Opzioni terapeutiche nel carcinoma prostatico metastatico...
Transcript of Opzioni terapeutiche nel carcinoma prostatico metastatico...
II SESSIONE: “GENITO-URINARIO”
Opzioni terapeutiche nel carcinoma prostatico metastatico sensibile alla castrazione (mHSPC)
Dott. Davide Bimbatti UOC Oncologia Medica
AOUI Verona
Tutor: Dott. Umberto Basso
AIOM Giovani 2017 Davide Bimbatti
Agenda
1. Standard initial treatment options
2. Chemotherapy: Docetaxel
3. Hormone therapy: Abiraterone
4. Next generation androgen receptor agonists
5. Patient choice
6. Future challenges
Standard initial treatment options - ADT
AIOM Giovani 2017 Davide Bimbatti
James ND et al. Survival with newly diagnosed metastatic
prostate cancer in the “docetaxel era”: data from 917
patients in the control arm of the STAMPEDE trial (MRC
PR08, CRUK/06/019). Eur Urol 2015;67:1028-1038
Tangen CM et al. Improved Overall Survival Trends of Men
with Newly Diagnosed M1 Prostate Cancer: A SWOG
Phase III Trial Experience (S8494, S8894 & S9346). The
Journal of urology. 2012;188(4):1164-1169.
The Prostate Cancer Trialists’ Collaborative Group (PCTCG). Lancet 2000; 355: 1491–98
27 randomised trials involved 8275 men with metastatic (88%) or locally advanced (12%) prostate cancer. Half were over 70 years of age, and follow-up was typically for about 5 years.
Addition of an antiandrogen to AS improved the 5-year survival by about 2% or 3% (depending on whether the analysis includes or excludes the cyproterone acetate trials), but the range of uncertainty as to the true size of this benefit runs from about 0% to about 5%
Standard initial treatment options - ADT vs BAT
AIOM Giovani 2017 Davide Bimbatti
The Prostate Cancer Trialists’ Collaborative Group (PCTCG). Lancet 2000; 355: 1491–98
27 randomised trials involved 8275 men with metastatic (88%) or locally advanced (12%) prostate cancer. Half were over 70 years of age, and follow-up was typically for about 5 years.
Addition of an antiandrogen to AS improved the 5-year survival by about 2% or 3% (depending on whether the analysis includes or excludes the cyproterone acetate trials), but the range of uncertainty as to the true size of this benefit runs from about 0% to about 5%
Standard initial treatment options - ADT vs BAT
AIOM Giovani 2017 Davide Bimbatti
AIOM Giovani 2017 Davide Bimbatti
Hussain M et al. Intermittent versus Continuous Androgen Deprivation in Prostate Cancer. NEJM 2013;368(14):1314-1325.
Standard initial treatment options - Intermittent
AIOM Giovani 2017 Davide Bimbatti
Standard initial treatment options - Intermittent
Hussain M et al. Intermittent versus Continuous Androgen Deprivation in Prostate Cancer. NEJM 2013;368(14):1314-1325.
AIOM Giovani 2017 Davide Bimbatti
Standard initial treatment options - ADT vs Bicalutamide
Sweeney CJ et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. NEJM 2015 Aug 20;373(8):737-46.
Chemotherapy - Docetaxel - CHAARTED
AIOM Giovani 2017 Davide Bimbatti
Inclusion Criteria:
• Pathological diagnosis of
prostate cancer with elevated
PSA
• Radiologic evidence of
metastatic disease;
• ECOG 0, 1 or 2
• Prior adjuvant ADT was
allowed if the duration of
therapy was 24 months or less
and progression had occurred
more than 12 months after
completion of therapy.
• Patients who were receiving
ADT for metastatic disease
were eligible if there was no
evidence of progression and
treatment had commenced
within 120 days before
randomization.
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N
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D
1:1
ADT+Docetaxel
ADT
Primary Outcome
• Overall Survival
AIOM Giovani 2017 Davide Bimbatti
Sweeney CJ et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. NEJM 2015 Aug 20;373(8):737-46.
Chemotherapy - Docetaxel - CHAARTED
High volume: • presence of visceral metastases or • ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis
Chemotherapy - Docetaxel - CHAARTED
AIOM Giovani 2017 Davide Bimbatti
Sweeney CJ et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. NEJM 2015 Aug 20;373(8):737-46.
James ND et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016 Mar 19;387(10024):1163-77.
