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Dott. G. Di Lorenzo
Metastatic hormone-sensitive
prostate cancer
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JCO 2019
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mHSPC 2018: Radiotherapy in oligometastatic disease
mHSPC 2019: Addition of Enzalutamide to ADT
mHSPC 2019: Addition of Apalutamide to ADT
CRPC M0 2019: Darolutamide, Enzalutamide, Apalutamide
8 YEARS OF PROGRESS IN
PROSTATE CANCER
Clinical decision making in a rapidly evolving landscape of life-prolonging therapy… JCO 2019
2015
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TAX327 (DOC/P ‒ mCRPC): 2.7 mo2
TROPIC (DOC/P CAB/P ‒ mCRPC): 2.4 mo3-4
COU-AA-301 (DOC/P ABI/P ‒ mCRPC): 4.6 mo5
COU-AA-302 (ABI/P pre-DOC ‒ mCRPC): 4.4 mo6
PREVAIL (ENZA pre-DOC ‒ mCRPC): 4.0 mo7
STAMPEDE ‒ M1 (DOC/P + ADT ‒ mHSPC): 15.0 mo8
CHAARTED – M1 De Novo (DOC/P + ADT – mHSPC): 16.8 mo9
LATITUDE De Novo (ABI/P+ADT-mHSPC) 16.8 mo10 STAMPEDE (ABI/P +ADT –mHSPC): not yet reached
PROSPER – M0 CRPC (ENZA) not yet reached
SPARTAN –M0 CRPC (ABI/P) not yet reached
TITAN: HSPC: APALUTAMIDE HR: 0.67 ENZAMET: HSPC: ENZALUTAMIDE HR: 0.67
1. Kantoff PW. J Clin Oncol. 1999;7:2506–13; 2. Tannock IF. N Engl J Med. 2004;351:1502–12; 3. de Bono JS et al. Lancet. 2010;376:1147–54; 4. Sartor O. J Clin Oncol. 2011;29(S15):abstract 4525 (podium presentation); 5. Fizazi K . Lancet Oncol. 2012;13:983–92 (supplementary appendix); 6. Ryan CJ. Lancet Oncol. 2015;16:152–60; 7. Beer TM. Eur Urol. 2017;71:151–54; 8. James ND et al. Lancet. 2016;387:1163–77; 9. Sweeney C et al. Ann Oncol. 2016;27(suppl 6):10 .Final Analysis of atitude ASCO GU 2019 Fizazi et al.Abstr. 141
2004
2010
2013
2011
2014
2015
2016
2017
2018
2019
History:
OS gain in prostate cancer
6 years
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Local therapy
Androgen deprivation therapy (ADT)
Therapies after ADT
Death
ADT
mCRPC post-
docetaxel
mCRPC Asymptomatic or mildly
symptomatic
M+ Hormone sensitive
ADT + Abiraterone
Enzalutamide
Abiraterone Abiraterone
Docetaxel Cabazitaxel
Enzalutamide ADT +
Docetaxel
tempo
Carico di malattia
Ca prostatico: uno scenario in evoluzione
RT+ OT/Docetaxel
CRPC M0
RADIUM 223
enzalutamide
Apalutamide
Darolutamide
RADIUM 223
ADT + Enza
ADT +
Apalutam.
