Metastatic HSPC: State of the Art Management in 2021
A/ Prof Ravindran Kanesvaran
Deputy Head and Senior Consultant , Division of Medical Oncology
National Cancer Centre Singapore
1
Disclosures
Research Support/P.I.
Sanofi, Janssen
Speakers Bureau
Astellas, Bayer, Janssen, Pfizer, Mundipharma,
Sanofi, MSD, BMS, Novartis
Honoraria
Astellas, Bayer, Janssen, Pfizer, Mundipharma,
Sanofi, MSD, BMS, Amgen
Scientific Advisory Board
2
Astellas, Bayer, Janssen, Pfizer, Mundipharma, MSD,
BMS
Outline
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Case study
Current mHSPC treatment
Guidelines
Summary
Case Study
• Mr X is a 74 year-old Chinese male
• Retired teacher who stays alone
• Comorbidities: Diabetes for 10 years , well controlled
on Metformin
• Presents to GP with lower urinary tract symptoms (
LUTS) for 2 months prior and recent onset LBP
• Referred to a urologist
4
Physical Examination
•
•
•
•
•
•
ECOG performance status: 0
BP: 130/80, PR: 70bpm
Lungs: clear
CVS: S1,S2 heard with no murmurs
Neurological exam: normal
PA: Soft, non tender abdomen with no
organomegaly
• DRE: Hard craggy prostate
5
Diagnosis
• TRUS biopsy done
• Histopath: Gleason 5+4 adenocarcinoma of the prostate
• CT scan of Thorax, Abd and pelvis: multiple bilateral
inguinal lymphadenopathy, bone lesions in the pelvis,
scapula, and spine and 2 suspicious lesions in the lung
suggestive of mets
• Bone scan: confirmed presence of osteoblastic lesions in
pelvis , spine, skull, and scapula
• Biochem: Corrected Ca-2.50mmol/L, ALP-1100 U/L
(raised),
• PSA: 450 ng/ml
6
High Volume/ High Risk
CHAARTED

Visceral metastases (extranodal)
LATITUDE
Meets at least 2 of 3 high-risk criteria
AND/OR

Bone Metastases
• At least 4 or more bone lesions
• One of which must be outside of
the vertebral column or pelvis
Sweeney et al NEJM 2015
7
• Gleason score of
≥8
• Presence of ≥ 3 lesions on bone scan
• Presence of measurable visceral lesion
Fizazi et al NEJM 2017
How would you treat him?
What would be your choice of treatment at this point?
A. GNRH agonist (with short course of Bicalutamide
1 week before and 2 weeks after)
B. Combined androgen blockade with GNRH agonist
and Anti-androgen (bicalutamide)
C. GNRH agonist and docetaxel chemotherapy
D. GNRH agonist with NHT
8
Outline
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•
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Case study
Current mHSPC treatment
Guidelines
Summary
History of mHSPC systemic
treatment
TITAN7
APA + ADT
improves OS
ARCHES8
ENZA + ADT
improves PFS
ADT
1941
10
Akaza et al.1
Bicalutamide +
ADT
2009
CHAARTED2,3
STAMPEDE4
Doc + ADT
improves OS
2015
STAMPEDE5
LATITUDE6
AAP + ADT
improves OS
2017
ENZAMET9
ENZA + ADT
improves OS
1. Akaza H, et al. Cancer. 2009;115:3437-45. 2. Sweeney CJ, et al. N Engl J Med. 2015;373:737-46. 3. Kyriakopoulos CE, et al. J Clin Oncol. 2018;36:1080-7. 4. James ND, et
al. Lancet. 2016;387:1163-77. 5. James ND, et al. N Engl J Med. 2017;377:338-51. 6. Fizazi K, et al. J Clin Oncol. 2019;37 Suppl 141:141. 7. Chi KN, et al. N Engl J Med.
2019;381:13-24. 8. Armstrong AJ, et al. J Clin Oncol. 2019 Nov 10;37(32):2974-2986. 9. Davis ID, et al. N Engl J Med 2019;381:121-31.
2019
Patient and study characteristics of
chemohormonal studies
GETUG-AFU 15
CHAARTED
STAMPEDE
2004-2008
2006-2012
2005-2013
385
790
1776
100%
100%
61%
Patients with highvolume mHSPC
47.5 % (183)
65 % (514)
?
