Post on 26-Mar-2015
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