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Topics to discuss
Hormone-sensitive disease
-High volume/high risk
-Low volume/low risk
-Future perspectives
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Abiraterone or Docetaxel: this is the question... . Overall Efficacy comparison
Subgroup Efficacy comparison -Tumor burden
-Disease presentation
Toxicity
Quality of life
Costs and treatment duration
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Vale et Al. Lancet Oncol 2016
Overall Survival in M1
Failure-free Survival in M1
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Rydzewska et Al. Eur J Canc 2017
Overall Survival in M1
Progression-free survival in M1 (clin/radiol)
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Kyriakoupulos et Al. JCO 2018
Overall Survival High-volume Overall Survival Low-volume
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Kyriakoupulos et Al. JCO 2018
OS High-volume De novo M OS Low-volume De novo M
OS High-volume prior local Ther OS Low-volume prior local Ther
Clear
Benefit
Likely
to
Benefit
No
Benefit
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Hormone Sensitive Prostate Cancer
17
Latitude study
N Engl J Med. 2017 June 4
[Epub ahead of print]
Stampede study
N Engl J Med. 2017 June 3 [Epub ahead of print]
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Internal Use Only
18
High risk – definition from LATITUDE
High-risk prognosis is defined as having at least 2 of the following 3 risk factors:
(1) Gleason score of ≥8
(2) Presence of 3 or more lesions on bone scan
(3) Presence of visceral metastasis
The high-risk prognostic factor of Gleason score ≥8 was selected based on data from the SWOG 9346 study
– Gleason score ≥8: strong predictor for risk of death (HR=1.58 and p <0.0001)
The second and third high-risk prognostic factors are both related to high volume disease (defined as 3 or more lesions by bone scan or involvement of viscera).
– A single-center study of 286 patients: OS was 3.1 years in those with high volume disease compared with 7.8 years in those with low volume disease
Clinicaltrials.gov: NCT01715285; Hussain M, et al. J Clin Oncol 2006;24:3984-3990; Millikan RE, et al. J Clin Oncol 2008;26:5936-5942.
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Statistically significant 38% risk reduction of death
0
0 6 12 18 24 30 36 42
20
40
60
80
100
Months
Overa
ll S
urv
ival (%
)
No. at risk
ADT + AA + P 597 565 529 479 388 233 93 9
602 564 504 432 332 172 57 2
Hazard ratio, 0.62 (95% CI, 0.51-0.76) P<0.0001
ADT + AA + P, not reached
ADT + placebo 34.7 mo
ADT + placebos
19
No. of events: 406 (48% of 852)
ADT + AA + P: 169
ADT + placebos: 237
Presented by: Karim Fizazi
Median follow-up:
30.4 months
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Events 262 Control | 184 abiraterone plus prednisone
HR 0.63 95% CI 0.52 to 0.76 P-value 0.00000115
SOC
SOC+AAP
OS – STAMPEDE “abiraterone plus prednisone comparison”
James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session
It represents a 37%
improvement in
survival
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Kyriakoupulos et Al. JCO 2018 Fizazi et Al. NEJM 2017
High volume Disease
CHAARTED High risk Disease
LATITUDE vs
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Patients selection according to Tumor Burden
in phase III trials of mHSPC
Docetaxel Abiraterone
High Volume vs Low Volume mHSPC
(prospectively stratified)
CHAARTED Criteria
• Visceral metastases
• ≥4 Bone lesions with ≥1 beyond
the vertebral bodies and pelvis
High Risk de novo mHSPC
(all randomized)
LATITUDE Criteria
At least two of the following:
• Gleason Score ≥8
• ≥3 Bone lesions
•Visceral metastases
NEWS FROM
ESMO 2018
Abiraterone : improved OS also stratifing for High volume
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POST -HOC-ANALYSIS FROM STAMPEDE
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Sydes et ESMO 2017
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Sydes et ESMO 2017
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Aim: The objective of this study was to compare ITCs with AAP + ADT vs Doc + ADT on HRQoL and pain PROs in patients with mCNPC.
Mean Change in PRO Scores from Baseline for FACT-P (A) and BPI (B) from LATITUDE and CHAARTED
ASCO GU 2018
Indirect comparison showed that patients receiving AAP + ADT had improvements in HRQoL after 3 months, compared with Doc + ADT; these effects were sustained up to 1 year after treatment.
Feyerabend S, et al. Poster presented at ASCO-GU 2018; abstract 200.
Indirect treatment comparison (ITC) of AA + P and Doc on PROs in mCNPC
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Docetaxel or Abiraterone
Summary
Docetaxel Abiraterone
Efficacy FFS Probably better
Efficacy OS Equally appropiate Equally appropiate
High Volume Dis.
Low Volume Dis.