Chemotherapy - Docetaxel - STAMPEDE
AIOM Giovani 2017 Davide Bimbatti
Primary Outcome
• Overall Survival
James ND et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016 Mar 19;387(10024):1163-77.
Chemotherapy - Docetaxel - STAMPEDE
AIOM Giovani 2017 Davide Bimbatti
ADT+Docetaxel: mOS 81 months
Hazard ratio for death with ADT+Docetaxel: 0.78 (95% CI, 0.66-0.93) P=0.006
ADT alone: mOS 71 months
Chemotherapy - Docetaxel - GETUG-15
AIOM Giovani 2017 Davide Bimbatti
Inclusion Criteria:
• Histologically confirmed
adenocarcinoma
• Radiologically proven
metastatic disease
• Karnofsky score ≥70%
• No previous chemotherapy
for metastatic disease
• ADT for patients with
metastatic disease could
have been initiated no more
than 2 months
• In the neo adjuvant and
adjuvant settings or in the
context of isolated PSA
increase, previous
chemotherapy or ADT, or
both, were allowed, with the
condition that the treatment
had been discontinued at
least 12 months before
inclusion
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1:1
ADT+Docetaxel
ADT
Gravis G et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate
cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol 2013; 14: 149–58
Primary Outcome
• Overall Survival
Chemotherapy - Docetaxel - GETUG-15
AIOM Giovani 2017 Davide Bimbatti
ADT+Docetaxel: mOS 58,9 months
Hazard ratio for death with ADT+Docetaxel: 1.01, (95% CI, 0.75-1.36) P=0.955
ADT alone: mOS 54,2 months
Gravis G et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate
cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol 2013; 14: 149–58
Fizazi K et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. NEJM 2017 Jun 4
Hormone therapy - Abiraterone - LATITUDE
AIOM Giovani 2017 Davide Bimbatti
Inclusion Criteria:
• ECOG 0 to 2 • Newly diagnosed pathologically
confirmed prostate cancer • High-risk, metastatic, castration-
sensitive prostate cancer. • At least two of the three
following high-risk factors: a Gleason score of 8 or more, at least 3 bone lesions, and the presence of measurable visceral metastasis.
• Allowed 3 months or less of androgen-deprivation or one course of palliative radiation or surgical therapy to treat symptoms associated with metastatic disease.
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1:1
ADT+Abiraterone
+prednisone
ADT+placebos
Primary Outcomes
• Overall Survival
• Radiographic Progression free survival
Fizazi K et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. NEJM 2017 Jun 4
Hormone therapy - Abiraterone - LATITUDE
AIOM Giovani 2017 Davide Bimbatti
ADT+Abiraterone:
3y OS 66%
ADT+placebos: 3y OS 49%
ADT+Abiraterone
mrPFS: 33 m
ADT+placebos:
mrPFS 18,4 m
James ND et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. NEJM 2017 Jun 3
Hormone therapy - Abiraterone - STAMPEDE
AIOM Giovani 2017 Davide Bimbatti
Relapsing after previous RP or RT with ≥1 of:
• PSA ≥4ng/ml and rising with doubling time <6m
• PSA ≥20ng/ml
• Node-positive
• Metastatic
Newly-diagnosed
Any of:
• Metastatic
• Node-Positive
• ≥2 of: Stage T3/4 PSA≥40ng/ml Gleason 8-10
Primary Outcome
• Overall Survival
Hormone therapy - Abiraterone - STAMPEDE
AIOM Giovani 2017 Davide Bimbatti
Events 262 Control | 184 abiraterone plus prednisone
HR 0.63 95% CI 0.52 to 0.76 P-value 0.00000115
SOC: 3y OS 76%
SOC+AAP: 3y OS 83%
James ND et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. NEJM 2017 Jun 3
AIOM Giovani 2017 Davide Bimbatti
Summary - Results
CHAARTED STAMPEDE
DOC GETUG 15 LATITUDE
STAMPEDE ABI
mFU (months) 28,9 43 50 30,4 40
mOS (months) (HR)
57,6 vs 44 (0,61)
81 vs 71 (0,78)
58,9 vs 54,2 (1,01)
NR vs 34,7 ND
3y OS (%) ̴70 vs 55 ̴77 vs 73 64,2 vs 62,9 66 vs 49
(0,62) 83 vs 76
(0,63)
mFFS or mrPFS (months)
ND 37 vs 20 ND 33 vs 14,8 43,9 vs 30
3y FFS (%) ND ̴52 vs 39 ND ND 75 vs 45
AIOM Giovani 2017 Davide Bimbatti
Summary - Patients characteristics
CHAARTED STAMPEDE
DOC GETUG 15 LATITUDE
STAMPEDE ABI
N+ o M+ (%) 100 75 100 100 70
M1 at diagnosis (%)
100 58 70 100 50
High volume bone mets*
(%)
66 NA NA 98 NA
Visceral disease (%)
15 ̴7 14 ̴14 <12
Gleason score 8-10 (%)
60 70 57 98 75
*CHAARTED: ≥4 with ≥1 beyond vertebral bodies and pelvis; LATITUDE: ≥3 lesions.
