Clinical Challenges in the Treatment of Symptomatic Patients with Advanced Disease Frans M. J. Debruyne, MD, PhD Professor and Chairman Department of Urology University Medical Center Nijmegen Nijmegen, The Netherlands

Therapeutic Options by Stage for Prostate Cancer T3a XRT w/ HT P for some patients T1a WW P XRT T1b – 1c P XRT HT – with or w/o P or XRT T3b XRT w/ HT T2 P XRT HT – with or w/o P or XRT D3 Chemo- therapy w/ or w/o HT T4 HT, possibly w/XRT D1.5 XRT P HT Combi- nation D1,D2 HT WW = watchful waiting P = prostatectomy XRT = radiation HT = hormone therapy

Testosterone Influence on Prostate Cancer (PC) In preclinical models In preclinical models – T stimulates the growth of PC cells In clinical studies In clinical studies – T correlates with PAP – T correlates with PSA – T correlates with symptom flare FDA accepts T as surrogate endpoint for PC treatment FDA accepts T as surrogate endpoint for PC treatment

LHRH Agonists T Surge vs Orchiectomy Leuprolide vs Orchiectomy Impact on Mean Serum T Levels Smith JA. Urology. 1985;25:106. With permission from Elsevier Science. Level MIU/mL Day Leuprolide Orchiectomy Week Time from First Dose

Agarwal DK, et al. BJU Int. 2000;85:690. LHRH Agonists Impact of T Surge on PSA Study evaluating changes in PSA and T levels in response to LHRH agonist therapy in patients with benign and malignant prostate cancer Study evaluating changes in PSA and T levels in response to LHRH agonist therapy in patients with benign and malignant prostate cancer –45 patients received LHRH agonist depot 1 week before prostate biopsy; 9 served as control Patients with cancer had significantly greater increase in serum PSA and T following LHRH agonist injection than those in benign or control groups Patients with cancer had significantly greater increase in serum PSA and T following LHRH agonist injection than those in benign or control groups

Sharifi R, et al. Urology. 1998;51:271. T Escape 45 patients treated with LHRH analog 45 patients treated with LHRH analog 2% experienced transient escape 2% experienced transient escape 10% projected (based on 1-sided 95% upper confidence bound for number of patients with an escape) to experience escape 10% projected (based on 1-sided 95% upper confidence bound for number of patients with an escape) to experience escape

1. Mahler C. Cancer. 1993;72(12 suppl): Thompson IM, et al. J Urol. 1990;144: Agarwal DK, et al. BJU Int. 2000;85: Kuhn JM, et al. N Engl J Med. 1989;321: Bhasin S, et al. J. Androl.1994;15:386. T Surge vs Symptom Flare Surge Definition Definition –Acute biochemical (PSA) or hormonal (T, LH, FSH) increase after LHRH agonist initiation 1-3 Patients at risk Patients at risk –Recipients of LHRH agonist therapy 1 Flare Definition Definition –Clinical worsening of symptoms due to LHRH agonist-induced T surge 1,4 Reported cases Reported cases –4%–33% of all patients receiving LHRH agonist therapy 1 Up to 63% of advanced stage patients (n = 19) 5 Up to 63% of advanced stage patients (n = 19) 5

Combination LHRH Agonist + Anti-androgen Initial Survival Extremely Positive Labrie. Proc Natl Acad Sci USA. 1984;81:3861. With permission of the National Academy of Sciences (US). % Surviving Combination therapy at start ORCH/DES/LHRH-A alone followed by combination therapy 100 Year of Treatment

Combined Androgen Blockade Most Recent Survival Data Prostate Cancer Trialists Collaborative Group. Lancet. 2000;355: Time Since Randomization (Years) 0 Androgen suppression only Androgen suppression + anti-androgen Proportion Alive (%) 8000 prostate cancer patients in 27 trials of anti-androgen (nilutamide, flutamide, or cyproterone acetate) Treatment better by 0.7% (SE 1.1) Log rank 2P > % 23.6% Absolute difference 1.8% (SE 1.3) 6.2% 5.5%

Kuhn JM, et al. N Engl J Med. 1989;321:413. With permission of the Massachusetts Medical Society. Combined Androgen Blockade Surge Remains an Issue Day of Treatment 1 LHRH + anti-androgen LHRH alone 20 Plasma Testosterone (nmol/L) Day of Treatment Plasma LH Levels (IU/L)

Combined Androgen Blockade Issues Adverse effects Adverse effects –Gynecomastia –Liver toxicity –GI disturbance Patient inconvenience Patient inconvenience –2 drugs Economics Economics –Oral agents not covered by Medicare

Initial Gland Size (cc) 3233–4142 No Day 29-16% -24% -23% Day % -24% -36% Day % -34% -43% Range at exit -19 to -37% -24 to -48% -28 to -46% Mean size at baseline (cc) Mean size at study exit (cc) Abarelix Injectable Prostate Gland Volume Reduction: Phase II Study Data on file. Praecis Pharmaceuticals Inc. % Reduction

