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

Clinical Challenges in the Clinical Challenges in the Treatment of Symptomatic Treatment of Symptomatic

Patients with Patients with Advanced DiseaseAdvanced Disease

Frans M. J. Debruyne, MD, PhDFrans M. J. Debruyne, MD, PhDProfessor and ChairmanProfessor and Chairman

Department of UrologyDepartment of Urology

University Medical Center Nijmegen University Medical Center Nijmegen

Nijmegen, The NetherlandsNijmegen, The Netherlands

Therapeutic Options by StageTherapeutic Options by Stagefor Prostate Cancerfor Prostate Cancer

T3aXRT w/ HT

P for some patients

T1aWWPXRT

T1b–

1cPXRTHT – with or w/o P or XRT

T3bXRT w/ HT

T2PXRTHT – with or w/o P or XRT

D3Chemo-therapy w/ or w/o HT

T4HT, possibly w/XRT

D1.5XRTPHTCombi- nation

D1,D2HT

WW = watchful waitingP = prostatectomy

XRT = radiationHT = hormone therapy

Testosterone Influence on Testosterone Influence on Prostate Cancer (PC)Prostate Cancer (PC)

In preclinical models In preclinical models

T stimulates the growth of PC cells T stimulates the growth of PC cells In clinical studiesIn clinical studies

T correlates with T correlates with PAP PAP

T correlates with T correlates with PSA PSA

T correlates with T correlates with symptom flare symptom flare FDA accepts T as surrogate endpoint for PC FDA accepts T as surrogate endpoint for PC

treatmenttreatment

LHRH AgonistsLHRH AgonistsT “Surge” vs OrchiectomyT “Surge” vs Orchiectomy

Leuprolide vs Orchiectomy Impact on Mean Serum T LevelsLeuprolide vs Orchiectomy Impact on Mean Serum T Levels

Smith JA. Urology. 1985;25:106. With permission from Elsevier Science.

Le

vel M

IU/m

L

Day

1000

0

Leuprolide

Orchiectomy

0

200

400

600

800

4 8 8401 4 5 7 9 11 13 15 18 24 30 5 7 9 11 13 17 27 37 47 57 67 77 87

Week

Time from First Dose

Agarwal DK, et al. BJU Int. 2000;85:690.

LHRH AgonistsLHRH AgonistsImpact of T “Surge” on PSA Impact of T “Surge” on PSA

Study evaluating changes in PSA and T levels Study evaluating changes in PSA and T levels in response to LHRH agonist therapy in patients in response to LHRH agonist therapy in patients with benign and malignant prostate cancerwith benign and malignant prostate cancer

– 45 patients received LHRH agonist depot 45 patients received LHRH agonist depot 1 week before prostate biopsy; 9 served1 week before prostate biopsy; 9 servedas controlas control

Patients with cancer had significantly greater Patients with cancer had significantly greater increase in serum PSA and T following LHRH increase in serum PSA and T following LHRH agonist injection than those in benign oragonist injection than those in benign orcontrol groupscontrol groups

Sharifi R, et al. Urology. 1998;51:271.

T “Escape”T “Escape”

45 patients treated with LHRH analog45 patients treated with LHRH analog 2% experienced transient escape 2% experienced transient escape 10% projected (based on 1-sided 95% 10% projected (based on 1-sided 95%

upper confidence bound for numberupper confidence bound for numberof patients with an escape) to of patients with an escape) to experience escapeexperience escape

1. Mahler C. Cancer. 1993;72(12 suppl):3799. 4.Thompson IM, et al. J Urol. 1990;144:1479.2. Agarwal DK, et al. BJU Int. 2000;85:690. 5. Kuhn JM, et al. N Engl J Med. 1989;321:413.3. Bhasin S, et al. J. Androl.1994;15:386.

T Surge vs Symptom FlareT Surge vs Symptom Flare

SurgeSurge DefinitionDefinition

– Acute biochemical Acute biochemical (PSA) or hormonal (PSA) or hormonal (T, LH, FSH) increase (T, LH, FSH) increase after after LHRH agonist LHRH agonist initiationinitiation1-31-3

Patients at risk Patients at risk

– Recipients Recipients of LHRH of LHRH agonist therapyagonist therapy11

FlareFlare DefinitionDefinition

– Clinical worsening of Clinical worsening of symptoms due to LHRH symptoms due to LHRH agonist-induced T surgeagonist-induced T surge1,41,4

Reported casesReported cases

– 4%–33% of all patients 4%–33% of all patients receiving LHRH agonist receiving LHRH agonist therapytherapy11

Up to 63% of advanced Up to 63% of advanced stage patients (n = 19)stage patients (n = 19)55

Combination LHRH Agonist + Combination LHRH Agonist + Anti-androgenAnti-androgen

Initial Survival Extremely PositiveInitial Survival Extremely Positive

Labrie. Proc Natl Acad Sci USA. 1984;81:3861. With permission of the National Academy of Sciences (US).

