Trattamento del paziente Resistente alla Castrazione (CRPC)€¦ · See CRPC M0 See CRPC M1 M1 Low...

I TUMORI DELLA PROSTATA

Gaetano Facchini

SSD di Oncologia Clinica Sperimentale di Uro-Andrologia

Istituto Nazionale Tumori Fondazione “G. Pascale” – IRCCS

Napoli

Trattamento del paziente Resistente alla Castrazione

(CRPC)

Facchini G

Advanced Prostate Cancer

HSPC

M0 Orchiectomy

LH-RH agonist ± AA LR-RH antagonist

See CRPC M0

See CRPC M1

M1

Low Volume

Continuous ADT See CRPC M1

High Volume

Continuous ADT + Docetaxel x 6 cycles ?

High Risk Continuous ADT +

Abiraterone ?

CRPC

M0 Clinical Trial

Observation (PSADT>10 m) Apalutamide + ADT (PSADT<10 m)

M1

Asymptomatic Mildly symptomatic

Abiraterone Enzalutamide

Docetaxel

Docetaxel Enzalutamide Abiraterone

Symptomatic Docetaxel

Radium 223

Abiraterone Enzalutamide Cabazitaxel Radium 223

Facchini G


HSPC

M0 Orchiectomy


See CRPC M0

See CRPC M1

M1

Low Volume


High Volume



Abiraterone ?

CRPC

M0 Clinical Trial


M1



Docetaxel



Radium 223


SPARTAN

PROSPER

ARAMIS

Facchini G


HSPC

M0 Orchiectomy


See CRPC M0

See CRPC M1

M1

Low Volume


High Volume



Abiraterone ?

CRPC

M0 bservation (PSADT>10 m)

Apalutamide + ADT (PSADT<10 m) Darolutamide + ADT (PSADT<10 m) Enzalutamide + ADT (PSADT <10 m)

M1



Docetaxel



Radium 223


Observation (PSADT>10 m) Apalutamide + ADT (PSADT<10 m) Darolutamide + ADT (PSADT<10 m) Enzalutamide + ADT (PSADT <10 m)

Facchini G


HSPC

M0 Orchiectomy


See CRPC M0

See CRPC M1

M1

Low Volume


High Volume



Abiraterone ?

CRPC

M0 bservation (PSADT>10 m)

Apalutamide + ADT (PSADT<10 m) Enzalutamide + ADT (PSADT <10 m)

M1



Docetaxel



Radium 223



Facchini G


HSPC

M0 Orchiectomy


See CRPC M0

See CRPC M1

M1

Low Volume


High Volume



Abiraterone ?

CRPC

M0 Observation (PSADT>10 m)


M1



Docetaxel



Radium 223



Facchini G


HSPC

M0 Orchiectomy


See CRPC M0

See CRPC M1

M1

Low Volume


High Volume



Abiraterone ?

CRPC



M1



Docetaxel


Docetaxel Radium 223


COU-AA-302 ABIRATERONE

PREVAIL ENZALUTAMIDE


Rathkopf DE et al. Eur Urol 2014; [Epub ]

Ryan C et al. ESMO 2014; Abstract 7530 (oral presentation)

mCRPC I Line Therapy

COU-AA-302

ABIRATERONE

Beer TM, et al. ASCO-GU 2014; Oral presentation; ClinicalTrials.gov identifier: NCT01212991.

ADT=androgen-deprivation therapy; mCRPC=metastatic castration-resistant prostate cancer; OS=overall survival; rPFS=radiographic progression-free survival.

PREVAIL Phase III Study

mCRPC I Line Therapy

ENZALUTAMIDE

Facchini G


HSPC

M0 Orchiectomy


See CRPC M0

See CRPC M1

M1

Low Volume


High Volume



Abiraterone ?

CRPC



M1


Abiraterone Enzalutamide (Docetaxel)



Radium 223



Ongoing trial

Key Eligibility:

• 1L mCRPC

• All-comer

• “NHA naïve”

• “Taxane naïve”

• ECOG 0-1

PROpel Study

Primary: • rPFS (investigator primary, BICR sensitivity)

Key Secondary (alpha spend): • Time to first subsequent therapy or death (TFST)

• Time to pain progression (TTPP)

• OS

Other Secondary: • TT opiate, SSRE, CTC response, HRQOL, PFS2

olaparib + abiraterone

n = 360

placebo + abiraterone

n = 360

1:1 (Blinded) N = 720

Stratification factors: • Metastases: Bone only vs Visceral vs Other

• Prior Taxane at mHSPC: Yes vs No

DCO = data cut-off, BICR = Blinded Independent Central Review

Stat assumptions

• rPFS: Target HR = 0.68, median 24.3 vs 16.5m (△7.8 mo)

– DCO-1; 324 events,~31m = 89% power

– DCO-2; 397 events,~39m = 97% power

• OS: Target HR = 0.8, median 36 vs 45m (△9 mo)

– Interim (DCO-2; 272 events) = 22% power (or 35% if TFST and TTpain stat sig)

– Final (DCO-3; 334 events) = 38% power (or 52% if TFST and TTpain stat sig)

Ongoing trial

Study Design

Primary endpoint:

• rPFS

Secondary endpoints:

• OS

• Time to chronic opioid use

• Time to pain progression

• Time to cytotoxic chemotherapy

Nira +

AA-P

Placebo +

AA-P

R

A

N

D

O

M

I

Z

A

T

I

O

N

• Biomarker

Positive

• L1 mCRPC

Cohort 1 (with DRD)

N=400 1:1

Placebo + AA-P

Nira + AA-P

R A N D O M I Z A T I O N

• Biomarker Negative

• L1 mCRPC

Cohort 2 (without DRD)

N=600

1:1

STUDY 64091742PCR3001 MAGNITUDE

Ongoing trial

Facchini G


HSPC

M0 Orchiectomy


See CRPC M0

See CRPC M1

M1

Low Volume


High Volume



Abiraterone ?