Tollerability Preferred Often preferred
Duration 4 months 2 years
Costs More affordable Less affordable
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Despite early Docetaxel or Abiraterone
20% of patients die to 24 months
Kyriakoupulos et Al. JCO 2018
CHAARTED
Overall Survival High-volume
LATITUDE
Overall Survival High-risk
James et Al. NEJM 2017
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29
Evidence network After ASCO 2019????????
NSAA+ADT
ENZAMET9
Apa+ADT
TITAN10
Enza+ADT ARCHES8
ADT alone
AA+P+ADT Doce+ADT
LATITUDE1
STAMPEDE2
(Arm G vs A)
CHAARTED4
GETUG-AFU155
STAMPEDE (Arm C vs A)6
STAMPEDE3 (Arm C vs G)
Radiotherapy+ADT
STAMPEDE7
(Arm H vs A)
1. Fizazi K, et al. N Engl J Med. 2017 Jul 27;377(4):352-360; 2. James N, et al. N Engl J Med. 2017 Jul 27;377(4):338-351; 3. Sydes MR, et al. Ann Oncol. 2018 May 1;29(5):1235-1248; 4. Sweeney et al. N Eng J Med 2015; 378(8): 737-746; 5. Gravis G, et al. Eur Urol. 2016 Aug;70(2):256-62; 6. James et al. Lancet 2016; 387(10024):1163-77; 7. Parker CC, et al. Ann Oncol 2018;29(Suppl 8):LBA5_PR; 8. Armstrong AJ, et al. ASCO-GU 2019. Poster and oral presentation (Abstract 687); 9. NCT02446405; 10. NCT02489318
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June, 2019
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TITAN Study Design
31
mCSPC Patient Eligibility Distant metastatic disease by ≥ 1 lesion on bone scan Castration sensitive ECOG PS 0 or 1 On-Study Requirement Continuous ADT Stratifications Gleason score at diagnosis (≤ 7 vs ≥ 8) Region (North America and EU vs all other countries Prior docetaxel (yes vs no) Permitted Prior docetaxel ADT ≤ 6 mo for mCSPC or ≤ 3 yr for local disease Local treatment completed ≥ 1 yr prior
Apalutamide 240 mg daily + ADT
(n = 525)
Placebo + ADT (n = 527)
Dual primary end points •OS • rPFS
Secondary end points • Time to cytotoxic chemotherapy • Time to pain progression • Time to chronic opioid use • Time to skeletal-related event
1:1
RA
ND
OM
IZA
TIO
N
N = 1052
“All-comer” patient population
Exploratory end points • Time to PSA progression • Second progression-free survival
(PFS2) • Time to symptomatic progression
ECOG, Eastern Cooperative Oncology Group performance status; PSA, prostate-specific antigen; rPFS, radiographic progression-free survival.
Kim N. Chi, MD
Dec 2015 – Jul 2017
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TITAN OS: Apalutamide Significantly Reduced the Risk of Death by 33%
33 Kim N. Chi, MD
CI, confidence interval; NE, not evaluable.
Pat
ien
ts W
ho
Wer
e A
live
(%)
100
75
50
25
0
No. at risk Apalutamide Placebo
525 527
513 509
490 473
410 387
165 142
14 16
0 0
0 6 12 18 24 30 36 Months
Apalutamide + ADT
Placebo + ADT
Apalutamide
(n = 525)
Placebo
(n = 527)
Median, mo (95%
CI)
NE (NE-NE) NE (NE-NE)
HR (95% CI) 0.67 (0.51-0.89)
P value 0.0053
82%
74%
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First Subsequent Therapy for Prostate Cancer
34
Proportion of Patients receiving subsequent therapy Apalutamide + ADT Placebo + ADT
Patients who discontinued treatment for any reasona and remained alive, n 170 271
Patients receiving subsequent systemic prostate cancer therapy at data cutoff,c n (%) 87 (51.2) 190 (70.1)
Distribution of reported subsequent therapy n = 87 n = 190
Hormonal therapy, n (%) 44 (50.6) 98 (51.6)
Abiraterone acetate plus prednisone 21 (24.1) 45 (23.7)
Bicalutamide 16 (18.4) 31 (16.3)
Enzalutamide 3 (3.4) 17 (8.9)
Chemotherapy, n (%) 35 (40.2) 73 (38.4)
Docetaxel 29 (33.3) 67 (35.3)
Cabazitaxel 1 (0.4) 2 (1.1)
Other therapy, n (%) 8 (9.2) 19 (0.1)
Radium-223 2 (2.3) 4 (2.1)
Sipuleucel-T 2 (2.3) 5 (2.6) aReasons for discontinuation were disease progression, adverse event, withdrawal by patient, death, physician decision, and protocol violation.
