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ESMO SUMMIT LATIN AMERICA 2019Prostate cancer
Clinical cases discussion
LUIS ANTONIO LARA MEJÍA MD
Medical Oncology Fellow
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México
CHAIR: MARIA TERESA BOURLON DE LOS RIOS MD MS
CLINICAL CASE 1
CASE PRESENTATION
A 58-year-old male, lawyer, married, born and living in Mexico City.
• Family History:
o No relevant family history.
• Past Medical History:
o Tobacco use → 12 pack-years. Discontinued 2 years ago.o Hypertension (2015) → well-controlled, treated with enalapril 5
mg BID.
HISTORY OF PRESENT ILLNESS
06/2011 11/2011
Lower urinary tract symptoms Dysuria and suprapubic pain
Physical exam
• DRE: enlarged prostate gland.
Lab tests
• PSA: 9 ng/mL
Transrectal biopsy • Prostate biopsy: benign prostatic
hyperplasia
Procedures
• TURP: benign prostatic hyperplasia.
Lab tests
• PSA: 15 ng/mL
HISTORY OF PRESENT ILLNESS
05/2016
Cough, exertional dyspnea, unintentional weight loss
(15 kg in 5 months).
Physical exam
• Bilateral pleural effusion.• Left supraclavicular lymph node.
Chest CT scan
• Bilateral pleural effusion, right lung mass.
Thoracentesis
• Exudative pleural effusion. • No malignant cells in cytology
Laboratory tests
• Hb 10 Leu 3 Neu 66% Plt 222• Cr 0.9 BUN 14• TB 0.5 ALT 7 AST 22 ALP 209• TP 6 Alb 3.8• PSA: 909 ng/mL
Left supraclavicular
lymph node
Right lungmass
Bilateral pleural effusion
Retroperitoneal LAD
Left iliac LAD
Post-TURP changes
Sclerotic bone lesions
99TC-MDP BONE SCAN
RADIOLOGY
Chest, abdomen and pelvis CT scan
• Heterogeneous prostate (post-TUPR)• Inferior vena cava compression• Pelvic, retroperitoneal and left supraclavicular LAD• Bilateral pleural effusion• Right lung mass
99Tc-MDP bone scan
• Multiple axial and peripheral bone metastases
PATHOLOGY
Left supraclavicular LN excisional biopsy
• Undifferentiated metastatic acinar adenocarcinoma.
Lung mass percutaneous biopsy
• Metastatic prostate adenocarcinoma (PSA+, prostatic ALP+)
What would be your approach in the treatment of this patient?
QUESTION 1
At presentation• Multidisciplinary approach• Early chemotherapy or highly effective antiandrogen therapy at
diagnosis
CHAARTEDPatients with hormone-sensitive metastatic prostate cancer
397
ADT + Docetaxel
75mg/m2 3w
393
ADT
N = 790ADT + docetaxel 57.6 months
HR 0.61 (95% CI 0.47-0.80)
ADT alone
44 months
p < 0.001
Subgroup analysis
- High-volume vs low-volume disease
N Engl J Med. 2015 Aug 20;373(8):737-46
CHAARTEDHigh volumen disease
ADT + docetaxel 49.2 months
HR 0.60 (95% CI 0.45-0.81)
p < 0.001
ADT alone
32.2 months
N Engl J Med. 2015 Aug 20;373(8):737-46
CHAARTED + STAMPEDE + GETUG-AFU15
OS 4 years; absolute benefit 9% (40 to 49%)
Lancet Oncol. 2016 17(2):243-56
23% reduction in the risk of death
LATITUDEPatients with hormone-sensitive metastatic prostate cancer
597
ADT +
abiraterona +
prednisone
602
ADT +
placebo
N = 1199
Follow-up
30.4 months
High-risk features
- Gleason score ≥ 8
- Three or more bone lesions
- Visceral disease
OS: 34.7 months vs NR
N Engl J Med. 2017 Jul 27;377(4):352-360
ARCHES Patients with hormone-sensitive metastatic prostate cancer
574 ADT +
enzalutamide
160mg/d
576
ADT +
Placebo
N = 1150
Follow up: 14.4 m
PE: rPFS
67% distant metastases,
63% High-volume disease
66% GSC >8
18% prior docetaxel
J Clin Oncol 37, 2019 (suppl 7S; abstr 687)
ENDPOINT ENZ + ADT PBO + ADT HR
rPFS NR 19.4 m 0.39p<0.0001
PSA undetectable
68.1% 17.6%
ORR 83.1% 63.7%
Do you have any preference in choosing abiraterone or enzalutamide vs docetaxel as first-line treatment for hormone-sensitive disease?
