ESMO SUMMIT LATIN AMERICA 2019 · abiraterona + prednisone 602 ADT + placebo N = 1199 Follow-up...

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!