MALATTIA METASTATICA RESISTENTE ALLA ...2014/11/25 · LA BIOLOGIA, I PAZIENTI, LE TERAPIE?...

MALATTIA METASTATICA RESISTENTE ALLA CASTRAZIONE:

COME CAMBIANO LA BIOLOGIA, I PAZIENTI, LE TERAPIE?

Alessandra Mosca

SC Oncologia Medica

AOU Maggiore della Carità, Novara Università degli Studi del Piemonte Orientale

A

Roma, 24 ottobre 2014

Guidelines onProstate Cancer

N. Mottet (chair), P.J. Bastian, J. Bellmunt,

R.C.N. van den Bergh, M. Bolla, N.J. van Casteren, P. Cornford,

S. Joniau, M.D. Mason, V. Matveev, T.H. van der Kwast,

H. van der Poel, O. Rouvière, T. Wiegel

© European Association of Urology 2014

Table 20.1: Definition of CRPC

Castrate serum testosterone < 50 ng/ml or 1.7 nmol/L plus either: Biochemical progression: Three consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with PSA > 2 ng/mL.

or

Radiological progression: The appearance of two or more bone lesions on bone scan or enlargement of a soft tissue lesion using RECIST (Response Evaluation Criteria in solid tumours) (22).

Castrate serum testosterone Biochemical progression:

plus either:

or

Radiological progression:

mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca

M1 Hormone sensitive ADT (+ Chemo?) PD

PC

Biochemical Radiographic Clinical

ADT (+

Changes in:

Biology: clonal selections, tumor heterogeneity Patients: PSA only? disease burden? symptoms?

Therapy: a plethora of drugs

D mCRPC


Two models for progression to CRPC: adaptation and selection.1

-Adaptation: tumor cells acquire new alterations thus surviving the castrated state. -Selection: outgrowth of rare, pre-existing cells, capable of surviving hormonal therapy.

Progression “hormone sensitive CRPC”


Zong Y et al. Nat Rev Urol 2013

AR expression may differ between primary and metastastic sites in the same patient

Lymph node mets

High AR staining Low AR staining

Prostate


Fleischmann A, Prostate 2011

Metastatic castration-resistant prostate cancer revealsintrapatient similarity and interpatient heterogeneityof therapeutic kinase targetsJustin M. Drakea, Nicholas A. Grahamb,c, John K. Leed,e, Tanya Stoyanovaa, Claire M. Faltermeiere, Sudha Sudf,Björn Titzb,c, Jiaoti Huangg,h,i, Kenneth J. Pientaf,j, Thomas G. Graeberb,c,g,k,l, and Owen N. Wittea,c,l,m,1

PNAS 2013


Biological changes in CRPC

Seruga B et al, Nat Rev Clin Oncol 2011


Abiraterone (Phase III COU-302): primary resistance

Fig. 4 – Maximal prostate-specific antigen (PSA) decline from baseline. A negative percentage indicates a decline in PSA. A positive percentage indicatesthat the patient never has a decline in PSA.

≥50% PSA decline: Abiraterone 68.0%

Rathkopf DE et al, Eur Urol 2014


100

75

50

25

0

–25

–50

–75

–100

Max

imum

PSA

cha

nge

fr

om b

asel

ine(

%)

Enzalutamide (n=854)

Placebo (n=777)

Number of patients Number of patients 200 400 600 200 400 600

•  Enzalutamide is not approved for use in chemotherapy-naive mCRPC patients. Only patients who had both baseline and post-baseline assessments were included in this analysis.

Enzalutamide (Phase III Prevail): primary resistance

≥50% PSA decline: Enzalutamide 78.0%

Armstrong AJ, et al. ASCO 2014; Abstr 5007


• • • • • 

PSA response: Docetaxel 45.0% (TAX 327) PSA response: Docetaxel 63.5% (Venice)

+ Docetaxel

Docetaxel (Phase III TAX 327): low responders

+ Docetaxel


Berthold DR, J Clin Oncol 2008 Tannock IF, Lancet Oncol 2013

Hormone sensitive PC -> ADT (+ Chemo?) PD


D mCRPC

Pts:

Asymptomatic  Mildly symptomatic the same patients?  Moderately symptomatic -> by ECOG PS? By BPI-SF?  Heavily symptomatic

-PSA?