QUESTION 2
The patient started treatment with:
- Leuprolide 22.5 mg SC every three months + bicalutamide 50 mg every day for four weeks.
- Docetaxel 75 mg/m2 every 21 days for 6 cycles.
MANAGEMENT
PSA RESPONSE
0
100
200
300
400
500
600
700
800
900
1000
26-may-16 29-may-16 19-jun-16 02-jul-16 02-sep-16 23-sep-16 15-oct-16 05-nov-16 26-nov-16 11-feb-17 21-Apr-17
PSA level
Leuprolide+
bicalutamide
Docetaxel1st cycle
Docetaxel6th cycle
Initial response ADT + docetaxel
Post ChemotherapyPre Chemotherapy
Post Chemotherapy
Initial response ADT + docetaxel
Pre Chemotherapy
INITIAL RESPONSE ADT + DOCETAXEL
Post ChemotherapyPre Chemotherapy
PSA course
Adequate response
Radiographic partial response (RECIST 1.1)
ECOG 1 Tolerable ADT-related side effects.
Grade 1 fatigue, grade 1 nausea.
TREATMENT RESPONSE AND ADVERSE EVENTS
HISTORY OF PRESENT ILLNESS
06/2018 06/2018
Asymptomatic, ECOG 0 CRPC
Lab tests• PSA: 4.66 → 6.86 ng/mL• Serum testosterone: 0.14 ng/dL
Imaging• CT scan: stable visceral disease,
new bone lesions• Bone scan: new axial and
appendicular bone lesions
1.39 1.43
1.42 1.5
1.8
4.66
6.86
012345
678
Apr-1
7Ma
y-17
Jun-
17Ju
l-17
Aug-
17Se
p-17
Oct-1
7No
v-17
Dec-1
7Ja
n-18
Feb-
18Ma
r-18
Apr-1
8Ma
y-18
Jun-
18
What is the best treatment option for this patient?
QUESTION 2
DRUGS APPROVED FOR CRPC
OPTIONS IN CRPC SETTING
DrugPSA response
>50%Overallsurvival
HR
Docetaxel 45% 2.4m 0.76 Visceral disease, significant pain.
Cabazitaxel 39% 2.4m 0.70 Previous chemotherapy, neutropenia
Sipuleucel T <5% 4.1m 0.78 Low tumour burden, high cost.
Abiraterone(postQT) 38% 4.6m 0.74 Few symptoms, prednisone use, hypertension,
hypocalemia.Abiraterone (preQT) 62% 5.2m 0.79Enzalutamide(postQT) 54% 4.8m 0.63
Visceral disease, no prednisone, seizures <1%.Enzalutamide(preQT) 78% 2.2m 0.71
Radium-223 --- 2.8m 0.70 Only bone disease.
The patient continued ADT therapy with leuprolide and started with:
- Enzalutamide 160 mg/daily.
- Zoledronic acid 4 mg every 3 months.
MANAGEMENT
PSA RESPONSE - CRPC
Enzalutamide started
Enzalutamide PFS 6 months
0
1
2
3
4
5
6
7
8
PSA level
PSA level
Radiographic stable disease
(RECIST 1.1)
ECOG 1
Tolerable ADT-related side effects
Grade 1 fatigue
PFS 6 months Clinical benefit
PATIENT FOLLOW UP
CLINICAL CASE 2
A 77-year-old Mexican male, married, born and living in Mexico City.
