Chemioterapia, abiraterone, enzalutamide: evidenze, indicazioni, cros-resistenza. Quali sequenze? G....

Chemioterapia, abiraterone, enzalutamide: evidenze, indicazioni, cros-resistenza. Quali sequenze?

G. CartenìDirettore U.O.S.C. di Oncologia Medica A.O.R.N.A. Cardarelli Napoli

Prima e seconda linea di trattamento

mHDPC mCRPC

HDPC - HSPC DCT sensitive mCRPC DCT Refractory mCRPC

mCRPC

Cabazitaxel

Enzalutamide

Zoledronic Acid ?

Alpharadin

± AWS

ADT

Mitox. + Pdn

Abiraterone

Wait & See ?

Docetaxel

Abiraterone

Sipuleucel-T

Abiraterone

Docetaxel

DCT Rechallenge

Denosumab ?

Alpharadin

Asymptomatic: - W&S or AA/Enz.

Bone Symptoms: - DCT or Alphar.

Visceral Mets: DCT

Enzalutamide

EnzalutamideDocetaxel

High Grade Tumours

Allowed Allowed

AllowedNot Allowed

AllowedNot Allowed

Allowed Allowed

Visceral Metastases

Symptomatic Cases

Asymptomatic Cases *

TAX-327 COU-302 / PREVAIL

Which possible changes in Decision

Making in the Pre-CT Setting ?

Docetaxel resistant CRPC: il problema delle sequenze.

Nuovi agenti ormonali

CHT

Do

cetaxel


CHT



Abiraterone

Enzalutamide

Cabaziataxel

Cabaziataxel

Cabaziataxel

Cabaziataxel

Abiraterone

Enzalutamide

Abiraterone

EnzalutamideAbiraterone

Enzalutamide

x 3 strategie x 6 combinazioni

Se aggiungiamo RAD-223 il quadro si complica!

Possiamo escludere la CHT dal trattamento del CRPC Docetaxel resistant?

Qual è la giusta posizione dei nuovi agenti ormonali e della CHT?

in second line for mCRPC

GLEASON SCORE ( 7 vs >7)

Short prior HT before CT ( 24 vs > 24 months)

PD during DOCETAXEL (primary and acquired)

PD after DOCETAXEL ( 3, 6 months)

Liver metastases

Visceral metastases

CT-CT-HT vs CT-HT-CT sequences

PS

Testosterone levels

Toxicity to prior treatment

Comorbidity : liver, hematologic, Hypertension and cardiac disorders

Suggested and Potential biologic and clinical parameters

Future Oncol June 2013

Cox Proportional Hazards Regression for

PFSCharacteristic Hazard Ratio (95% CI) p-value

Univariable

Months of Prior Hormonal Therapy 0.96 (0.92, 0.99) 0.019

Time to PD Following Docetaxel 0.98 (0.89, 1.09) 0.75

Prior Cycles of Docetaxel 0.99 (0.93, 1.06) 0.80

Age 0.97 (0.93, 1.01) 0.11

Baseline PSA (/100) 0.93 (0.77, 1.11) 0.42

PSA Doubling Time 0.95 (0.84, 1.08) 0.46

Gleason Score 0.86 (0.64, 1.16) 0.33

Gleason Score, ≥8 versus ≤7 0.50 (0.26, 0.95) 0.033

Visceral Disease 2.74 (1.33, 5.65) 0.006

ECOG, 1 versus 0 1.28 (0.83, 1.98) 0.27

Prior Abiraterone 1.58 (0.55, 4.48) 0.39

Multivariable

Visceral Disease 4.16 (1.86, 9.30) <0.001

Gleason Score, ≥8 versus ≤7 0.36 (0.18, 0.72) 0.004

Di Lorenzo et al. Future Oncol 2013

Predictors of poor response to ABI

● 408 mCRPC pts enrolled in 19 centres

● Gleason at diagnosis: 8-10: 51.2% 7: 36.1% <7: 12.7%

● Median duration of ABI therapy: 6.1 months

● Predictors of poor response to ABI: Univariate: age, Gleason, number of mets, baseline

PSA, duration of HT, number of lines of chemo, duration of chemo

Multivariate analysis: Gleason 8-10predict POOR response to ABI

Azria et al. ASCO GU 2012 (poster 149)


GLEASON SCORE (>7) cabazitaxel

Short prior HT before CT ( 24 vs > 24 months)



Liver metastases

Visceral metastases


PS

Testosterone levels




Gleason Score e cabazitaxel OS

Tropic and EAP posthoc analysis

Conclusioni:

●OS e PFS in patients treated with Cabazitaxel not related to: Gleason Score (0-7; 8-10) Duration of HT pre-TXT (+/- 20 Months )

●Multivariate analysis: SHORT OS and PFS in pts with low PS (ECOG 2), high ALP and PAIN

Oudard et al, ASCO GU 2013

Abstract # 137 : Efficacy of cabazitaxel and its relationship with predictors of poor response to second hormonal therapies (2d HT) in metastatic castration-resistant prostate cancer (mCRPC). ( J2 ) Stephane Oudard - Department of Medical Oncology, Georges Pompidou European Hospital

PSA RR, PFSand lenght of ADT pre-

docetaxel

Conclusioni: A previous duration of prostate cancer sensitivity to ADT ≥16 months is the only significant predictive factor for efficacy of subsequent endocrine manipulations in patients with CRPC. This parameter shall be integrated into the decision-making process for these patients

Loriot Y. et al, ASCO 2012


GLEASON SCORE ( >7) cabazitaxel

Short prior HT before CT ( 24 months) cabazitaxel



Liver metastases

Visceral metastases


PS

Testosterone levels




Patients who progressed while receiving docetaxel

100

90

80

70

60

50

40

30

20

10

0

0 6 12 18 24 30 Time (Months)