-PSA-DT? (cut off?)

l

Are bone, lung, liver mets

equivalent (RR, OS)?


Pre-chemotherapy PSADT predicts OS

Armstrong et al. Clin Canc Res 2007


Pre-chemotherapy PSADT in TAX327

Armstrong et al, Clin Canc Res 2007


Disease site predicts OS Updated Prognostic Model for Predicting Overall Survivalin First-Line Chemotherapy for Patients With MetastaticCastration-Resistant Prostate CancerSusan Halabi, Chen-Yen Lin, W. Kevin Kelly, Karim Fizazi, Judd W. Moul, Ellen B. Kaplan, Michael J. Morris,and Eric J. Small

J Clin Oncol 32:671-677. © 2014

Over

all S

urvi

val (

prob

abili

ty)

Total Points

1.0

0.8

0.6

0.4

0.2

60 120 180 240 300 360

18-month survival probability24-month survival probability30-month survival probability36-month survival probability48-month survival probabilityMedian survival months

Points

Opioid analgesic use

LDH

Disease site

ECOG PS

Albumin (g/dL)

Hemoglobin (g/dL)

Alkaline phosphatase (U/L)

PSA (ng/mL)

12

18

24

30

36

Tim

e (m

onth

s)

0 10 20 30 40 50 60 70 80 90 100

No

Yes

≤ 1 × ULN

> 1 × ULN

Lymph node only Any visceral

Bone/bone + lymph node

20

1

6 5.5 5 4.5 4 3.5 3 2.5 2 1.5 1

17 16 15 14 13 12 11 10 9 8 7

33 55 90 148 245 403 665 1,097 1,808 2,981 4,915

0 2.7 148.4 8,103.1

0.4 20.1 1,096.6

Disease siteLymph node only Any visceral

Bone/bone + lymph node

ECOG PS20

1

PSA (ng/mL)0 2.7 148.4 8,103.1

0.4 20.1 1,096.6


BPI-SF Measurement of Affective and Activity Pain Interference Usingthe Brief Pain Inventory (BPI): Cancer and Leukemia Group B70903*

Thomas M. Atkinson, PhD1, Susan Halabi, PhD2, Antonia V. Bennett, PhD3, Lauren Rogak,MA3, Laura Sit, BA3, Yuelin Li, PhD1, Ellen Kaplan, MA2, Ethan Basch, MD, MSc3, and forthe Cancer and Leukemia Group B

Pain Med. Author manuscript; available in PMC 2013 October 15.

Conclusions—These results confirm that the BPI can be used to quantify the degree to whichpain separately interferes with affective and activity aspects of a patient's everyday life. These

Patient-reported outcome labeling claims andmeasurement approach for metastaticcastration-resistant prostate cancer treatments inthe United States and European UnionMarci J Clark1*, Nimanee Harris1, Ingolf Griebsch2, Dagmar Kaschinski2 and Catherine Copley-Merriman1Health and Quality of Life Outcomes 2014, 1:104 y

Conclusions: PRO label claims were commonly granted across the mCRPC products reviewed. Among themeasures reviewed, only the BPI-SF worst pain item supported US label claims. The BPI-SF worst pain item isrecommended for pain assessment for the evaluation of new mCRPC treatments.


Hormone sensitive PC -> ADT (+ Chemo?) PD


D mCRPC

Pts:

Asymptomatic  Mildly symptomatic the same patients?  Moderately symptomatic -> By BPI-SF? By ECOG PS?  Heavily symptomatic

l

i

Are bone, lung, liver mets

equivalent (RR, OS)?