• Family History:
o No relevant family history
• Past Medical History:
o No past medical history
CASE PRESENTATON
HISTORY OF PRESENT ILLNESS
08/2016 10/2016
Lower urinary tract symptoms & weight los (7kgs)
Physical exam
• DRE: enlarged prostate gland.
Lab tests
• PSA: 121 ng/mL
Transrectal biopsy • Acinar adenocarcinoma, Gleason
5+5, with extraprostatic extension
Imaging studies
Radiological images• CT scan: abdominal
retroperitoneal lymphadenopathy• Bone scan: left iliac bone lesion
Up-front metastatic
disease
Up front metastatic disease
Pelvic adenopathiesEnlarged prostateAnterior rectal invasion
99TC-MDP BONE SCAN
HISTORY OF PRESENT ILLNESS
10/2016 02/2017
1st line hormone-sensitivedisease 6 cycles docetaxel 75mg 3W
PSA response • 25 ng/ml
• PSA 142 ng/ml• Leuprolide 7.5mg/month +
bicalutmide• Docetaxel for 6 cycles
Biochemical response
142
4733 30 25 19 21
020406080
100120140160
12/08/2016 12/09/2016 12/10/2016 12/11/2016 12/12/2016 12/01/2017
PSA level
PSA level
1st cycleDocetaxel
Cycle 6Docetaxel
Leuprolide +Bicalutamide
After 6 cycles ofDocetaxel
Partial response• Nodal disease
HISTORY OF PRESENT ILLNESS
02/2018
Biochemical progression• PSA: 62 ng/mL• Testosterone 0.1• CT scan: stable disease• Bone scan: stable disease
04/2018
CRPC
Docetaxel rechallenge (no access to other therapies)
• Docetaxel 3 cycles: • PSA clinical response
• Docetaxel: 5th docetaxel cycle Lower back pain & fatigue clinical & biochemical progression • PSA: 67 ng/mL21
62
28
67
0
20
40
60
80
01/01/2018 01/02/2018 01/03/2018 01/04/2018
PSA level
PSA level Testosterone
Cycle 3
Docetaxel rechallenge
Cycle 5docetaxel
Unilateral hydronephrosis
Progression of nodal disease
What is your experience with docetaxel rechallenge in castration resistance disease?
QUESTION 1
DOCETAXEL RECHALLENGE GETUF- AFU15 Retrospective analysis
Rechallenge after ADT + D in mCNPC1. bPFS2. Maximum decline of PSA3. OS
N=245 (71%)
134 ADT alone 111 ADT + docetaxel
First or second line treatment for mCRPCN=42
1st line ADT ADT + D
Docetaxel 38% 20%
Bicalutamide 43% 17%
ABI or ENZ 84.2% 53%
14%
45%
No correlation between time to progressionafter upfront ADT + D & PSA response on rechallenge
Eur Urol. 2018 May;73(5):696-703
PFSBiochemical
6 m
4.1 m
1st or 2nd line3.4 m
DOCETAXEL RECHALLENGE Local evidence (México)
% change in PSA levels after docetaxelrechallenge
Dis
ease
free
sur
viva
l(%
)
PFSm 31.8 sem(95%IC 16.6-42.4)
Weeks
Retrospective analysis (2015-2017)
N = 8
Docetaxel + ADT CRPC
1st line Docetaxel
rechallenge
Median of cycles: 5.8
Gonzalez et al (2018) INCMNSZ
25%
ASSESSMENT FOR OTHER THERAPIES
08/2018 08/2018
Ga68 PSMA PET/CTExpression of PSMA disease
• Node & bone disease • Disease progression
Imaging studies
Ga68 PSMAPET/CT
Positive PSMA expression
Positive PSMA expression
HISTORY OF PRESENT ILLNESS
09/2018 01/2019
2nd line in CRPC
• 177Lu-PSMA 617 for 3 cycles• Every ≈ 8weeks.• Previous clinical assessment.