Median follow up
83.9 months
29 months
43 months
up to 9
6
6
no
no
yes
Accrual
Total sample size
Patients with mHSPC
Cycles of docetaxel
Prednisone
11
Sweeney et al. N Eng J Med 2015; 378(8): 737-746;
Gravis G, et al. Eur Urol. 2016 Aug;70(2):256-62;
James et al. Lancet 2016; 387(10024):1163-77
Overall survival results
Patients, N
De novo M1
GETUG-AFU 15
CHAARTED
STAMPEDE**
385
790
2962
71%
75%
61%
62.1
57.6
60
13.5 months
(48.6 to 62.1)
HR=0.88 P=0.3
13.6 months
(44 to 57.6)
HR=0.61 P<0.001
15 months***
(45 to 60)
HR 0.76 P=0.005
Survival, all patients
Median survival,
months
Survival benefit
Survival
Survival high-volume metastases
Survival benefit
Survival
4.7 months
(35.1 to 39.8)
17 months
(32.2 to 49.2)
HR=0.78 P=0.14
HR=0.60 P<0.001
*Not head-to-head comparison studies
**Includes patients with M0 disease
***M1 61% patients only, no further subgroups
NE, not evaluated
12
Sweeney et al. N Eng J Med 2015; 378(8): 737-746;
Gravis G, et al. Eur Urol. 2016 Aug;70(2):256-62;
James et al. Lancet 2016; 387(10024):1163-77
NE
NE
Meta-analysis OS
•
Results based on 2993 men/2198 events
Vale et al. Lancet Oncol 2016; 17(2):243-56
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CHAARTED Updated
Kyriakopoulus et al JCO 2018
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Stampede Updated Analysis @ESMO 2019
Overall Survival: All Patients
James N et al ESMO 2019
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Updated Analysis @ESMO 2019
Overall Survival: All Patients
James N et al ESMO 2019
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Chemo-hormonal Therapy in
mHSPC: HK experience
HK
Castration resistance-free survival
ADT+chemo vs ADT alone:
17.6 vs 8 mos (p=0.002)
(Remark: 96.9% high-volume disease)
CHAARTED study
ADT+chemo vs ADT alone:
20.2 vs 11.7 mos (p=<0.001)
(Remark: 65% high-volume disease)
A Territory-wide, Multicenter, Age- and Prostate-specific Antigen-matched Study Comparing Chemohormonal Therapy and
Hormonal Therapy Alone in Chinese Men With Metastatic Hormone-sensitive Prostate Cancer. Clin Genitourin Cancer. 2019.
Corresponding author: Darren MC Poon
Teoh JYC et al. Clin Genitourin Cancer. 2019; e203-e208
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Chemohormonal related-adverse: HK
experience vs RCT
mHSPC
mCRPC
1. Poon DMC, et al. Asia-Pac J Clin Oncol. 1-6. 2. Poon DMC, et al. Prostate Int. 2015;3:51–55. 3.Sweeney CJ, et al. N Engl J Med. 2015;373:737-46. 4. James ND, et al. Lancet. 2016;387:1163-77.
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History of mHSPC systemic
treatment
TITAN7
APA + ADT
improves OS
ARCHES8
ENZA + ADT
improves PFS
ADT
1941
20
Akaza et al.1
Bicalutamide +
ADT
2009
CHAARTED2,3
STAMPEDE4
Doc + ADT
improves OS
2015
STAMPEDE5
LATITUDE6
AAP + ADT
improves OS
2017
ENZAMET9
ENZA + ADT
improves OS
1. Akaza H, et al. Cancer. 2009;115:3437-45. 2. Sweeney CJ, et al. N Engl J Med. 2015;373:737-46. 3. Kyriakopoulos CE, et al. J Clin Oncol. 2018;36:1080-7. 4. James ND, et
al. Lancet. 2016;387:1163-77. 5. James ND, et al. N Engl J Med. 2017;377:338-51. 6. Fizazi K, et al. J Clin Oncol. 2019;37 Suppl 141:141. 7. Chi KN, et al. N Engl J Med.
