LATITUDE and STAMPEDE -

Evolution in the treatment of

metastatic prostate cancer
Dr Lincoln Tan
MBBS,MRCS(Edin),FRCS(Glasg),FAMS
Consultant
Dept of Urology, NUH
Surgical Oncology, National Cancer Institute Singapore
Disclaimer
• The meeting is organized and supported by Johnson & Johnson Indonesia
• The views expressed in this session are those of the individual speaker
members and do not necessarily reflect the views of Johnson & Johnson
Indonesia
• The session may include discussions on off-label use of drugs or those
not yet approved use, for the sole purpose of having a full exchange of
scientific information .
Disclosures
• Speaker : Janssen, Astellas, Bayer
• Consultant : Janssen, Astellas, Ferring
• Research support : Beckman-Coulter
1941 – ADT - The beginning of treatment
of advanced prostate cancer
Rapid increase in treatment options for
mCRPC
 Dramatic change in treatment for hormone
sensitive advanced/metastatic prostate cancer
STAMPEDE STAMPEDE LATITUDE
GETUG 15 CHAARTED
ADT / DOC ADT/ABI ADT/ABI

2013 2014 2015 2017 2017

6
 Study Design
Patients
• Newly diagnosed adult men ADT
R + Abiraterone 1000 Efficacy end points
with high-risk mHNPC A
N mg QD Co-primary:
D + Prednisone 5 mg • OS
Meets at least 2 of 3 high-
O QD
risk criteria M (n=597) • rPFS
• Gleason score of I Secondary: time to
≥8 Z
• Presence of ≥ 3 lesions • Pain progression
E
on bone scan D ADT • PSA progression
• Presence of measurable + placebos • Next symptomatic
visceral lesion 1:1 (n=602) skeletal event
Stratification factors • Chemotherapy
• Presence of visceral disease • Subsequent PC therapy
(yes/no)
• ECOG PS (0, 1 vs 2)

• Conducted at 235 sites in 34 countries in Europe, Asia-Pacific, Latin America, and Canada
• Designed and fully enrolled prior to publication of CHAARTED/STAMPEDE results
 Treatment arms were well balanced
ADT + Abiraterone- ADT + Placebos
Prednisone (n = 602)
(n = 597)

Age (yr), n (%)

< 65 221 (37) 233 (39)
65–69 112 (19) 134 (22)
70–74 141 (24) 115 (19)
≥ 75 123 (21) 120 (20)
Median (range) 68.0 (38-89) 67.0 (33-92)

Gleason score at initial diagnosis, n (%)

<7 4 (0.7) 1 (0.2)
7 9 (2) 15 (2)
≥8 584 (98) 586 (97)

Baseline pain score (BPI-SF Item 3), n (%)

0–1 284 (50) 288 (50)
2–3 123 (22) 137 (24)
≥4 163 (29) 154 (27)

Patients with ≥ 3 bone metastases at screening, n/N (%) 586/597 (98.2) 585/602 (97.2)

Patients with high risk at screening, n (%) n

597 601
Gleason score ≥ 8 + ≥ 3 bone lesions
573 (96) 569 (95)
Gleason score ≥ 8 + measurable visceral disease
82 (14) 87 (14)
≥ 3 bone lesions + measurable visceral disease
84 (14) 85 (14)
Gleason score ≥ 8 + ≥ 3 bone lesions + measurable visceral
71 (12) 70 (12)
disease
 Overall Survival

 At a median follow-up of 30.4 months (48% of total deaths), the addition of abiraterone acetate
and prednisone to ADT significantly improved OS, with a 38% reduction in the risk of death
 The 3-year OS rate was 66% in the ADT-abiraterone-prednisone group compared with 49% in
the ADT-placebos group
Treatment effect of ADT-abiraterone on OS was consistently
favorable across nearly all pre-specified subgroups
 Radiographic Progression-free Survival

 Patients in the ADT-abiraterone-prednisone group had a 53%

reduction in the risk of radiographic progression or death
compared with patients receiving ADT plus placebos
 Superiority of ADT-abiraterone-prednisone over ADT-placebos was
observed for all secondary end points
ADT-Abiraterone-
ADT-Placebos Hazard Ratio
Prednisone P Value*
(n = 602) (95% CI)
(n = 597)