Imaging studies
Evaluation of response
Biochemicalresponse
PSA RESPONSE WITH 177LU-PSMA 617
67
20.39
0.45 0.490.1 0.10
10
20
30
40
50
60
70
80
Sep-18 Oct-18 Nov-18 Dec-18 Jan-19 Feb-19
PSA level
PSA Testosterone
1rst Lu-PSMA
2nd Lu-PSMA
3rd Lu-PSMA
Response after 177Lu-PSMA 617
Pre 177Lu-PSMA 617 Post 177Lu-PSMA 617
- Response of bone lesions
Response after 177Lu-PSMA 617
Pre 177Lu-PSMA 617 Post 177Lu-PSMA 617
- Response of nodal disease
Response after 177Lu-PSMA 617
Pre 177Lu-PSMA 617 Post 177Lu-PSMA 617
- Response of nodal disease & bone lesions
Response after 177Lu-PSMA 617
Pre 177Lu-PSMA 617 Post 177Lu-PSMA 617
- Response of nodal disease & bone lesions
Response after 177Lu-PSMA 617
Pre 177Lu-PSMA 617 Post 177Lu-PSMA 617
- Response of bone lesions
What is the evidence to support Lu-PSMA 617 in the treatment of CRPC?
QUESTION 2
GERMAN STUDY177LU-PSMA-617
J Nucl Med. 2017 Jan;58(1):85-90
Retrospective2014-2015
N = 145
1-4 Cycles (8-12wk appart)2-8 GBq
Inclusion Criteria:-Progressive mCRPC (HEAT/chemotherapy)-PSMA expression of most lesions-”Adequate” bone marrow and renal function
20-30% Concommitant HEAT
PSA response 45%
Any PSA decline 60%
Odds Ratio for Biochemical Response:
Lower response:Presence of visceral metastases: OR 0.26 P=0.01.Alkaline phosphatase ≥220 U/L, OR 0.21 P=0.01.
Higher response:Higher number of therapy cycles (≥3), OR 5.83 P=0.02.
N = 43
Follow up: 25 months
Characteristics % patients
Age 71 y
PSA / PSA DT 189 / 2.4 months
Previous lines of CT 1L 40% / 2L 40%
Previous treatments Abiraterone 83%Docetaxel 80%
Cabazitaxel 47%Bifosfonates 73%
>20 mets 93%
Baseline characteristics
PSA decline >50%• 57%PSA decline >30%• 70%
177LU-PSMA-617Australian pase 2 trial
Lancet Oncol 2018 Jun;19(6):825-833
177LU-PSMA-617Results
47% 4 cycles80% 3 cycles
Endpoints % patients
ORR 82% (nodal & visceral)
CR 29%
PR 53%
SD 0%
DP 12%
Lancet Oncol 2018 Jun;19(6):825-833
Adverse Events Grade 1-4 / G3-4
Dry mouth 87%
Lymphocitopenia 40% / 37%
Thrombocytopenia 40% / 13%
Fatigue 53%
Would you consider it now a standard of care? Based on a phase 2 trial
What are your expectations about the phase 3 trial Vision study?
QUESTION 3
CLINICAL CASE 3
A 66-year-old Peruvian male, lawyer, married, living in Mexico City.
• Family History:
o No relevant family history.
• Past Medical History:
O No past medical history
CASE PRESENTATON
HISTORY OF PRERSENT ILLNESS
05/2013 06/2013
Dysuria & hematuria
Physical exam
• DRE: enlarged prostate gland.