Kim N. Chi, MD
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35
TITAN & SPARTAN – safety profile STUDY TITAN1 SPARTAN2
POPULATION mHSPC “all comers” High risk nmCRPC
Apalutamide + ADT (n = 524)
Placebo + ADT (n = 527)
Apalutamide + ADT (n = 803)
Placebo + ADT (n = 398)
Any AE 507 (96.8) 509 (96.6) 775 (96.5) 371 (93.2)
Grade 3 or 4 AEs 221 (42.2) 215 (40.8) 362 (45.1) 136 (34.2)
Any SAE 104 (19.8) 107 (20.3) 199 (24.8) 92 (23.1)
Any AE leading to treatment discontinuation 42 (8.0) 28 (5.3) 85 (10.6) 28 (7.0)
AE leading to death 10 (1.9) 16 (3.0) 10 (1.2) 1 (0.3)
Adverse Event, n (%) All Grades Grade ≥ 3 All Grades Grade ≥ 3 All Grades Grade ≥ 3 All Grades Grade ≥ 3
Rash 142 (27.1) 33 (6.3) 45 (8.5) 3 (0.6) 191 (23.8) 42 (5.2) 22 (5.5) 1 (0.3)
Fatigue 103 (19.7) 8 (1.5) 88 (16.7) 6 (1.1) 244 (30.4) 7 (0.9) 84 (21.1) 1 (0.3)
Fall 39 (7.4) 4 (0.8) 37 (7.0) 4 (0.8) 125 (15.6) 14 (1.7) 36 (9.0) 3 (0.8)
Hypothyroidism 34 (6.5) 0 6 (1.1) 0 65 (8.1) 0 8 (2.0) 0
Fracture 33 (6.3) 7 (1.3) 24 (4.6) 4 (0.8) 94 (11.7) 22 (2.7) 26 (6.5) 3 (0.8)
Seizure 3 (0.6) 1 (0.2) 2 (0.4) 0 2 (0.2) 0 0 0
1. Chi K, et al. ASCO 2019. Oral presentation (abstract 5006); 2. Smith MR, et al. N Engl J Med. 2018 Apr
12;378(15):1408-1418
Not head-to-head trials
June, 2019
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June, 2019
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ENZAMET Treatment 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
R
A
N
D
O
M
I
Z
E
ARM A:
Testosterone Suppression
+ standard NSAA
ARM B:
Testosterone Suppression
+ Enzalutamide (160
mg/d)
Evaluate
every
12 weeks
Evaluate
every
12 weeks
CRPC therapy at
investigator’s
discretion at
progression
Follow for time
to progression
and overall
survival
• Prior to randomization testosterone suppression up to 12
weeks and 2 cycles of docetaxel was allowed.
• Intermittent ADT and cyproterone were not allowed
• NSAA: 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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Primary endpoint: Overall survival
Proportion alive at 36 months (95% CI)
NSAA Enzalutamide
0.72 (0.68 to 0.76) 0.80 (0.75 to 0.83)
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Concurrent Docetaxel: Prespecified Subgroup of Interest (Biology and Treatment Implications)
Presented by: Christopher J. Sweeney, MBBS
Clinical Progression-Free Survival Overall Survival
Testosterone
Suppression
+
Docetaxel
N=503
(71% High Volume)
Testosterone
Suppression
+
No Docetaxel
N=622
(37% High Volume)
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JCO 2019
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Radiotherapy to the primary tumour for newly
diagnosed, metastatic prostate cancer
(STAMPEDE): a randomised controlled phase 3
trial
•Christopher C Parker, MD •Prof Nicholas D James, PhD •Christopher D Brawley, MSc •Prof Noel W Clarke, ChM •Alex P Hoyle, MRCS •Adnan Ali, MBBS
Lancet 2018, Oct.