Probably NO

BPI-SF

Probably NO

-PSA?

-PSA-DT? (cut off?) Probably PSADT (cut off? 3 mos?)

ECOG PS mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca

Fig. 1.

Metastatic Hormone-Sensitive and Castration-Resistant Prostate Cancer: A Decade of Progress and Ongoing Discoveries

Leonel Hernandez-Aya, MD, and Maha Hussain, MD, FACP, FASCO

2014 Genitourinary Cancers Symposium

Educational Summaries


CRPC: MOLECULAR TARGETS

Adapted from George et al, Prostate 2011

Taxanes Taxanes


How to choose the treatment for mCRPC currently?

-No head-to-head studies

-No prospective sequencing trials

-No predictive markers

-Difficult response assessment for bone mets

-Likely cross-resistance among drugs

Considering:

Clinical trials results mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca

Table 1. FDA-Approved Drugs for mCRPC with OS or PFS ImprovementDrug Mechanism of Action Clinical Trial Clinical Setting Main Study Results FDA Approval

Docetaxel Binds and stabilizes tubulin

TAX3277 Docetaxel vs. mitoxantrone

mCRCP Improved OS18.9 vs. 16.5 months (HR 0.76; 95% CI: 0.62-0.94)

2004

SWOG 99168Docetaxel/estramustine vs. mitoxantrone

mCRPC Improved OS17.5 vs 15.6 months (HR 0.8; 95% CI: 0.67-0.97)

Cabazitaxel Binds and stabilizes tubulin

TROPIC9 (755 patients)Cabazitaxel vs. mitoxantrone

mCRPC—post-docetaxel Improved OS 15.1 months vs. 12.7 months(HR 0.70; 95% CI: 0.59-0.83)

2010

Sipuleucel-T Immunotherapy;dendritic vaccine

IMPACT16(512 patients)Sipuleucel vs. placebo

mCRPC—asymptomatic or minimally symptomatic

Improved OS25.8 vs. 21.7 months (HR 0.78; 95% CI: 0.61-0.98)

2010

Abiraterone CYP-17A inhibitor COU-AA-30118 (1,195 patients)Abiraterone/prednisone vs. placebo/prednisone

mCRPC—post-docetaxel Improved OS15.8 vs. 11.2 months(HR: 0.74; 95% CI: 0.64-0.86)

2011

COU-AA-30212 (1,088 patients)Abiraterone/prednisone vs. placebo/prednisone

mCRPC—chemotherapy-naïve Improved PFS16.5 vs. 8.3 months(HR: 0.53; 95% CI: 0.45-0.62)

2012

Enzalutamide Androgen receptor blocker

AFFIRM19 (1,199 patients)Enzalutamide vs. placebo

mCRPC—post-docetaxel Improved OS 18.4 vs. 13.6 months(HR: 0.63; 95% CI: 0.53-0.75)

2012

PREVAIL13NCT01212991(Approximately 1,680 patients)Enzalutamide vs. placebo

mCRPC—chemotherapy-naïve Pending

Xofigo (radium-223)

Radio-pharmaceutical,alpha-emitter, and calcium mimetic

ALSYMPCA17 (921 patients)Placebo-controlled

mCRPC—patients ineligible for docetaxel or post- docetaxeland with symptom-atic bone metastases only

Improved OS14.0 vs. 11.2 months(HR 0.70; 95% CI: 0.55-0.88)

2013


Educational SummariesMetastatic Hormone-Sensitive and Castration-Resistant Prostate Cancer: A Decade of Progress and Ongoing Discoveries


. FDA-Approved Drugs

Improved r-PFS and OS (34.7 vs 30.3 mos; HR 0.81 (pre-planned HR 0.8)

Improved r-PFS and OS (32.4 vs 30.2 mos; HR 0.71)

2014


Table 1. FDA-Approved Drugs for mCRPC with OS or PFS ImprovementDrug Mechanism of Action Clinical Trial Clinical Setting Main Study Results FDA Approval

