanced prostate cancer. Furthermore, castration induces secondary responses that may be of shorter duration than if started initially, although the overall period of hormonally responsive prostate cancer is more than 4 years. UROLOGY 62: 99–104, 2003. © 2003 Elsevier Inc. A ndrogen deprivation therapies (ADTs) such as luteinizing hormone-releasing hormone ago- nists and bilateral orchiectomy are associated with a growing list of previously unrecognized toxici- ties. Each ADT induces castrate levels of testoster- one, causing side effects such as hot flashes, loss of libido,and osteoporosis. As a result, patients are seeking alternative hormonal treatments for ad- vanced prostate cancer, 1–3 including intermittent therapy 4 and antiandrogen monotherapy. 5 Antian- drogens may have less toxicity than ADT, for in- stance with libido and physical capacity. 6 – 8 How- ever, randomized trials suggest that antiandrogen monotherapy is inferior to standard ADT in con- trolling cancer, especially in patients with metasta- ses. 6 –9 Finasteride has minimal activity by itself in the treatment of advanced prostate cancer, 10 but combination studies suggest that finasteride and flutamide is active and may preserve sexual func- tion. 11–14 In 1994, a Phase II study was initiated of finas- teride and flutamide as initial hormonal treatment of patients with newly diagnosed metastatic pros- tate cancer or a rising prostate-specific antigen (PSA) level after local therapy. 11 Results suggested This study was supported by a grant from the C. Brendan Noonan, Jr. Charitable Foundation to W.K. Oh. From the Lank Center for Genitourinary Oncology, Depart- mentof MedicalOncology, and Department of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts; Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Depart- ment of Radiation Oncology, Beth Israel Deaconess Medical Cen- ter;and Department of Medical Oncology, Massachusetts Gen- eral Hospital, Boston, Massachusetts Reprint requests: William K. Oh, M.D., Lank Center for Geni- tourinary Oncology, Department of MedicalOncology, Dana- Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115 Submitted: November 25, 2002,accepted (with revisions): February 11, 2003 ADULT UROLOGY © 2003 E LSEVIER INC . 0090-4295/03/$30.00 ALL RIGHTS RESERVED doi:10.1016/S0090-4295(03)00145-6 99