Secondary end points

Time to pain progression — mo NR 16.6 0.70 (0.58–0.83) < 0.001

Time to PSA progression — mo 33.2 7.4 0.30 (0.26–0.35) < 0.001

Time to next symptomatic skeletal

NR NR 0.70 (0.54–0.92) 0.009
event — mo

Time to chemotherapy — mo NR 38.9 0.44 (0.35–0.56) < 0.001

Time to subsequent prostate cancer
NR 21.6 0.42 (0.35–0.50) < 0.001
therapy — mo

Exploratory end point

Patients with a PSA response

91 67 1.36 (1.28–1.45)* < 0.001
(decline ≥ 50% from baseline) — %
Improved OS despite ADT alone group receiving more
Subsequent Life-prolonging Therapy
ADT-Abiraterone- ADT-Placebos
Prednisone (n = 602)
(n = 597)
Agent no of patients (%)*

n = 314 n = 469

Abiraterone acetate plus prednisone 10 (3) 53 (11)

Cabazitaxel 11 (4) 30 (6)

Docetaxel 106 (34) 187 (40)

Enzalutamide 30 (10) 76 (16)

Radium-223 11 (4) 27 (6)

*Patients who discontinued treatment and were eligible for subsequent therapy.

 The numbers of patients receiving one or multiple life-prolonging therapies

totaled 125 (21%) in the ADT-abiraterone-prednisone group and 246 (41%) in
the ADT-placebos group
 Summary of Adverse Events

ADT-Abiraterone- ADT-Placebos
Adverse Event Prednisone (n = 602)
(n = 597)

no of patients (%)

Any adverse event 558 (93) 557 (93)

Grade 3 or 4 adverse event 374 (63) 287 (48)

Any serious adverse event 165 (28) 146 (24)

Any adverse event leading to treatment

73 (12) 61 (10)
discontinuation

Adverse event leading to death 28 (5) 24 (4)

 Adverse Events of Special Interest
ADT-Abiraterone- ADT-Placebos
Adverse Event
Prednisone (n = 597) (n = 602)

Gr 3 Gr 4 Gr 3 Gr 4

no of patients (%)
Hypertension 20 0 10 0.2

Hypokalemia 10 0.8 1 0.2

ALT increased 5 0.3 1 0

Hyperglycemia 4 0.2 3 0

AST increased 4 0.2 1 0

Bone pain 3 0 3 0

Cardiac disorder 3 0.8 1 0

Atrial fibrillation 0.3 0 0.2 0

Anemia 2 0.5 4 0.2

Back pain 2 0 3 0

Fatigue 2 0 2 0

Spinal cord compression 2 0 1 0.5

Comparison of AEs with mCRPC cohort
Mineralocorticoid side effects higher in
LATITUDE compared to CRPC trials
• Difference may be attributable :
• Use of stricter grading with version 4.0 of the Common Terminology Criteria
for Adverse Events
• Prednisone dose 5mg compared to 10mg
• Longer duration on treatment (24months in the LATITUDE trial vs. 13.8
months in COU-AA-3022
 LATITUDE: Patient-Reported
Outcomes
• This analysis was carried out to explore health-related QoL
differences between ADT + AA + P and ADT + Placebos

Instrument Assessed
BPI-SF Pain and pain interference
BFI Fatigue and fatigue interference
FACT-P (version 4) Health-related QoL, pain and prostate cancer symptoms
EQ-5D-5L Health status: Visual Analogue Scale (VAS, 0-100)
Health utility: summarizing status across 5 domains (mobility, self-care,
usual activity, pain/discomfort, anxiety/depression) converted to
health utility index value (0-1)
BPI-SF, Brief Pain Inventory Short Form; BFI, Brief Fatigue Inventory; EQ-5D-5L, EuroQol 5-dimension, 5-level questionnaire visual analog scale;
FACT-P, Functional Assessment of Cancer Therapy-Prostate; PRO, patient-reported outcome; QoL, quality of life. 5
 ADT + AA + P Significantly Improved Pain
Mean Change From Baseline
37% Reduction of Risk for Worst Pain
Progression Differed at Cycle 2

100
0.6

80
ADT + AA + P, NR 0.4
Patients without worst pain

Mean change from baseline

in worst pain score (BPI-SF)
progression (%)

60 0.2 Worse
ADT + Placebos, NR

40 0.0

20 -0.2
Better
HR 0.63 (95% CI, 0.52-0.77)
P < 0.0001
-0.4
0
0 6 12 18 24 30 36 42 0 1 2 3 4 5 6 7 8 9 1011 1213 15 17 19 21 23 25 27 29 31 33
Months Cycle*
Patients at risk
ADT + AA + P 597 456 356 299 218 115 47 2
ADT + AA + P ADT + Placebos
ADT + Placebos 602 387 246 162 99 44 10 1