Docetaxel Binds and stabilizes tubulin

TAX3277 Docetaxel vs. mitoxantrone

mCRCP Improved OS18.9 vs. 16.5 months (HR 0.76; 95% CI: 0.62-0.94)

2004

SWOG 99168Docetaxel/estramustine vs. mitoxantrone

mCRPC Improved OS17.5 vs 15.6 months (HR 0.8; 95% CI: 0.67-0.97)

Cabazitaxel Binds and stabilizes tubulin

TROPIC9 (755 patients)Cabazitaxel vs. mitoxantrone

mCRPC—post-docetaxel Improved OS 15.1 months vs. 12.7 months(HR 0.70; 95% CI: 0.59-0.83)

2010

Sipuleucel-T Immunotherapy;dendritic vaccine

IMPACT16(512 patients)Sipuleucel vs. placebo

mCRPC—asymptomatic or minimally symptomatic


2010

Abiraterone CYP-17A inhibitor COU-AA-30118 (1,195 patients)Abiraterone/prednisone vs. placebo/prednisone

mCRPC—post-docetaxel Improved OS15.8 vs. 11.2 months(HR: 0.74; 95% CI: 0.64-0.86)

2011

COU-AA-30212 (1,088 patients)Abiraterone/prednisone vs. placebo/prednisone

mCRPC—chemotherapy-naïve Improved PFS16.5 vs. 8.3 months(HR: 0.53; 95% CI: 0.45-0.62)

2012

Enzalutamide Androgen receptor blocker

AFFIRM19 (1,199 patients)Enzalutamide vs. placebo

mCRPC—post-docetaxel Improved OS 18.4 vs. 13.6 months(HR: 0.63; 95% CI: 0.53-0.75)

2012

PREVAIL13NCT01212991(Approximately 1,680 patients)Enzalutamide vs. placebo

mCRPC—chemotherapy-naïve Pending

Xofigo (radium-223)

Radio-pharmaceutical,alpha-emitter, and calcium mimetic

ALSYMPCA17 (921 patients)Placebo-controlled


Improved OS14.0 vs. 11.2 months(HR 0.70; 95% CI: 0.55-0.88)

2013

Metastatic Hormone-Sensitive and Castration-Resistant Prostate Cancer: A Decade of Progress and Ongoing Discoveries



Educational Summaries

. FDA-Approved Drugs

errrrononone/e/e///prprprpppp ededednininisososoono/o/o/o/o/o/o/////ppr ded inisone

Improved r-PFS and OS (32.4 vs 30.2 mos; HR 0.71)

ALALSYSYMPMPM CAClPlPlac bbeboo-----ccccc

ss..... mimittoxa tntrone

Docetaxel/estraaiiimittttoxa tttntrone

pp pp

p p

Abiraterone CYP-17A inhibitor

Enzalutamide Androgen Receptor blocker

Improved r-PFS and OS (34.7 vs 30.3 mos; HR 0.81) (pre-planned HR 0.8)

Improved OS (16.1 vs 11.5 mos; HR 0.7)

EnEnzazalulutatamimidede v vs.s. p pppppplalacecebobo

Visceral Mets ____________

Yes No No

Improved OS (16.1 vs 11.5 mos; HR 0.7)

Main Study Results


Improved OS17.5 vs 15.6 months (HR 0.8; 95% CI: 0.67-0.97)