Lab tests
• PSA: 19 ng/mL
Imaging studies• CT scan: enlarged prostate (72.3
cc) and a lesion with peripheral reinforcement
• Bone scan: no disease
Radical prostatectomy• Prostate acinar adenocarcinoma,
Gleason 4+5= 9, seminal vesicle invasion, LVI (+), PNI (+), surgical margins (-). PSA 0.40 ng/ml
Transrectal biopsy• Acinar adenocarcinoma, Gleason
5+5=10.
High risk prostate cancer
HISTORY OF PRERSENT ILLNESS
PSA persistence0.4 ng/ml
Adjuvantradiotherapy0.01 ng/ml
Surveillance
DFS 3.9 years
PSA RESPONSE WITH ADT
07/2017 10/2017
Asymptomatic
Biochemical recurrence• Started on leuprolide 22.5mg
three-monthly
Combine androgen blockade• Started on bicalutamide 50mg/d
0.01
1.12
2.3
3.4
5.2
3.2
2.11.7
3.2
5.7
4.1 3.9
5.6
7.3
0
1
2
3
4
5
6
7
8
PSA Testosterone
Hormonalblockade
PSA DT3.4 months
Doubleblockade
CRPC
Imaging evaluationNED
PSA DT4.5 months
CRPC M0 disease
09/2018 02/2019
7.3
9.5
11.4
13.9
0.2 0.180
2
4
6
8
10
12
14
16
Aug-18 Sep-18 Oct-18 Nov-18 Dec-18 Jan-19 Feb-19
PSA level
PSA Testosterone
Asymptomatic
Imaging evaluationNED
Imaging studies
PSA DT7.3 months
BIOCHEMICAL RECURRENCEOctober 2017 January 2019
Enlarged prostate
CRPCM0 disease
Given the patient history and social background,what would be your strategy to treat this patient?
QUESTION 1
1. Apalutamide (Spartan) 2. Enzalutamide (Prosper)3. Darolutamide (Aramis)
4. Surveillance
PSA response: 89.7 vs 2.2%
High risk patientsFollow up: 20.3 m
SPARTAN NON METASTATIC CRPC
1207 patients
806 apalutamide240mg/d
401 patientsplacebo
40.5 m16.2 m
• PSA doubling time < 10m• Continuous ADT• N0 (83.5%), N1 (16.5%)
PO: Metastasis-free survival
24.3m
N Engl J Med 2018; 378:1408-1418
SUMMARY CRPC M0 disease
STUDYDrug
Control arm
NFollow up
mPFSHR
Absolute benefit
Presentation Costs
SPARTANApalutamide
Placebo 1207 px20.3 m
40.5 mHR 0.28
24.3 m 120 tabs60mg
12,196 USD
PROSPER Enzalutamide
Placebo 1401 px18.5m
36.6 mHR 0.29
21.9 m 120 tabs40mg
12,065USD
ARAMIS Doralutamide
Placebo 1509 px17.9 m
40.4 mHR 0.41
22 m 120 tabs300mg
>12,150USD
N Engl J Med 2018; 378:1408-1418N Engl J Med 2018; 378:2465-2474
• Do you have a preference for any of the NAAD (novel androgen axis drugs) in this scenario?
QUESTION 2
ADVERSE EVENTS
AE´s SPARTAN PROSPER ARAMIS
Any AE 96.5% 87% 83.2%Grade 3 or 4 45.1% 31% 24.7%
Fatigue 30.4% 33% 12.1%Rash 23.8% 13% 2.9%
Fracture 11.7% 17% 4.2%Dizziness 9.3% 10% 4.5%
Mental-impairment disorder 5.1% 5% 0.9%Seizure 0.2% <1% 0.2%
History of seizureswere excluded
N Engl J Med 2018; 378:1408-1418N Engl J Med 2018; 378:2465-2474
• Would you consider this strategy cost effectivenessfor Latin American countries?
QUESTION 3
Xtandi costs$73,299 MXN pesos / monthly
$ 38,444 USD / monthly
Treatment costs for 40 months$ 2,931,960 pesos
$ 153,802 USD
Thank you!