CRPC



M1





Radium 223


TAX 327 DOCETAXEL

SWOG 9916 DOCETAXEL

ALSYMPCA RADIUM 223


Docetaxel: STANDARD OF CARE 1° linea chemioterapica

TAX 327 study Tannock et al. N Eng J Med 2004;351:1502-1512

SWOG study Petrylak et al. N Eng J Med 2004;351:1513-1520

Study diagram Study of Pembrolizumab Plus Docetaxel vs Placebo Plus Docetaxel in Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer

KEYNOTE-921 Ongoing trial

HR 0,695; IC 95% 0,552-0,875

P=0,00285

Placebo, n=268

OS mediana: 11,2 mesi

OS

Mesi

% s

en

za

SR

E

HR 0,610; IC 95% 0,461-0,807

P=0,00046

Cloruro di Radio-223, n=541

Mediana: 13,5 mesi

Placebo, n=268

Mediana: 8,4 mesi

Cloruro di Radio-223, n=541

OS mediana: 14 mesi

1° SRE

ALSYMPCA: Phase III trial

ERA 223 (NCT02043678)

Post-Hoc Subgroup Analysis of Fractures by

Baseline BHA Use

Patients with

≥1 fracture (%)

29

15

37

11

7

15 15

10

5

0

Overall population

20

25

30

40

35

Patients with BHAs at baseline Patients without BHAs at baseline

AAP + placebo

AAP + radium-223

AAP, abiraterone acetate and prednisone/prednisolone; BHA, bone health agent; NE, not estimable.

COME E’ CAMBIATA L’INDICAZIONE

Vecchia Indicazione Nuova Indicazione (dal 13 luglio 2018)

Xofigo indicato per il trattamento di pazienti adulti con tumore della prostata resistente alla castrazione, con metastasi ossee sintomatiche e senza metastasi viscerali note.

Xofigo in monoterapia o in combinazione con analogo LHRH è indicato per il trattamento di pazienti adulti con tumore della prostata resistente alla castrazione metastatico (mCRPC), con metastasi ossee sintomatiche e senza metastasi viscerali note, in progressione dopo almeno due precedenti linee di terapia sistemica per mCRPC (oltre ad analogo LHRH), o ineleggibili per qualsiasi altro trattamento sistemico disponibile nel mCRPC.


HSPC

M0 Orchiectomy


See CRPC M0

See CRPC M1

M1

Low Volume


High Volume



Abiraterone ?

CRPC

M0 Clinical Trial


M1



Docetaxel Enzalutamide Abiraterone (Cabazitaxel)




AFFIRM ENZALUTAMIDE


HSPC

M0 Orchiectomy


See CRPC M0

See CRPC M1

M1

Low Volume


High Volume



Abiraterone ?

CRPC

M0 Clinical Trial


M1






TROPIC CABAZITAXEL


AFFIRM ENZALUTAMIDE

mCRPC II line therapy

PFS

OS

CABAZITAXEL


Primary endpoint: OS

COU-AA-301 Phase III study

ABIRATERONE

Fizazi, Lancet Oncology 2012


ENZALUTAMIDE

OS + 4.8 Mesi

AFFIRM

Facchini G.


HSPC

M0 Orchiectomy ADT

See CRPC M0

See CRPC M1

M1

Low Volume

Continuous ADT ABIRATERONE (se High Risk)

See CRPC M1

High Volume

Continuous ADT + DOCETAXEL x 6 cycles

ABIRATERONE (se Higth Risk)

?

High Risk

Continuous ADT + ABIRATERONE

Continuous ADT + DOCETAXEL x 6 cycles (se High Volume)

?

CRPC



M1




Symptomatic Docetaxel Abiraterone

Enzalutamide Cabazitaxel


CARD – Study design

Stratification Factors: Eastern Cooperative Oncology Group (ECOG) performance status (0-1 Vs. 2),

extent of metastatic spread (low Vs. high) and timing of AR targeted agent (before Vs. after docetaxel).

High volume metastatic disease is defined as: Visceral metastases and/or ≥ 4 bone metastases (with at least one beyond pelvis

and vertebral column).

Low volume metastatic disease is defined as: No visceral metastases and < 4 bone metastases.

Ongoing trial

CO39385: Study design Studio di fase III multicentrico, randomizzato, per valutare l’effetto di atezolizumab (anticorpo anti pd-l1) in associazione a

enzalutamide rispetto a enzalutamide in monoterapia in pazienti con tumore della prostata metastatico resistente alla castrazione dopo

fallimento di un inibitore della sintesi degli androgeni e dopo fallimento, ineleggibilità o rifiuto di un regime a base di taxani

Ongoing trial

mCRPC POST CHAARTED

mCRPC POST CHAARTED

• No prospective data exist

• Small and few retrospective studies

• Data on sequencing from a retrospective follow up of men on the GETUG AFU-15 trial (ADT vs ADT+Docetaxel in mHSPC)

Docetaxel PSA response

ADT alone

Lavaud et al. Eur Urol 2018; 73(5):696-703

ADT+Docetaxel

Grazie

Trattamento del paziente Resistente alla Castrazione (CRPC)€¦ · See CRPC M0 See CRPC M1 M1 Low...

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