Improved r-PFS and OS (34.7 vs 30.3 mos; HR 0.81) (pre-planned HR 0.8)


mCRPC—chemotherapy-naïve

pCCClilili iinicalll SSSettttttiiingg

mCRCP

mCRPCAsymptomatic

Mildly symptomatic Moderately symptomatic

Heavily symptomatic

Asymptomatic Mildly symptomatic

Ineligible for docetaxel with

symptomatic bone mets only

2.4 mos

4.4 mos

5.1 mos

Venice study: docetaxel (control arm) OS 21.2 mos


ComparatorChoice of Comparator. An inappropriate comparator can have a

significant effect on a trial’s results. A striking example of this is theglobal ARCC (Study Evaluating Interferon And CCI-779 InAdvanced Renal Cell Carcinoma) trial, which compared temsir-olimus vs. IFN vs. a combination of the 2 in patients with mRCCand a poor prognosis.8 The increased OS observed with temsir-olimus may have been because IFN in this population is deleteriousand led to increased mortality compared with temsirolimus. The

Considerations for the Design of Future ClinicalTrials in Metastatic Renal Cell Carcinoma

Bernard Escudier,1 Daniel Y.C. Heng,2 Arthur Smyth-Medina,3 Camillo Porta4Clinical Genitourinary Cancer February 2014

Were proper the comparators in recent RCTs for mCRPC? Can we translate observations from mRCC RCTs?

Comparators in mCRPC RCTs: Mitoxantrone ; Prednisone ; Placebo


original article

Th e n e w e ngl a nd j o u r na l o f m e dic i n e

Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy

Charles J. Ryan, M.D., Matthew R. Smith, M.D., Ph.D., Johann S. de Bono, M.B., Ch.B., Ph.D., Arturo Molina, M.D., Christopher J. Logothetis, M.D., Paul de Souza, M.B., Ph.D.,

Karim Fizazi, M.D., Ph.D., Paul Mainwaring, M.D., Josep M. Piulats, M.D., Ph.D., Siobhan Ng, M.D., Joan Carles, M.D., Peter F.A. Mulders, M.D., Ph.D.,

Ethan Basch, M.D., Eric J. Small, M.D., Fred Saad, M.D., Dirk Schrijvers, M.D., Ph.D., Hendrik Van Poppel, M.D., Ph.D., Som D. Mukherjee, M.D., Henrik Suttmann, M.D., Winald R. Gerritsen, M.D., Ph.D., Thomas W. Flaig, M.D., Daniel J. George, M.D.,

Evan Y. Yu, M.D., Eleni Efstathiou, M.D., Ph.D., Allan Pantuck, M.D., Eric Winquist, M.D., Celestia S. Higano, M.D., Mary-Ellen Taplin, M.D.,

Youn Park, Ph.D., Thian Kheoh, Ph.D., Thomas Griffin, M.D., Howard I. Scher, M.D., and Dana E. Rathkopf, M.D., for the COU-AA-302 Investigators*

Jan 2013

Abiraterone pre-chemo

Docetaxel

End points

Co-primary: -Radiographic PFS -OS

-OS

Treatment arm Abiraterone + Prednisone Docetaxel+Prednisone

Control arm Prednisone Mitoxantrone+Prednisone Symptoms Asymptomatic/

Mildly symptomatic Asymptomatic -> Symptomatic

Visceral mts No Yes

original article

The new england journal of medicine

Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer

Ian F. Tannock, M.D., Ph.D., Ronald de Wit, M.D., William R. Berry, M.D., Jozsef Horti, M.D., Anna Pluzanska, M.D., Kim N. Chi, M.D.,

Stephane Oudard, M.D., Christine Théodore, M.D., Nicholas D. James, M.D., Ph.D., Ingela Turesson, M.D., Ph.D.,

Mark A. Rosenthal, M.D., Ph.D., and Mario A. Eisenberger, M.D., for the TAX 327 Investigators

2004

Mitoxantrone+Prednisone

Yes

Co-primary: RRRRRRRRRRRaaaadddddddddddiiiiiiiiiiiooooggggrrrraaaapppphhhhhhhhhhhiiiiiiiiiiiiicc

Asymptomatic -> SymptomaticA i S

STUDY DESIGN



Pain (%)‡ 45

Extent of disease (%)

Bone metastases 90

Visceral disease 22

Measurable lesions 40


(PPI >2)