AIOM Giovani 2017 Davide Bimbatti
Next-generation androgen receptor (AR) antagonist - APALUTAMIDE
TITAN: STUDY DESIGN
Study population:
(estimated 1000 pts)
• Diagnosis of prostate adenocarcinoma.
• Metastatic disease documented by >= 1
bone lesions.
• ECOG PS grade of 0 or 1
• Permitted previous docetaxel treatment:
maximum of 6 cycles, last dose <=2
months, stable disease or better
• Other allowed prior treatment for
mHSPC: a) Maximum of 1 course of
radiation or surgical intervention;
radiation therapy for metastatic lesions
must be completed prior to
randomization; b) Less than or equal to
(<=) 6 months of ADT
• Allowed prior treatments for localized
prostate
Primary Outcome
• Radiographic Progression-Free Survival
• Overall Survival
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1:1
Apalutamide plus
ADT
Placebo plus ADT
A Phase 3 Randomized, Placebo-controlled, Double-blind Study of Apalutamide Plus Androgen Deprivation Therapy
(ADT) Versus ADT in Subjects With Metastatic Hormone-sensitive Prostate Cancer (mHSPC).
ClinicalTrials.gov. NCT02489318
AIOM Giovani 2017 Davide Bimbatti
Next-generation androgen receptor (AR) antagonist - DAROLUTAMIDE
ARASENS: STUDY DESIGN
Study population:
(estimated 1300 pts)
• Histologically or cytologically confirmed
adenocarcinoma of prostate.
• Metastatic disease
• Candidates for ADT and docetaxel.
Started ADT with or without first
generation anti androgen, but no longer
than 12 weeks before randomization
• An Eastern Cooperative Oncology Group
(ECOG) performance status of 0 or 1
• Adequate bone marrow, liver and renal
function
Primary Outcome
• Overall Survival
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1:1
BAY1841788
/darolutamide
(ODM-
201)+standard
ADT+Docetaxel
Placebo +
standard ADT +
Docetaxel
A Randomized, Double-blind, Placebo Controlled Phase III Study of ODM-201 Versus Placebo in Addition to Standard
Androgen Deprivation Therapy and Docetaxel in Patients With Metastatic Hormone Sensitive Prostate Cancer.
ClinicalTrials.gov. NCT02799602
AIOM Giovani 2017 Davide Bimbatti
Patient choice
Paziente 1 Paziente 2
Età 60 80
Provenienza Verona Provincia di VR
Lavoro Impiegato Contadino
PSA screening Saltuario Mai
Clinica Dolore lombare recente Dolori lombari da tempo
Sedi di malattia 4 lesioni ossee (3+1) 4 lesioni ossee (3+1)
Gleason Score 4+5 4+4
Valore di PSA 17 8
Patient choice
AIOM Giovani 2017 Davide Bimbatti
Presented By Alberto Briganti at 2017 ASCO Annual Meeting
Patient choice
AIOM Giovani 2017 Davide Bimbatti
Presented By Karim Fizazi at 2017 ASCO Annual Meeting
AIOM Giovani 2017 Davide Bimbatti
Future challenges
Stratify patients in the best and homogeneous way:
o researching new clinical or biomolecular prognostic factors
o to standardize selection criteria for the clinical trial in order to have
similar populations
Give the right therapy to the right patient:
o Avoiding over treating patients with indolent disease
Use the known therapy as best as possible:
o to do head-to-head trials
o then evaluate possible combinations
o and check the best sequences
Understand the role of locoregional treatments on primitive tumor
Check the effectiveness and the best sequence of treatments already
known to progression from the mHSPC setting
Grazie per l’attenzione!