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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
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
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”
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
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
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
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
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
Biological changes in CRPC
Seruga B et al, Nat Rev Clin Oncol 2011
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
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
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
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
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
• • • • •
PSA response: Docetaxel 45.0% (TAX 327) PSA response: Docetaxel 63.5% (Venice)
+ Docetaxel
Docetaxel (Phase III TAX 327): low responders
+ Docetaxel
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
Berthold DR, J Clin Oncol 2008 Tannock IF, Lancet Oncol 2013
Hormone sensitive PC -> ADT (+ Chemo?) PD
Biochemical Radiographic Clinical
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)?
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
Pre-chemotherapy PSADT predicts OS
Armstrong et al. Clin Canc Res 2007
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
Pre-chemotherapy PSADT in TAX327
Armstrong et al, Clin Canc Res 2007
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
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
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
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.
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
Hormone sensitive PC -> ADT (+ Chemo?) PD
Biochemical Radiographic Clinical
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
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
CRPC: MOLECULAR TARGETS
Adapted from George et al, Prostate 2011
Taxanes Taxanes
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
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
2014 Genitourinary Cancers Symposium
Educational SummariesMetastatic Hormone-Sensitive and Castration-Resistant Prostate Cancer: A Decade of Progress and Ongoing Discoveries
Leonel Hernandez-Aya, MD, and Maha Hussain, MD, FACP, FASCO
. 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
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
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
. 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 OS18.9 vs. 16.5 months (HR 0.76; 95% CI: 0.62-0.94)
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—patients ineligible for docetaxel or post- docetaxeland with symptom-atic bone metastases only
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
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
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
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
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
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy
Pain (%)‡ 45
Extent of disease (%)
Bone metastases 90
Visceral disease 22
Measurable lesions 40
Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer
(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
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy
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
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
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 )
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
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
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy
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
Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer
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: come cambiano biologia, pazienti, terapie? Alessandra Mosca
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
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
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
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
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
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca
MULTIDISCIPLINARY APPROACH TO mCRPC PATIENTS
mCRPC: come cambiano biologia, pazienti, terapie? Alessandra Mosca