% S

urv

ivin

g

Combination therapy at startORCH/DES/LHRH-A alonefollowed by combination therapy

100

Year of Treatment

75

50

25

00 1 2

6430

47

36

25

128

88 84 74

53

Combined Androgen BlockadeCombined Androgen BlockadeMost Recent Survival DataMost Recent Survival Data

Prostate Cancer Trialists’ Collaborative Group. Lancet. 2000;355:1491.

100

Time Since Randomization(Years)

0

Androgen suppression onlyAndrogen suppression + anti-androgen

80

60

40

20

05 10

Pro

po

rtio

n A

live

(%

)8000 prostate cancer patients in 27 trials of anti-androgen (nilutamide, flutamide, or cyproterone acetate)

Treatment betterby 0.7% (SE 1.1)Log rank 2P > 0.1

25.4%

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 BlockadeCombined Androgen BlockadeSurge Remains an IssueSurge Remains an Issue

Day of Treatment1

LHRH + anti-androgenLHRH alone

20

Pla

sma

Tes

tost

ero

ne

(nm

ol/

L)

16

12

8

4

02 3 4 5 6 7 8 9 10 11 12 13 14 18 22 29

Day of Treatment1

40

30

20

10

02 3 4 5 6 7 8 9 10 11 12 13 14 18 22 29

Pla

sma

LH

Lev

els

(IU

/L)

Combined Androgen BlockadeCombined Androgen BlockadeIssuesIssues

Adverse effectsAdverse effects

– GynecomastiaGynecomastia

– Liver toxicityLiver toxicity

– GI disturbanceGI disturbance Patient inconveniencePatient inconvenience

– 2 drugs2 drugs EconomicsEconomics

– Oral agents not covered by MedicareOral agents not covered by Medicare

Initial Gland Size Initial Gland Size (cc)(cc) ≤32≤32 33–4133–41 ≥42≥42

No.No. 1212 1414 1010

Day 29Day 29 -16%-16% -24% -24% -23% -23%

Day 57Day 57 -34% -34% -24% -24% -36% -36%

Day 85 Day 85 -32% -32% -34% -34% -43% -43%

Range at exitRange at exit -19 to -37% -19 to -37% -24 to -48% -24 to -48% -28 to -46% -28 to -46%

Mean size Mean size at baseline (cc) at baseline (cc) 2626 3838 6565

Mean size Mean size at study exit (cc) at study exit (cc) 1919 2424 4141

Abarelix Injectable Prostate Gland Abarelix Injectable Prostate Gland Volume Reduction: Phase II StudyVolume Reduction: Phase II Study

Data on file. Praecis Pharmaceuticals Inc.

% Reduction% Reduction

Experience “Surge”Experience “Surge”

Increase in TIncrease in T

LHRH +/-aaLHRH +/-aan = 33n = 33

27 (82%)27 (82%)

33 (100%)33 (100%)

Abarelix DepotAbarelix Depotn = 209n = 209

00

00

Abarelix Depot Phase IIAbarelix Depot Phase IIRapidity of Castration

% Castration% Castration

Day 8Day 8

Day 13Day 13

Day 27Day 27

LHRH+/-aaLHRH+/-aan = 33n = 33

0%0%

0%0%

100%100%

Abarelix DepotAbarelix Depotn = 209n = 209

77%77%

83%83%

98%98%

Testosterone SurgeTestosterone Surge

Abarelix Study 149-98-04: Abarelix Study 149-98-04: A Multicenter Study of Abarelix in A Multicenter Study of Abarelix in

Patients with Prostate Cancer in Whom Patients with Prostate Cancer in Whom

LHRH Agonists Are ContraindictatedLHRH Agonists Are Contraindictated

Abarelix Study 149-98-04:Abarelix Study 149-98-04:Study DesignStudy Design

Multicenter, nonrandomized studyMulticenter, nonrandomized study 72 patients with advanced, life-threatening, symptomatic 72 patients with advanced, life-threatening, symptomatic

prostate cancer prostate cancer – Bone pain from prostate cancer skeletal metastasesBone pain from prostate cancer skeletal metastases

31 (43%)31 (43%)– Impending neurologic compromise 6 (8%)Impending neurologic compromise 6 (8%)– Retroperitoneal adenopathy with ureteral obstruction 9 Retroperitoneal adenopathy with ureteral obstruction 9

(13%)(13%)– Enlarged prostate gland or pelvic mass 26 (35%)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 149-98-04:Abarelix Study 149-98-04:Study EndpointsStudy Endpoints

Abarelix 100 mg IM administered days 1, 15, 29, 57, 85, 113, Abarelix 100 mg IM administered days 1, 15, 29, 57, 85, 113, 141, and 169141, and 169

Primary endpoint Primary endpoint

– Avoidance of surgical castrationAvoidance of surgical castration Secondary endpointsSecondary endpoints

– PSA levelPSA level

– Anticancer responseAnticancer response

– Symptomatic improvements (early and late assessment Symptomatic improvements (early and late assessment of urinary function, bone pain, and narcotic analgesic of urinary function, bone pain, and narcotic analgesic use)use)

SafetySafety

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)

23

17

81529

81529

162122

111313

12 (75)13 (62)14 (64)

9 (82)11 (85)10 (77)

3 (19)2 (10)1 (4)

000

1 (6)6 (29)7 (32)

2 (18)2 (15)3 (23)

Abarelix Study 149-98-04:Abarelix Study 149-98-04:“Early” Assessment of Urinary “Early” Assessment of Urinary

Symptomatology Through Day 29Symptomatology Through Day 29

Data on file. Praecis Pharmaceuticals Inc.