2019;381:13-24. 8. Armstrong AJ, et al. J Clin Oncol. 2019 Nov 10;37(32):2974-2986. 9. Davis ID, et al. N Engl J Med 2019;381:121-31.
2019
So , Docetaxel or Abi in mHSPC?
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Courtesy of Oliver Sartor
LATITUDE
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Fizazi et al Lancet Oncol 2019
Overall Survival: LATITUDE
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
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
Fizazi K, et al. Poster presented at ASCO 2018; abstract 5023.
LATITUDE: Asian Subset
A/E:
comparable
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ARCHES STUDY DESIGN
Key eligibility criteria
• mHSPC (confirmed by bone scan,
CT, or MRI), histologically
confirmed adenocarcinoma
• ECOG Performance Status 0 to 1
• Current ADT duration <3 months
unless prior docetaxel, then <6
months
Stratification factors
• Volume of disease (low vs. high*)
• Prior docetaxel therapy for mHSPC
(none, 1–5, or 6 cycles)
Key discontinuation criteria
N = 1150
Enzalutamide
160 mg/day + ADT
R
1:1
Placebo + ADT
Radiographic progression, unacceptable
toxicity, or initiation of an investigational
agent or new therapy for prostate cancer
rPFS final
analysis
Overall survival
(OS) interim
analysis
OS final
analysis
While on study, study visits occurred at week 1, week 5, week 13 and every 12 weeks thereafter. Study drug administration continued until radiographic
progression.
*Defined as metastases involving the visceral or, in the absence of visceral lesions, ≥4 bone lesions, ≥1 of which must be in a bony structure beyond the vertebral column and pelvic
bone
Armstrong A et al. J Clin Oncol. 2019 Jul 22:JCO1900799. doi: 10.1200/JCO.19.00799. [Epub ahead of print]
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ARCHES – Primary Endpoint
Median, months
(95% CI)
ENZA + ADT
NR
(NR, NR)
61%
PBO + ADT
19.0
(16.6, 22.2)
Reduction in Risk
of rPFS
Hazard ratio (HR), 0.39
(95% CI, 0.03, 0.50);
P<0.001
Armstrong A et al. J Clin Oncol. 2019 Jul 22:JCO1900799. doi: 10.1200/JCO.19.00799. [Epub ahead of print]
27
ENZAMET STUDY DESIGN – OPEN LABEL
Stratification
Volume of metastases*
- High vs Low
Planned Early Docetaxel
- Yes vs No
ECOG PS
- 0-1 vs 2
Anti-resorptive therapy
-Yes vs No
Comorbidities
ACE-27**: 0-1 vs 2-3
Study Site
N = 1125
R
1:1
Enzalutamide 160 mg/day +
Testosterone Suppression
Non-Steroidal Anti-Androgen*
+ Testosterone Suppression
Evaluate every
12 weeks
•
Testosterone suppression = Luteinizing hormone-releasing hormone agonists (or orchidectomy)
•
Prior to randomization testosterone suppression up to 12 weeks and 2 cycles of docetaxel was allowed.
•
Intermittent ADT and cyproterone were not allowed
•
Non-Steroidal Anti-Androgen: bicalutamide; nilutamide; flutamide
*High volume: visceral metastases and/or 4 or more bone metastases (at least 1 beyond pelvis and vertebral column)
**Adult Co-morbidity Evaluation-27
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Davis ID et al. NEJM. 2019; 381:121-131
• CRPC therapy at investigator’s
discretion at progression
• Follow for time to progression
and overall survival
ENZAMET: Enzalutamide in allcomers
Davis ID, et al. N Engl J Med. 2019;381:121-31.
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Christopher Sweeney, MBBS. 2019 ASCO Annual Meeting.
