NUEVO PARADIGMA DEL BLOQUEO ANDROGÉNICO - Abordaje temprano del paciente con CPRCm
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Abordaje temprano del paciente con CPRCm
NUEVO PARADIGMA DEL BLOQUEO
ANDROGÉNICO
L.M. ANTÓN APARICIO
Servicio Oncología médica.
Complejo Hospitalario Universitario A Coruña
THE WAVE THAT BECAME A TSUNAMI
THE WAVE…
...THAT BECAME…
… A TSUNAMI
OVERVIEW
• Within a normal prostate, the AR (regulated by testosterone and
dihydrotestosterone) has a homeostatic function to balance the rate of cell
proliferation with the rate of apoptosis.
• Testosterone or dihydrotestosterone binds to the ligand-binding domain (LBD)
of the AR, causing conformational change and activation of the receptor.
• This leads to homodimer formation and nuclear translocation from the
cytoplasm.
• In the nucleus, it binds to androgen response elements of DNA, recruiting co-
factors (co-activators or co-repressors) that regulate transcription genes (i.e.
PSA).
Gelman EP J Clin Oncol 2002;20:3001-3015 Shafi AA et al Pharmacol Ther 2013;140:223-238
Bennet NC et al. Int J Biochem Cell Biol 2010;42:813-827 Heinlein CA et al Endocr Rev 2004;25:276-308
Androgen and AR action in castration-resistant prostate cancer.
Mechanism of castration-resistant prostate cancer. Several mechanisms
promote the progression of castration-resistant prostate cancer
Androgen and AR action. Genome organization of the
human androgen receptor gene and the functional
domain structure of the androgen receptor protein. (A)
Androgen and AR signaling in prostate cells.
OVERVIEW
• In malignant prostate cells, the AR signalling
pathway drives uncontrolled growth and the
balance between the rate of cell proliferation and
the rate of apoptosis is lost.
• The AR signalling pathway plays a key role in all
phases of prostate cancer from disease to disease
progression, including metastatic transformation
and spread.
• Reactivation of the AR signalling pathway is
considered to be a key driver of CPRC
progression.
Knudsen KE et al Expert Rev Endocrinol Metab 2011;6:483-493
Hu R et al Expert Rev Endocrinol Metab 2010; 5:753-764
…FROM THE SEA SURFACE TO THE DEEP
THE DISEASE CONTINUUM IN PROSTATE CANCER
Localised Castration Anti- Chemotherapy
therapy* androgens
PSA tumor volume
M0 BCR M0 CRPC
EMBARK PROSPER
P3 study P3 study
Chemo-naïve
Ongoing Ongoing PREVAIL
P3 study Post-chemo
M1 HSPC
AFFIRM
ARCHES
P3 study
P3 study†
Ongoing
Asymptomatic Symptoms
Non-metastatic
Non-Metastatic Metastatic
Metastatic
Castration Resistant
Time
*Radiotherapy, prostatectomy;†Metastatic at time of diagnosis. M0 BCR=non-metastatic biochemical recurrence; M0 CRPC=non-metastatic castration-
resistant prostate cancer; M1 HSPC=metastatic hormone sensitive prostrate cancer; PSA=prostate-specific antigen.
Figure adapted from George D. Urology – The Gold Journal 2013. Available at: http://education.goldjournal.net/path.php?1396:bxvcs.
Last accessed February 2016. Confidential and proprietary. For non-promotional use only. Do not copy or distribute.THE 5 BIG WAVES
• AFFIRM phase 3 ENZALUTAMIDE vs PLACEBO
post-chemotherapy
• PREVAIL phase 3 ENZALUTAMIDE vs PLACEBO
pre-chemotherapy
• STRIVE phase 2 ENZALUTAMIDE vs BICALUTAMIDE
either non- or metastatic
• TERRAIN phase 2 ENZALUTAMIDE vs BICALUTAMIDE
asymptomatic/minimally
• UPWARD phase 4 ENZALUTAMIDE
SecurityINCREASED SURVIVAL WITH ENZALUTAMIDE IN PROSTATE
CANCER AFTER CHEMOTHERAPY
H.I. Scher, K. Fizazi, F.Saad, M.E. Taplin, C.N. Sternberg, K.Miller, R.deWit, P.Mulders, K.N. Chi, N. d:
Shore, A.L. Armstromg, T. W. Flaig, A.Flechon, P. Mainwaring, M. Fleming, J.D. Hainsworth, M.Hirmand, B.
Selby, L.Seely, And J. S. de Bono.N. Engl J. Med. 2012.
AFFIRM PHASE 3 ENZALUTAMIDE VS PLACEBO
POST-CHEMOTHERAPYENZALUTAMIDE IN MCRPC PATIENTS POST-CHEMOTHERAPY
• AFFIRM is a Phase 3 randomised, double-blind, placebo-controlled trial evaluating the safety
and efficacy of enzalutamide in patients with mCRPC after chemotherapy
Enzalutamide
mCRPC 160 mg QD
1–2 prior (n=800) Primary endpoint:
R
chemotherapy
2:1 • OS
regimens* Placebo
(N=1199)† QD
(n=399)
*At least one cycle of docetaxel (glucocorticoids were allowed but not required); †Patients were excluded from the trial if they had
brain metastases,
a history of seizure or any condition that may pre-dispose to seizure.