*1 cycle = 28 days. 9
 ADT + AA + P Significantly Improved
Fatigue
Mean Change From Baseline
35% Reduction in Risk of
Differed at Cycle 5
Worst Fatigue Progression
100

0.4
80 ADT + AA + P, NR
fatigue progression (%)
Patients without worst

Mean change from baseline

in worst fatigue score (BFI)
60 0.2
ADT + Placebos, NR Worse

40 0.0

20
HR 0.65 (95% CI, 0.53-0.81) -0.2 Better
P = 0.0001
0
0 6 12 18 24 30 36 42
-0.4
Months
0 1 2 3 4 5 6 7 8 9 10111213 15 17 19 21 23 25 27 29 31 33
Patients at risk
465 372 305 216 118 44 2 Cycle*
ADT + AA + P 597
ADT + Placebos 602 407 259 171 106 46 14 1
ADT + AA + P ADT + Placebos

*1 cycle = 28 days. 11
 ADT + AA + P Significantly Improved HRQoL (FACT-
P)
15% Reduction in Risk of Mean Change From Baseline
0.6
HRQoL Degradation Differed at Cycle 5

0.4
100
Patients without degradation
in FACT-P total score (%)

80 0.2

FACT-P total score

Better

60 ADT + AA + P, 12.9 mo

0.0
40
ADT + Placebos, 8.3 mo

20 -0.2 Worse
HR 0.85 (95% CI, 0.74-0.99)
P = 0.0322
0
0 6 12 18 24 30 36 42 -0.4
Months
Patients at risk
ADT + AA + P 597 338 250 202 135 65 20 0
0 1 2 3 4 5 6 7 8 9 10111213 15 17 19 21 23 25 27 29 31 33
ADT + Placebos 602 309 192 119 77 33 7 0
Cycle*
ADT + AA + P ADT + Placebos

*1 cycle = 28 days. 13
 Time to Degradation of HRQoL (FACT-P) Was Improved or
Maintained With Addition of AA + P to ADT

ADT + AA + P ADT + Placebos

Score (95% CI) (n = 597) (n = 602) HR P value
FACT-P subscales
Trial outcome index 18.43 (14.36-22.64) 9.23 (7.43-11.17) 0.73 (0.63-0.85) 0.0001
Physical wellbeing 14.36 (10.15-18.20) 7.43 (6.51-9.20) 0.75 (0.65-0.87) 0.0001
Pain-related subscale 10.18 (8.31-14.78) 6.47 (5.55-7.46) 0.76 (0.66-0.88) 0.0001
Prostate cancer–specific subscale 8.31 (6.47-11.07) 5.55 (4.60-7.33) 0.81 (0.70-0.93) 0.0025
FACT-G general function subscale 12.91 (9.33-18.43) 8.31 (7.36-11.07) 0.87 (0.75-1.01) 0.0584
Functional wellbeing 7.36 (5.55-9.23) 5.45 (3.78-6.41) 0.89 (0.78-1.03) 0.1089
Emotional wellbeing 16.13 (10.18-20.70) 10.15 (8.31-14.82) 0.92 (0.79-1.08) 0.3056
Social and family wellbeing 3.78 (2.89-4.70) 5.49 (4.60-6.44) 1.06 (0.92-1.23) 0.3810

14
Patient recruitment in STAMPEDE-Abi

A: Standard-of-care*
(SOC)
(N=957)

G: SOC +
abiraterone +
prednisolone
(SOC+AAP)
(N=960)

Accrual
Open:Nov 2011; Closed:Jan 2014
Accrual: N=1,917

*SOC = ADT ± RT; AAP = abiraterone acetate + prednisolone

James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session
 Inclusion criteria
Newly-diagnosed Relapsing after previous RP or RT
Any of: Any of:
• Metastatic • Metastatic
• Node-Positive • Node-positive
• ≥2 of: Stage T3 or T4 • PSA≥4ng/ml, rising & doubling time <6m
PSA≥40ng/ml • PSA≥20ng/ml
Gleason 8, 9 or 10

All patients Full criteria

Written informed consent
Fit for all protocol treatment
www.stampedetrial.org
Fit for follow-up
 Outcome measures
Primary outcome measure Secondary outcome measures
Overall survival Adverse events
Prostate cancer specific survival
Symptomatic Skeletal-related events
Progression free survival (FFS – BFS)
Quality of life