TITAN Study Design
Key Eligibility Criteria
Castration sensitive
Distant metastatic disease by ≥ 1 lesion
on bone scan
ECOG PS 0 or 1
On-Study Requirement
Continuous ADT
Permitted
Prior docetaxel
ADT ≤ 6 mo for mCSPC or ≤ 3 yr for local
disease
Local treatment completed ≥ 1 yr prior
N = 1052
Dual primary end points
• OS
• rPFS
Dec 2015 –
Jul 2017
1:1 RANDOMIZATION
“All-comer” patient population
Apalutamide
240 mg daily + ADT
(n = 525)
Placebo + ADT
(n = 527)
Stratifications
Gleason score at diagnosis (≤ 7 vs ≥ 8)
Region (NA and EU vs all other countries)
Prior docetaxel (yes vs no)
Exploratory end points
• Time to PSA progression
• Second progression-free survival
(PFS2)
• Time to symptomatic progression
ECOG PS, Eastern Cooperative Oncology Group performance status;
NA, North America; PSA, prostate-specific antigen; rPFS, radiographic progression-free survival.
Kim N. Chi, MD
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Secondary end points
• Time to cytotoxic chemotherapy
• Time to pain progression
• Time to chronic opioid use
• Time to skeletal-related event
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TITAN: Final analysis results: OS
Key Takeaways
Figure 2. Risk of death reduced by 35% w/o crossover
adjustment
Endpoint
Median OS
APA + ADT
(n=525)
PBO + ADT
(n=527)
HR (95% CI)
P value
NE
52.2
0.65 (0.53-0.79)
<0.0001
Figure 3. Risk of death reduced by 48% w/ crossover
adjustment
Median OS (crossover
adjusted by IPCW)
NE
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39.8
0.52 (0.42-0.64)
<0.0001
Kim Chi et al , ASCO GU 2021
Primary endpoint: OS
Product
Docetaxel
Study
Median follow-up
AAP+ADT
GETUG-151,2
CHAARTED3
STAMPEDE
(Arm C) M1
pts4
LATITUDE5,6
83.9 months
53.7 months
43 months
51.8 months
40 months
0.76
(0.62-0.92)
0.005
15
(60 vs 45)
0.66
(0.56-0.78)
<0.0001
16.8
(53.3 vs 36.5)
0.61
(0.49-0.75)
NA
NA
NA
-
0.62
(0.52-0.74)
<0.0001
0.60
(0.46-0.78)
<0.001
-
0.72
(0.47−1.10)
0.1242
0.64
(0.42-0.97)
0.034
ENZA+ADT
APA+AFDT
STAMPEDE (arm
G) M1 pts7,12
ARCHES8
ENZAMET9
TITAN10,11
14.4 months
34 months
22.7 months
-
0.67
(0.52-0.86)
0.002
?
(NR vs NR)
0.67
(0.51-0.89)
p=0.0053
?
(NR vs NR)
-
0.80
(0.59‐1.07)
-
0.68
(0.50‐0.92)
-
-
0.43
(0.26‐0.72)
-
0.67
(0.34-1.32)
-
Primary endpoint
OS:
- HR
- (95% CI)
- P-value
- Benefit , mo
- Active arm vs
control arm, mo
#OS
0.88
0.72
(0.68-1.1)
(0.59–0.89)
0.3
0.0017
13.5
10.4
(62.1 vs 48.6) (57.6 vs 47.2)
OS – HV
- HR
- (95%
CI)
- P-value
0.78
(0.56-1.09)
0.1
0.63
(0.50 – 0.79)
<0.001
OS – LV
- HR
- (95%
CI)
- P-value
1.02
(0.67-1.55)
0.9
1.04
(0.70 – 1.55)
0.86
data reported as immature and not statistically significant
No head-to-head studies
1. Gravis G, et al. Lancet Oncol 2013; 14(2): 149–158; 2. Gravis G, et al. Eur Urol. 2016 Aug;70(2):256-62; 3. Kyriakopoulos CE, et al. J Clin Oncol. 2018 Apr
10;36(11):1080-1087; 4. James ND et al. The Lancet 2016 387, 1163-1177; 5. Fizazi K, et al. N Engl J Med. 2017 Jul 27;377(4):352-360; 6. Fizazi K, et al.
ASCO-GU 2019. Poster and oral presentation (Abstract 141); 7. James N, et al N Engl J Med. 2017 Jul 27;377(4):338-351; 8. Armstrong AJ, et al. ASCO-GU 2019.