= mildly symptomatic= asymptomatic

Visceral disease 22

( )‡Pain (%)‡ 45(PPI >2)

Bone metastases 90

= moderately/heavily symptomatic

y y py yt ti

y y p= moderately/heavily

Sites of disease

Bone

Lymph nodes

Visceral involvement

541 (88%)

330 (54%)

176 (29%)VViisceralll iinvolllvement 1177666 (((222999%%)))

Afl ibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trialIan F Tannock, Karim Fizazi, Sergey Ivanov, Camilla Thellenberg Karlsson, Aude Fléchon, Iwona Skoneczna, Francisco Orlandi, Gwenaelle Gravis,

Vsevolod Matveev, Sevil Bavbek, Thierry Gil, Luciano Viana, Osvaldo Arén, Oleg Karyakin, Tony Elliott, Alison Birtle, Emmanuelle Magherini,

Laurence Hatteville, Daniel Petrylak, Bertrand Tombal, Mark Rosenthal, on behalf of the VENICE investigators

PTS CHARACTERISTICS



TAX 327 Update 2008

m OS (mos) HR p-value

Docetaxel q3w 19.2 0.79 0.004

Docetaxel qw 17.8 0.87 0.086

Mitoxantrone 16.3 – –

OS benefit only in the 3weekly arm

OS: 18.9

OS: 34.7 mos

+ Docetaxel + Docetaxel Venice Study Tannock IF, Lancet Oncol 2013

Berthold, JCO 2008

RESULTS


Fig. 1 – Forest-plot analysis of the various subgroups treated on the TAX327 trial. At left are the subgroups defined, the

Docetaxel in asymptomatic mCRPC pts When to start cytotoxic therapy in asymptomatic patientswith hormone refractory prostate cancer?

P. Hamberga,*, P.C.M.S. Verhagenb, R. de Wita E U R O P E A N J O U R N A L O F C A N C E R 4 4 ( 2 0 0 8 )


TAX 327 OS: pain vs no pain/minimal

n 183 183 184 Median survival 23.0 21.1 19.8

Hazard ratio 0.73 0.95 p value 0.009 0.65

n 152 151 153

Median survival 14.9 15.1 12.8 Hazard ratio 0.85 0.8 p value 0.17 0.068

‘Asymptomatic pts may have adverse prognostic factors for survival that warrant the initiation of chemotherapy’

de Wit R, BJU Int 2008

Docetaxel q3w (n = 335)

Docetaxel qw (n = 334)

Mitoxantrone (n = 337)

PAIN

NO PAIN

Berthold DR, JCO 2008



Table 2. Adverse Events.*

Adverse EventAbiraterone–Prednisone

(N = 542)Prednisone Alone

(N = 540)

no. of patients (%)

Any adverse event 537 (99) 524 (97)

Grade 3 or 4 adverse event 258 (48) 225 (42)

Any serious adverse event 178 (33) 142 (26)

Adverse event leading to treat-ment discontinuation

55 (10) 49 (9)

Adverse event leading to death* 20 (4) 12 (2)

Adverse event of grade 1–4 in ≥15% of patients in either group

Fatigue 212 (39) 185 (34)

Back pain 173 (32) 173 (32)

Arthralgia 154 (28) 129 (24)

Nausea 120 (22) 118 (22)

Constipation 125 (23) 103 (19)

Hot flush 121 (22) 98 (18)

Diarrhea 117 (22) 96 (18)

Bone pain 106 (20) 103 (19)

Muscle spasm 75 (14) 110 (20)

Pain in extremity 90 (17) 85 (16)

Cough 94 (17) 73 (14)

* The most common adverse events leading to death were general disorders, including disease progression, a decline in physical health, and infections in-cluding pneumonia and respiratory tract infection.

A D V E R S E E V E N T S

Table 4. Adverse Events of Any Grade, or of Grade 3 or 4, That Occurred or Worsened during Treatment.