Intermediate Primary outcome measure PSA failure definition

– Failure-free survival (FFS) PSA fall >= 50%
First of:  24wk nadir + 50% and
PSA failure  >4ng/ml
Local failure
PSA fall of <50%
Lymph node failure
 failure at t=0
Distant metastases
Prostate cancer death
Survival in all patients
Events Events
262 SOC | 184 SOC+AAP 535 SOC | 248 SOC+AAP

HR 0.29
95% CI 0.25 to 0.34
P-value 0.377x10-61
SOC+AAP
SOC+AAP

HR 0.63 SOC
95% CI 0.52 to 0.76 SOC
P-value 0.00000115

This represents a 37% This represents a 71%

improvement in survival improvement in time to failure

SOC = ADT ± RT; AAP = abiraterone acetate + prednisolone

Survival in patients with metastatic disease
Events 368 deaths

SOC+AAP
SOC+AAP

SOC
HR 0.31
HR 0.61 95% CI 0.26-0.37
95% CI 0.49-0.75
SOC

SOC = ADT ± RT; AAP = abiraterone acetate + prednisolone

Survival in patients with nonmetastatic
disease
Events 78 deaths

SOC+AAP SOC+AAP

SOC

SOC
HR 0.75 HR 0.21
95% CI 0.48-1.18 95% CI 0.15-0.31

SOC = ADT ± RT; AAP = abiraterone acetate + prednisolone

James ND, et al. N Engl J Med 2017, doi: 10.1056/NEJMoa1702900
Docetaxel
Treatment started since first A G
progression SOC SOC+abi
SOC+AAP
Patients randomised 957 960
Patients with progression 535 (56%) 248 (26%)
SOC
Reported new treatment 477 (89%) 196 (79%)
Reported ―life-prolonging‖ treatment 310 (58%) 131 (53%)
Docetaxel 200 (37%) 115 (46%)
Enzalutamide 138 (26%) 25 (10%)
AR-targeting abiraterone plus prednisone 120 (22%) 8 (3%)
therapy
Radium-223 24 (5%) 19 (8%)
Cabazitaxel 28 (5%) 15 (6%)
SOC

Graph timed from first FFS event

SOC+AAP
 Safety
SOC-only
SOC+AAP
Safety population
Patients included in adverse event analysis 960 948
Grade 1-5 AE 950 (99%)
943 (99%)
Grade 3-5 AE 315 (33%)
443 (47%)
Grade 5 AE 3 9

Grade 3-5 AEs by category (incl. expected AEs)

Endocrine disorder (incl. hot flashes, impotence) 133 (14%)

129 (14%)
Cardiovascular disorder
(incl. hypertension, MI, cardiac dysrhythmia): 41 (4%) 92 (10%)

Musculoskeletal disorder: 46 (5%) 68 (7%)

Gastrointestinal disorder: 40 (4%) 49 (5%)

Hepatic disorder
Differences between LATITUDE and
STAMPEDE
I anticipate that these changes will be
included in future Guidelines
However …
• Cost /access is a big concern
• Median time on abiraterone
• LATITUDE – 24 months ( but potentially up to 42months)
• STAMPEDE – 33 months if continued to progression

• Better toxicity profile compared to chemotherapy

• But chemotherapy set duration and lower cost
 Conclusions
• Addition of AA + P to ADT provided consistent statistically significant
improvement in OS and disease progression; and clinically relevant benefits
in patient-reported outcomes compared with ADT + Placebos among
patients with newly diagnosed, high risk hsM1 PCa
• Use AA avoids chemotherapy and its rare but potentially life-threatening
complications, replaces short-term intravenous treatment with long-term
oral treatment, and may be more appropriate in a more elderly or
debilitated patient
• Should be considered a new standard of care for patients with newly
diagnosed, hormone sensitive high-risk advanced and M1PCa

16
Abiraterone inhibits androgen
biosynthesis

1) Testes 2) Adrenal gland

Androgen
Deprivation Abiraterone
Therapies

3) Prostate tumor cells

Abiraterone inhibits CYP17 in testes, adrenal
glands and prostate tumors
Does volume of mets matter?
• Consensus
• High volume disease is suitable for ADT + docetaxel x 6 cycles
• Controversy
• Low volume disease is debatable
• CHAARTED data stat insignificant
• STAMPEDE did not assess this subset
• Change
• LATITUDE – 98% 3 more bone mets
• STAMPEDE - no explicit assessment of low vol disease