Experience Surge Increase in T LHRH +/-aa n = (82%) 33 (100%) Abarelix Depot n = Abarelix Depot Phase II Abarelix Depot Phase II Rapidity of Castration % Castration Day 8 Day 13 Day 27 LHRH+/-aa n = 33 0%0%100% Abarelix Depot n = %83%98% Testosterone Surge

Abarelix Study : A Multicenter Study of Abarelix in Patients with Prostate Cancer in Whom LHRH Agonists Are Contraindictated

Abarelix Study : Study Design Multicenter, nonrandomized study Multicenter, nonrandomized study 72 patients with advanced, life-threatening, symptomatic prostate cancer 72 patients with advanced, life-threatening, symptomatic prostate cancer –Bone pain from prostate cancer skeletal metastases 31 (43%) –Impending neurologic compromise 6 (8%) –Retroperitoneal adenopathy with ureteral obstruction 9 (13%) –Enlarged prostate gland or pelvic mass 26 (35%) 1. Gaylis FD, et al. Presented at ASCO; May 31-June 3, 2003; Chicago, Ill. 2. Koch MO, et al. Presented at ASCO; May 31-June 3, 2003; Chicago, Ill.

Abarelix Study : Study Endpoints Abarelix 100 mg IM administered days 1, 15, 29, 57, 85, 113, 141, and 169 Abarelix 100 mg IM administered days 1, 15, 29, 57, 85, 113, 141, and 169 Primary endpoint Primary endpoint –Avoidance of surgical castration Secondary endpoints Secondary endpoints –PSA level –Anticancer response –Symptomatic improvements (early and late assessment of urinary function, bone pain, and narcotic analgesic use) Safety Safety 1. Gaylis FD, et al. Presented at ASCO; May 31-June 3, 2003; Chicago, Ill. 2. Koch MO, et al. Presented at ASCO; May 31-June 3, 2003; Chicago, Ill.

Signs/ Symptoms Baseline Incidence Day No. Evaluated No. Improved (%) No. Unchanged (%) No. Worsened (%) AUA symptom score (PVR) (75) 13(62) 14(64) 9(82) 11(85) 10(77) 3 (19) 2 (10) 1 (4) (6) 6 (29) 7 (32) 2 (18) 2 (15) 3 (23) Abarelix Study : Early Assessment of Urinary Symptomatology Through Day 29 Data on file. Praecis Pharmaceuticals Inc.

Baseline Day 2 Day 8 Day 15 Day 29 Day 85 Day 169 No. Evaluated MedianScore Range InterquartileRange – – – – – – – – – – – – – –4.7 Abarelix (N = 18) Median VAS Pain Score for Patients with Pain from Bony Metastases Who Took Narcotics for the Pain at Study Entry 1. Gaylis FD, et al. Presented at ASCO; May 31-June 3, 2003; Chicago, Ill.

Abarelix Study Disease Response Using NPCP Criteria Complete response Partial response Stable disease Progressive disease Objective overall response 12 Weeks (N = 43) No. (%) Response 24 Weeks (N = 40) No. (%) 3 (7) 14 (33) 21 (49) 5 (12) 38 (88) 0 10 (25) 20 (50) 10 (25) 30 (75) 1. Koch MO, et al. Presented at ASCO; May 31-June 3, 2003; Chicago, Ill.

Abarelix Study Summary of Clinical Outcomes 65 patients (90%) experienced 1 of the following improvements 65 patients (90%) experienced 1 of the following improvements –A decrease in VAS pain score and/or analgesic use –Improvement or stabilization of metastatic disease on diagnostic imaging –Improvement of urinary obstruction (measured by decrease in AUA symptom score or PVR volume, or urinary catheter removal) –Improvement of hydronephrosis or azotemia –Reversal of weight loss, fatigue, or anemia 100% of patients avoided surgical castration at 1 and 3 months 100% of patients avoided surgical castration at 1 and 3 months No patients required surgical castration during the follow- up phase of the study (median duration, 40 wk) No patients required surgical castration during the follow- up phase of the study (median duration, 40 wk) 1. Gaylis FD, et al. Presented at ASCO; May 31-June 3, 2003; Chicago, Ill. 2. Koch MO, et al. Presented at ASCO; May 31-June 3, 2003; Chicago, Ill.

Evolution of Prostate Cancer Hormonal Ablation Therapy: Summary Orchiectomy: first treatment option for achieving castrate levels of testosterone in prostate cancer patients Orchiectomy: first treatment option for achieving castrate levels of testosterone in prostate cancer patients –Problems: irreversible, QOL issues DES: first alternative to physical castration DES: first alternative to physical castration –Problems: cardiotoxicities, gynecomastia LHRH Agonist: a true alternative to achieve medical castration for prostate cancer patients LHRH Agonist: a true alternative to achieve medical castration for prostate cancer patients –Problems: surge, flare contraindications Anti-androgens: made possible the use of LHRH agonist in metastatic disease Anti-androgens: made possible the use of LHRH agonist in metastatic disease –Problems: cost, added toxicities GnRH antagonist: represent the next generation of treatment. For the first time a true rapid form of hormonal monotherapy is available GnRH antagonist: represent the next generation of treatment. For the first time a true rapid form of hormonal monotherapy is available