Poster and oral presentation (Abstract 687); 9. Davis, ID. N Engl J Med. 2019 Jun 2. [Epub ahead of print]; 10. Chi K, et al. ASCO 2019. Oral session (abstract
5006); 11. Chi K, et al. NEJM. 2019 [Epub Ahead of print]; 12. Hoyle AP, et al. Ann Oncol 2018;29(Suppl 8):LBA4
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Safety ( NHT in mHSPC)
LATITUDE1,2
STAMPEDE3,4
ARCHES5
ENZAMET6
TITAN7,8
ADT + AAP
(n = 597)
ADT +
PBOs
(n = 602)
SOC+AAP
(n=960)
SOC
(n=957)
ENZA+ADT
(n=572)
PBO+ADT
(n=574)
ENZA+ADT
(n=563)
NSAA+AD
T
(n=558)
APA + ADT
(n=524)
ADT + PBO
(n=527)
Any AE, n (%)
569 (95)
561 (93)
943 (99)
950 (99)
487 (85.1)
493 (85.9)
563 (100)
548 (98)
507 (96.8)
509 (96.6)
Grade 3 or 4 AEs, n
(%)
403 (68)
299 (50)
443 (47)
315 (33)
139 (24.3)
147 (25.6)
NA
NA
221 (42.2)
215 (40.8)
Any SAE,
n (%)
192 (32)
151 (25)
NA
NA
NA
NA
235 (42)
189 (34)
104 (19.8)
107 (20.3)
93 (16)
63 (11)
NA
NA
41 (7.2)
30 (5.2)
33 (5.9)
14 (2.5)
42 (8.0)
28 (5.3)
38 (6)
27 (5)
9 (1)
3 (<1)
14 (2.4)
10 (1.7)
6 (1)
7 (1)
10 (1.9)
16 (3.0)
Any AE leading to
treatment
discontinuation,
n (%)
AE leading to death, n
(%)
Not head-to-head comparison studies ; NA: not available
1. Fizazi K, et al. N Engl J Med. 2017 Jul 27;377(4):352-360]; 2. Fizazi K, et al. ASCO-GU 2019. Poster and oral presentation (Abstract 141); 3. James N, et
al. ASCO 2017. LBA5003 and Oral Abstract Session; 4. James N, et al. N Engl J Med. 2017 Jul 27;377(4):338-351; 5. Armstrong AJ, et al. ASCO-GU 2019.
Poster and oral presentation (Abstract 687); 6. Davis, ID. N Engl J Med. 2019 Jun 2. [Epub ahead of print]; 7. Chi K, et al. ASCO 2019. Oral session
(abstract 5006); 8. Chi K, et al. NEJM. 2019 [Epub Ahead of print]
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STAMPEDE Arm H: Role of RT to primary
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Parker et al. Lancet Dec 2018
Outline
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•
•
•
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Case study
Current mHSPC treatment
Guidelines
Summary
What do the Guidelines/ APCCC say?
ESMO Pan Asian
Adopted Guidelines
Chair: R Kanesvaran
Nov 2021
36
Parker et al, Ann Oncol 2020
ESMO Prostate Cancer Guidelines 2020
37
Gillessen S et al. Eur Uro. 2020;77(4)pp508-547
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Outline
•
•
•
•
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Case study
Current mHSPC treatment
Guidelines
Summary
Case Study ( continued)
• GNRH agonist with abiraterone acetate ( generic)
and prednisolone
• PSA drop was noted with a nadir (10ng/ml)
reached after 6 months of treatment
• PSA then started rising slowly over the next 12
months
• However interim imaging did no show any
progression and abiraterone acetate was continued
• Now at month 20, he is still asymptomatic
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Summary
• The treatment landscape for mHSPC is evolving rapidly
• Treatment selection will depend on the following factors:
-Access (incl cost), Patient factors and Disease related factors
• Monitoring requires imaging to present a more accurate measure of
disease burden (move beyond PSA )
• Personalised medicine is rapidly coming to the fore with genomic
profiling and targeted treatment
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THANK YOU
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Members of the SingHealth Group
Changi General Hospital • KK Women’s and Children’s Hospital • Singapore General Hospital
National Cancer Centre Singapore • National Dental Centre Singapore • National Heart Centre Singapore • National Neuroscience Institute • Singapore National Eye Centre
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