BaselineBaseline

Day 2Day 2Day 8Day 8Day 15Day 15Day 29Day 29Day 85Day 85Day 169Day 169

No.No.Evaluated Evaluated

MedianMedianScoreScore RangeRange

InterquartileInterquartileRangeRange

1818

171718181818181815151111

6.86.8

5.35.34.44.43.43.40.80.80.60.60.80.8

0.4–9.80.4–9.8

0.9–8.60.9–8.60.2–7.40.2–7.40.2–8.20.2–8.20.0–8.50.0–8.50.0–8.10.0–8.10.0–5.20.0–5.2

4.6–9.14.6–9.1

3.7–7.83.7–7.80.9–5.40.9–5.40.6–6.20.6–6.20.3–2.60.3–2.60.1–3.60.1–3.60.4–4.70.4–4.7

Abarelix (N = 18)Abarelix (N = 18)

Median VAS Pain Score for Patients with Median VAS Pain Score for Patients with Pain from Bony Metastases Who Took Pain from Bony Metastases Who Took Narcotics for the Pain at Study EntryNarcotics for the Pain at Study Entry

1. Gaylis FD, et al. Presented at ASCO; May 31-June 3, 2003; Chicago, Ill.

Abarelix Study 149-98-04Abarelix Study 149-98-04Disease Response Using Disease Response Using

NPCP CriteriaNPCP Criteria

Complete responseComplete responsePartial responsePartial responseStable diseaseStable diseaseProgressive diseaseProgressive diseaseObjective overall responseObjective overall response

12 Weeks12 Weeks(N = 43)(N = 43)No. (%)No. (%)ResponseResponse

24 Weeks24 Weeks(N = 40)(N = 40)No. (%)No. (%)

3 (7)3 (7)14 (33)14 (33)21 (49)21 (49)5 (12)5 (12)38 (88)38 (88)

0010 (25)10 (25)20 (50)20 (50)10 (25)10 (25)30 (75)30 (75)

1. Koch MO, et al. Presented at ASCO; May 31-June 3, 2003; Chicago, Ill.

Abarelix Study 149-98-04Abarelix Study 149-98-04Summary of Clinical OutcomesSummary of Clinical Outcomes

65 patients (90%) experienced ≥1 of the following 65 patients (90%) experienced ≥1 of the following improvementsimprovements– A decrease in VAS pain score and/or analgesic useA decrease in VAS pain score and/or analgesic use– Improvement or stabilization of metastatic disease Improvement or stabilization of metastatic disease

on diagnostic imagingon diagnostic imaging– Improvement of urinary obstruction (measured by Improvement of urinary obstruction (measured by

decrease in AUA symptom score or PVR volume, or decrease in AUA symptom score or PVR volume, or urinary catheter removal)urinary catheter removal)

– Improvement of hydronephrosis or azotemiaImprovement of hydronephrosis or azotemia– Reversal of weight loss, fatigue, or anemiaReversal of weight loss, fatigue, or anemia

100% of patients avoided surgical castration at 1 and100% of patients avoided surgical castration at 1 and3 months3 months

No patients required surgical castration during the follow-No patients required surgical castration during the follow-up phase of the study (median duration, 40 wk)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 Evolution of Prostate Cancer Hormonal Ablation Therapy: SummaryHormonal Ablation Therapy: Summary Orchiectomy: first treatment option for achieving castrate Orchiectomy: first treatment option for achieving castrate

levels of testosterone in prostate cancer patientslevels of testosterone in prostate cancer patients– Problems: irreversible, QOL issuesProblems: irreversible, QOL issues

DES: first alternative to physical castrationDES: first alternative to physical castration– Problems: cardiotoxicities, gynecomastiaProblems: cardiotoxicities, gynecomastia

LHRH Agonist: a true alternative to achieve medical castration LHRH Agonist: a true alternative to achieve medical castration for prostate cancer patientsfor prostate cancer patients– Problems: surge, flare contraindicationsProblems: surge, flare contraindications

Anti-androgens: made possible the use of LHRH agonist in Anti-androgens: made possible the use of LHRH agonist in metastatic diseasemetastatic disease– Problems: cost, added toxicitiesProblems: cost, added toxicities

GnRH antagonist: represent the next generation of treatment. GnRH antagonist: represent the next generation of treatment. For the first time a true rapid form of hormonal monotherapy is For the first time a true rapid form of hormonal monotherapy is available available