Adverse Event

Docetaxel Every 3 Wk (N=332)

Weekly Docetaxel (N=330)

Mitoxantrone Every 3 Wk (N=335)

percent

Grade 3 or 4 anemia 5 5 2

Grade 3 or 4 thrombocytopenia 1 0 1

Grade 3 or 4 neutropenia 32* 2† 22

Febrile neutropenia 3 0 2

Impaired LVEF‡ 10† 8† 22

Major decrease 1† 2* 7

Fatigue 53† 49† 35

Grade 3 or 4 5 5 5

Alopecia 65† 50† 13

Nausea, vomiting, or both 42 41 38

Diarrhea 32† 34† 10

Nail changes 30† 37† 7

Sensory neuropathy 30† 24† 7

Anorexia 17 21* 14

Change in taste 18† 24† 7

Stomatitis 20† 17† 8

Myalgia 14 14 13

Dyspnea 15* 14* 9

Tearing 10† 21† 1

Peripheral edema 19† 12† 1

Epistaxis 6 17† 2

≥1 Serious adverse event 26 29 20

Treatment-related death 0.3 0.3 1


Back pain 173 (32)

Fatigue 212 (39)

Febrile neutropenia 3

Grade 3 or 4 neutropenia 32*

Major decrease 1†

Impaired LVEF‡ 10†

Grade 3 or 4 5

Fatigue 53†

Nausea vomiting or both 42

Alopecia 65†

Table 3. Adverse Events of Special Interest.*

Adverse EventAbiraterone–Prednisone

(N = 542)Prednisone Alone

(N = 540)

Grade 1–4

Grade 3 or 4

Grade 1–4

Grade 3 or 4

Fluid retention or edema 150 (28) 4 (<1) 127 (24) 9 (2)

Hypokalemia 91 (17) 13 (2) 68 (13) 10 (2)

Hypertension 118 (22) 21 (4) 71 (13) 16 (3)

Cardiac disorder† 102 (19) 31 (6) 84 (16) 18 (3)

Atrial fibrillation 22 (4) 7 (1) 26 (5) 5 (<1)

ALT increased 63 (12) 29 (5) 27 (5) 4 (<1)

AST increased 58 (11) 16 (3) 26 (5) 5 (<1)

yp ( )

3

AAt iri lllal ffff bbibib irillllllllatiion 2222 ((4)4)

CCa ddrdiiac ddidiso ddrder†† 101022 (1(19)9)


mCRPC: hypothesis of current personalized treatment

Asymptomatic or

Mildly symptomatic

Moderately/Heavily symptomatic

Asymptomatic with only Biochemical PD

Biochemical and/or

Radiographic PD Watchful waiting? (PSA-DT >6 mos?)

-If bone mets: Abiraterone, Docetaxel

-If visceral mets: Docetaxel

-If relevant disease burden and/or short PSA-DT (<3mos?): Docetaxel

Docetaxel

B

Doceta

ful wa

axel


OPEN QUESTIONS in mCRPC:   Sequence (abiraterone, enzalutamide, docetaxel, radium-223 )

  Resistance (primary/acquired resistance; cross-resistance among drugs; neuroendocrine phenotype, )

  Predictive factors

  Association (abiraterone+enzalutamide, radium-223+abiraterone,

CT+abiraterone,..)

  Long-term adverse events (metabolic syndrome, osteoporosis, cardiovascular diseases, )

  Patient’s preference

  Costs


CONCLUSIONS in mCRPC

mCRPC is a heterogeneous disease   After progression to ADT, Docetaxel could be as active/efficacious

as Abiraterone

In absence of predictive markers,

-biochemical, clinical and radiographic behaviour of the disease -literature data -physician’s expertise -patient’s preference -costs

could lead in the choice of personalized treatment


MULTIDISCIPLINARY APPROACH TO mCRPC PATIENTS


MALATTIA METASTATICA RESISTENTE ALLA ...2014/11/25 · LA BIOLOGIA, I PAZIENTI, LE TERAPIE?...

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