ESMO SUMMIT LATIN AMERICA 2019 Prostate cancer Clinical cases - - PowerPoint PPT Presentation

ESMO SUMMIT LATIN AMERICA 2019

Prostate 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:
• No relevant family history.
• Past Medical History:
• Tobacco use → 12 pack-years. Discontinued 2 years ago.
• 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 lung mass 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

CHAARTED

Patients with hormone-sensitive metastatic prostate cancer

397 ADT + Docetaxel 75mg/m2 3w 393 ADT N = 790

ADT + 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

CHAARTED

High 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

LATITUDE

Patients 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 0.39 p<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

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

Docetaxel 1st cycle Docetaxel 6th cycle

Initial response ADT + docetaxel

Post Chemotherapy Pre Chemotherapy

Post Chemotherapy

Initial response ADT + docetaxel

Pre Chemotherapy

INITIAL RESPONSE ADT + DOCETAXEL

Post Chemotherapy Pre 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 1 2 3 4 5 6 7 8 Apr-17 May-17 Jun-17 Jul-17 Aug-17 Sep-17 Oct-17 Nov-17 Dec-17 Jan-18 Feb-18 Mar-18 Apr-18 May-18 Jun-18

 What is the best treatment option for this patient?

QUESTION 2

DRUGS APPROVED FOR CRPC

OPTIONS IN CRPC SETTING

Drug PSA response >50% Overall survival 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 0.79 Enzalutamide (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

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:
• No relevant family history
• Past Medical History:
• 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 adenopathies Enlarged prostate Anterior rectal invasion

99TC-MDP BONE SCAN

HISTORY OF PRESENT ILLNESS 10/2016 02/2017

1st line hormone-sensitive disease 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 47 33 30 25 19 21 20 40 60 80 100 120 140 160 12/08/2016 12/09/2016 12/10/2016 12/11/2016 12/12/2016 12/01/2017

PSA level

PSA level

1st cycle Docetaxel Cycle 6 Docetaxel Leuprolide + Bicalutamide

After 6 cycles of Docetaxel 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/mL

21 62 28 67 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 5 docetaxel

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 mCNPC 1. bPFS 2. Maximum decline of PSA 3. OS N=245 (71%) 134 ADT alone 111 ADT + docetaxel First or second line treatment for mCRPC N=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 progression after upfront ADT + D & PSA response on rechallenge

Eur Urol. 2018 May;73(5):696-703

PFS

Biochemical

6 m 4.1 m 1st or 2nd line 3.4 m

DOCETAXEL RECHALLENGE

Local evidence (México)

% change in PSA levels after docetaxel rechallenge Disease free survival (%)

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/CT Expression 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

Biochemical response

PSA RESPONSE WITH 177LU-PSMA 617

67 20.39 0.45 0.49 0.1 0.1 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 STUDY

177LU-PSMA-617

J Nucl Med. 2017 Jan;58(1):85-90

Retrospective 2014-2015 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-617

Australian pase 2 trial

Lancet Oncol 2018 Jun;19(6):825-833

177LU-PSMA-617

Results

47%  4 cycles 80% 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:
• 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 persistence 0.4 ng/ml Adjuvant radiotherapy 0.01 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 2.1 1.7 3.2 5.7 4.1 3.9 5.6 7.3 1 2 3 4 5 6 7 8 PSA Testosterone

Hormonal blockade PSA DT 3.4 months Double blockade CRPC

Imaging evaluation NED

PSA DT 4.5 months

CRPC M0 disease

09/2018 02/2019

7.3 9.5 11.4 13.9 0.2 0.18 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 evaluation NED Imaging studies

PSA DT 7.3 months

BIOCHEMICAL RECURRENCE

October 2017 January 2019

Enlarged prostate

CRPC M0 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 patients

Follow up: 20.3 m

SPARTAN

NON METASTATIC CRPC

1207 patients 806 apalutamide 240mg/d 401 patients placebo 40.5 m 16.2 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

STUDY Drug Control arm N Follow up mPFS HR Absolute benefit Presentation Costs SPARTAN Apalutamide Placebo 1207 px 20.3 m 40.5 m HR 0.28 24.3 m 120 tabs 60mg 12,196 USD PROSPER Enzalutamide Placebo 1401 px 18.5m 36.6 m HR 0.29 21.9 m 120 tabs 40mg 12,065 USD ARAMIS Doralutamide Placebo 1509 px 17.9 m 40.4 m HR 0.41 22 m 120 tabs 300mg >12,150 USD

N Engl J Med 2018; 378:1408-1418 N 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 seizures were excluded

N Engl J Med 2018; 378:1408-1418 N Engl J Med 2018; 378:2465-2474

• Would you consider this strategy cost effectiveness

for 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!