Pro

por

tion

of O

vera

ll S

urvi

val

Number at Risk

MTX + PREDCBZ + PRED

230239

172194

98130

3344

29

10

MTX + PRED CBZ + PRED

Symbols = Censors

MTX CBZ

10.9 13.8

ASCO GU 2011

Patients who progressed after completion with

docetaxel100

90

80

70

60

50

40

30

20

10

0

0 6 12 18 24 30 Time (Months)

Pro

por

tion

of O

vera

ll S

urvi

val

Number at RiskMTX + PREDCBZ + PRED

147139

128127

90101

3446

919

04

MTX + PRED CBZ + PRED

Symbols = Censors

MTX CBZ

15.6 18

ASCO GU 2011

Mukherji D. et al, ASCO 2012

37: acquired refractory and 7: primary refractory

Abiraterone PSA RR

Conclusions: patients refractory to docetaxel have very limited response to Abiraterone.0 responses among primary refractory


GLEASON SCORE ( 7 vs >7) cabazitaxel

Short prior HT before CT ( 24 vs > 24 months) cabazitaxel

PD during DOCETAXEL (primary ) cabazitaxel

PD after DOCETAXEL ( 3, 6 months) both options

Liver metastases

Visceral metastases


PS

Testosterone levels




Click to edit the outline text format Second Outline

Level Third Outline

Level Fourth

Outline Level Fifth

Outline Level

Sixth Outline Level

Seventh Outline Level

Eighth Outline Level

● Ninth Outline LevelFare clic per modificare stili del testo dello schema

Secondo livello Terzo livello

Quarto livello» Quinto livello

Exploratory analysis of the visceral disease (VD) patient subset in COU-

AA-301, a phase III study of abiraterone acetate (AA) in mCRPC

● COU-AA-301: 1.195 pazienti enrolled in the study. 352 (29%) showed visceral metastases while 843 (71%) no visceral met. (V-)

● OS in visceral negative: 17,1 vs 12,3 months with risk reduction of death 31% (p<0,001)

● OS in V+ ::12,9 vs 8,3 months with risk reduction of death of 21% (p=0,10)

Oscar B. Goodmanet al

ASCO GU 2013






Liver metastases cabazitaxel

Visceral metastases cabazitaxel


PS

Testosterone levels




Docetaxel resistant CRPC: il problema delle sequenze.

31% dei pazienti trattati con abiraterone riceve cabazitaxel in terza linea.

Sella a et al. ASCO-GU 2013 Abs 186

36% dei pazienti trattati con enzalutamide riceve abiraterone in terza linea.

Loriot et al. Ann. Oncol. 2013

Angelergues et al. ASCO 2013

49% dei pazienti trattati con docetaxel riceve due ulteriori linee.

40% Dei pazienti riceve due ulteriori linee dopo TXT

Angelergues et al, Abst 5063, ASCO 2013

● Conclusions: patients treated with 2 prior Docetaxel lines, PSA response >30% with Cabazitaxel and treated with new hormonal agents after Cabazitaxel experienced prolonges OS.

● Conversely intake of new hormonal agents before Cabazitaxel rather after was associated with a reduced OS from the first Docetaxel.

● Prospective randomized trials are needed.

•125 pts treated with cabazitaxel and retrospectively analyzed.

•Median OS from the first docetaxel was 65 mo in patients treated with abiraterone/enzalutamide after Cabazitaxel vs 39 mo in patients receiving these agents before Cabazitaxel.

Pazienti trattati n maniera sequenziale con abiraterone e cabazitaxel in 22 centri ospedalieri in Olanda.

90 pts treated

with TXT

Caba Abi

Abi Caba

48 pts

42 pts

Wissing et al. ESMO 2013, abs 2904

Overall survival Total PFS Total PSA-PFS

La sequenza Caba Abi vs. Abi Caba: esperienze cliniche. Caba Abi

(mos)Abi Caba

(mos)

Treatment duration 10.0 7.8

Median F-Up 21.2 21.0

Median OS 17.8 14.3

Total-PFS 7.7 5.5

PSA-PFS 9.6 6.4

Outcomes with different sequences of cabazitaxel and abiraterone acetate following docetaxel in metastatic castration-resistant prostate cancer (mCRPC).

Pazienti trattati n maniera sequenziale con abiraterone e cabazitaxel in 22 centri ospedalieri in Olanda.

113 pts inclusi

Caba Abi

Abi Caba

77 pts

36 pts

Sonpavde et al. ESMO 2013, abs 2905

La sequenza Caba Abi vs. Abi Caba: esperienze cliniche.

Median OS, TTF1, and TTF2 were analyzed by Kaplan-Meier method from start of second-line therapy post-D to death for OS, to end of second-line (TTF1), and to end of combined second- and third-line therapies (TTF2).








CT-CT-HT vs CT-HT-CT sequences cabazitaxel

PS 2

Testosterone levels




PS 2: HT









PS 2 abiraterone/enzalutamide

Testosterone levels













High Serum Testosterone levels abiraterone/enzalutamide












High Serum Testosterone levels abiraterone/enzalutamide

Toxicity to prior treatment abiraterone/enzalutamide

TO BE CONSIDER: AGE and Comorbidity : liver, hematologic, Hypertension and cardiac disorders


Un algoritmo è possibile?

Gallardo et al. Crit Rev Oncol/Hemat 2013, in press

Chemioterapia, abiraterone, enzalutamide: evidenze, indicazioni, cros-resistenza. Quali sequenze? G....

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