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Charteed Criteria: Low volume: until 3 lesions
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TAKE HOME MESSAGES (1)
● Several agents have improved OS in mHSPC;
●
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Patient and study characteristics: differences among the studies…..
Not head-to-head comparison studies
Docetaxel AAP+ADT ENZA+ADT APA+ADT
GETUG-15 CHAARTED STAMPEDE
(Arm C) LATITUDE
STAMPEDE (Arm G)
ARCHES ENZAMET TITAN
Study population
Total sample size, n 385 790 1776 1199 1917 1150 1125 1052
Patients with mHSPC
100% 100% 61% 100% 52% 100% 100% 100%
Patient subtypes M1 all comers M1 all comers M0 M1 all comers
M1 de-novo high-risk
M0 M1 all comers
M1 all comers M1 all comers M1 all comers
Patients with high-risk/high volume mHSPC
47.5% (183) 65 % (513) NE HR: 100% For M1 pts: HR: 52.5% HV: 55.4%
HV: 63% HV: 52% HV: 63%
Patients with de novo M1
71% 72.8% 58% 100% 49% 67%
61% (61.7% ENZA
and 59.5% NSAA)
81% (78.3% APA and 83.7%
PBO)
Treatment
Median follow up 83.9 months 53.7 months 43 months 51.8# 40 months 14.4 months 34 months 22.7 months
Study arm treatment duration, median
8 cycles 86% received 6
cycles 77% received 6
cycles 25.8 months# 33.2 months* 12.8 months NA 20.5 months
Prior docetaxel for mHSPC
Exclusion Exclusion Exclusion Exclusion Exclusion 18% 16% 10.7%
Concurrent docetaxel for mHSPC
Not allowed Not allowed Not allowed Not allowed Not allowed Not
allowed 45% Not allowed
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TAKE HOME MESSAGES (1)
● Although no level 1 evidence it is reasonable to
consider in low volume oligom:
-ADT (few met, long history)
ADT + ARPi (de novo M. or aggressive disease);
-RT to prostate;
In high volume: Doc
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TAKE HOME MESSAGES (2)
● Therapy in HSPC influences CRPC-therapy
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What are the first-line systemic options in castration-resistant prostate cancer after first-line treatment in the castration-sensitive setting?
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Efficacy of docetaxel in CRPC seems impaired after docetaxel in CSPC
With prior docetaxel
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Open questions (1)
● Best drug in HSPC?
Consider efficacy and toxicity (Abi/enza/apa/doc)
● Combination or sequence? Sequence (ENZAMET
trial)(PEACE 1 and ARASENS trials waiting)
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Open questions (2)
How do we best personalize therapy on the basis of
clinical subgroups? (histologies other than adenocarcinoma, poor PS, recent cardiac
events, prior seizures)
What is the role of focal therapy in the setting of effective
sistemic therapy?
( RT on prostate or also on metastases…Platon trial)
How should we incorporate molecular characteristics into
management? (PTEN, RB, p53)
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RB
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Open questions (3)
The evolution of imaging is a major confounding
factor
M1 disease by conventional imaging and those with M0
disease but M1 disease on next generetion imaging (PSMA-
PET)
Trials to date have not incorporated next generation
imaging
Future trials should seek to refine subgroup definitions by
incorporating newer imaging techniques
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Open questions (4)
If the patient achieves an undetectable PSA with
durable control (more than 2 years):
Is It reasonable to halt systemic therapy especially
if adverse events that are metabolic and QoL
impairing emerge and observe until biochemical
Progression?
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All Eligible Patients should benefit of all proven
and effective treatments………
But
Decision based on:
-Balance risks/benefits
-Comorbidities
-Emerging data
-Patients preferences
My Personal View and Hope…