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


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



Hussain M et al. Intermittent versus Continuous Androgen Deprivation in Prostate Cancer. NEJM 2013;368(14):1314-1325.

Standard initial treatment options - Intermittent


Standard initial treatment options - Intermittent

Hussain M et al. Intermittent versus Continuous Androgen Deprivation in Prostate Cancer. NEJM 2013;368(14):1314-1325.


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


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.

R

A

N

D

O

M

I

S

E

D

1:1

ADT+Docetaxel

ADT

Primary Outcome

• Overall Survival

High volume: • presence of visceral metastases or • ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis




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


Primary Outcome


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


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


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

R

A

N

D

O

M

I

S

E

D

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


Chemotherapy - Docetaxel - GETUG-15


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


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.

R

A

N

D

O

M

I

S

E

D

1:1

ADT+Abiraterone

+prednisone

ADT+placebos

Primary Outcomes


• 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


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


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


Hormone therapy - Abiraterone - STAMPEDE


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


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


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.


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


R

A

N

D

O

M

I

S

E

D

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


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


R

A

N

D

O

M

I

S

E

D

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


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


Presented By Alberto Briganti at 2017 ASCO Annual Meeting

Patient choice


Presented By Karim Fizazi at 2017 ASCO Annual Meeting


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!

Opzioni terapeutiche nel carcinoma prostatico metastatico...

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