Trattamento del paziente Resistente alla Castrazione (CRPC)

(1)

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)

(2)

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

Cabazitaxel Radium 223

(3)

Facchini G

Advanced Prostate

Cancer

HSPC

M0

Orchiectomy

See CRPC M0

See CRPC M1

M1

Low

High Volume

?

Abiraterone

?

CRPC

M0

Clinical Trial

M1

Docetaxel

Abiraterone

Radium 223

(4)

Facchini G

Advanced Prostate

Cancer

HSPC

M0

Orchiectomy

See CRPC M0

See CRPC M1

M1

Low

High Volume

?

Abiraterone

?

CRPC

M0

Clinical Trial

M1

Docetaxel

Abiraterone

Radium 223

(5)

Facchini G

Advanced Prostate

Cancer

HSPC

M0

Orchiectomy

See CRPC M0

See CRPC M1

M1

Low

High Volume

?

Abiraterone

?

CRPC

M0

Clinical Trial

M1

Docetaxel

Abiraterone

Radium 223

(6)

Facchini G

Advanced Prostate

Cancer

HSPC

M0

Orchiectomy

See CRPC M0

See CRPC M1

M1

Low

High Volume

?

Abiraterone

?

CRPC

M0

Clinical Trial

M1

Docetaxel

Abiraterone

Radium 223

SPARTAN

PROSPER

ARAMIS

(7)

(8)

(9)

(10)

(11)

(12)

(13)

Facchini G

Advanced Prostate

Cancer

HSPC

M0

Orchiectomy

See CRPC M0

See CRPC M1

M1

Low

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

Abiraterone

Radium 223

Cabazitaxel Radium 223 Observation (PSADT>10 m)

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

(14)

Facchini G

Advanced Prostate

Cancer

HSPC

M0

Orchiectomy

See CRPC M0

See CRPC M1

M1

Low

High Volume

?

Abiraterone

?

CRPC

M0

bservation (PSADT>10 m)

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

M1

Docetaxel

Abiraterone

Radium 223

(15)

Facchini G

Advanced Prostate

Cancer

HSPC

M0

Orchiectomy

See CRPC M0

See CRPC M1

M1

Low

High Volume

?

Abiraterone

?

CRPC

M0

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

M1

Docetaxel

Abiraterone

Radium 223

(16)

Facchini G

Advanced Prostate

Cancer

HSPC

M0

Orchiectomy

See CRPC M0

See CRPC M1

M1

Low

High Volume

?

Abiraterone

?

CRPC

M0

Observation (PSADT>10 m)

M1

Docetaxel

Abiraterone

Docetaxel Radium 223

COU-AA-302 ABIRATERONE PREVAIL ENZALUTAMIDE

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

(17)

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

(18)

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

(19)

Facchini G

Advanced Prostate

Cancer

HSPC

M0

Orchiectomy

See CRPC M0

See CRPC M1

M1

Low

High Volume

?

Abiraterone

?

CRPC

M0

M1

(Docetaxel)

Abiraterone

Radium 223

(20)

Ongoing trial

(21)

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

(22)

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

(23)

Facchini G

Advanced Prostate

Cancer

HSPC

M0

Orchiectomy

See CRPC M0

See CRPC M1

M1

Low

High Volume

?

Abiraterone

?

CRPC

M0

M1

(Docetaxel)

Abiraterone

Radium 223

TAX 327 DOCETAXEL SWOG 9916 DOCETAXEL ALSYMPCA RADIUM 223

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

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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

(25)

(26)

Study diagram

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

KEYNOTE-921

Ongoing trial

(27)

HR 0,695; IC 95% 0,552-0,875 P=0,00285

Placebo, n=268

OS mediana: 11,2 mesi

OS

Mesi

% senza SRE

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

(28)

ERA 223 (NCT02043678)

(29)

Post-Hoc Subgroup Analysis of Fractures by Baseline BHA Use

Patients with

≥1 fracture (%)

29

15

37

11

7

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.

(30)

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.

(31)

Advanced Prostate

Cancer

HSPC

M0

Orchiectomy

See CRPC M0

See CRPC M1

M1

Low

High Volume

?

Abiraterone

?

CRPC

M0

Clinical Trial

M1

(Docetaxel)

Abiraterone (Cabazitaxel)

COU-AA-301 ABIRATERONE

AFFIRM ENZALUTAMIDE

(32)

Advanced Prostate

Cancer

HSPC

M0

Orchiectomy

See CRPC M0

See CRPC M1

M1

Low

High Volume

?

Abiraterone

?

CRPC

M0

Clinical Trial

M1

(Docetaxel)

TROPIC CABAZITAXEL

COU-AA-301 ABIRATERONE

AFFIRM ENZALUTAMIDE

(33)

mCRPC II line therapy

PFS

OS

CABAZITAXEL

(34)

mCRPC II line therapy

Primary endpoint: OS

COU-AA-301 Phase III study

ABIRATERONE

Fizazi, Lancet Oncology 2012

(35)

mCRPC II line therapy

ENZALUTAMIDE

OS + 4.8 Mesi

AFFIRM

(36)

Facchini G.

Advanced Prostate

Cancer

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

M0

M1

(Docetaxel)

Cabazitaxel Observation (PSADT>10 m)

(37)

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

(38)

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

(39)

mCRPC POST CHAARTED

(40)

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

(41)

Slide 26

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