Recruitment in 156 centres from 15 countries across five continents between September 2009 and November 2010.
mCRPC=metastatic castrate-resistant prostate cancer; OS=overall survival; QD=once daily; R=randomisation.
Scher HI, et al. N Engl J Med 2012;367:1187–97.ENZALUTAMIDE DEMONSTRATED A SURVIVAL BENEFIT
ACROSS ALL PATIENT SUBGROUPS
BPI-SF=Brief Pain Inventory – Short Form; CI=confidence interval; ECOG=Eastern Cooperative Oncology Group;
HR=hazard ratio; LDH=lactate dehydrogenase; NYR=not yet reached; OS=overall survival; PSA=prostate-specific antigen.
Scher HI, et al. N Engl J Med 2012;367:1187–97.AFFIRM: Secondary End Points EJM
AFFIRM: VISCERAL METASTASES
Loriot Y et al. Cancer. 2016AFFIRM: VISCERAL METASTASES
Loriot Y et al. Cancer. 2016AFFIRM: CONCLUSSIONS
• These results validate androgen-receptor signaling as a key
therapeutic target throught the clinical spectrum of prostate cancer,
including in men who received previous chemotherapy
• Enzalutamide significantly prolonged survival in men with metastatic
castration-resistant prostate cancer after chemotherapyENZALUTAMIDE IN METASTATIC PROSTATE CANCER
BEFORE CHEMOTHERAPY.
T.M Beer, A.J Armstrong , D.E Rathkopf, Y. Loriot , C.N. Sternberg, C.S. Higano, P. Iversen, S.
Bhattacharya, J. Carles, S. Chowdhury, I.D. Davis, J.S. de Bono, C.P. Evans, K. Fizazi, A.M. Joshua, C.s.
Kim, G. Kimura, p. Mainwaring, H. Mansbach, K. Miller, S.B. Noonberg, F. Perabo, D. Phung, F. Saab, H.I.
Scher, M.E. Taplin, P.M. Venner and B. Tombal, for the PREVAIL Investigators*
PREVAIL PHASE 3
ENZALUTAMIDE VS PLACEBO
PRE-CHEMOTHERAPYENZALUTAMIDE IN CHEMOTHERAPY-NAÏVE MCRPC PATIENTS: STUDY
• PREVAIL is a Phase 3 randomised, double-blind, placebo-controlled trial evaluating the safety
and efficacy of enzalutamide in chemotherapy-naïve patients with mCRPC
Patients:
• 1717 patients with Co-primary endpoints:
mCRPC • OS
• Chemotherapy-naïve • rPFS
• Asymptomatic/ Enzalutamide
mildly symptomatic* 160 mg QD Secondary endpoints:
• (n=872)
ECOG PS 0–1
R • PSA response
• PSA progression, rPFS
1:1 • Soft-tissue response
progression or both in
bone or soft tissue with Placebo • Time to:
ADT QD – Initiation of
• Serum T ≤50 ng/dL (n=845) chemotherapy
• Steroids allowed but not – First SRE
required – PSA progression
• Ongoing ADT
*Patient scored less than four on BPI-SF-Q3.
Recruitment in 207 centres from 22 countries across four continents between September 2010 and September 2012.
ADT=androgen-deprivation therapy; BPI-SF=Brief Pain Inventory-Short Form; ECOG PS=Eastern Cooperative Oncology Group performance status;
mCRPC=metastatic castration-resistant prostate cancer; OS=overall survival; PSA=prostate-specific antigen; QD=once daily; R=randomised; rPFS=radiographic
progression-free survival; SRE=skeletal-related event; T=testosterone.
Beer TM, et al. N Engl J Med 2014;371:424–33.PREVAIL: OS
SUPPLEMENTARY FIG.S2 – SUBGROUP ANALYSIS FOR THE EXTENDED ANALYSIS OF OS
Beer TM et al. Eur Urol. 2016PREVAIL:CONCLUSIONS
• Enzalutamide significantly improved radiographic progression-free
survival (rPFS) and overall survival (OS) among men with
chemotherapy-naïve metastatic castration-resistant prostate cancer
• In men with minimally symptomatic or asymptomatic metastatic
prostate cancer who had not received chemotherapy, enzalutamide,
an oral therapy with an excellent side-effect profile, significantly
delayed the need for cytotoxic chemotherapy, and the deterioration
in quality of life and significantly improved overall survivalENZALUTAMIDE VERSUS BICALUTAMIDE IN CASTRATION-RESISTANT
PROSTATE CANCER: THE STRIVE TRIAL
David F. Penson, Andrew J. Armstrong, Raoul Concepcion, Neeraj Agarwal, carl Olsson, Lawrence
Karsh, Curtis Dunshee, Fong wang, Kenneth wu, Andrew krivosshik, de phung, and Celestia S. Higano.
J. Clin. Oncol, 2016
STRIVE PHASE 2
ENZALUTAMIDE vs BICALUTAMIDE
EITHER NON - OR METASTATIC• A multicentre, Phase 2, randomised, double-blind, efficacy and safety study in
asymptomatic or mildly symptomatic patients with progression despite primary ADT
Patient population
396 men with Enzalutamide Primary endpoint:
progressive mCRPC (M0 160 mg QD • PFS
or M1) (n=198) – Radiographic progression
Asymptomatic/mildly
– PSA progression
symptomatic R
– Death
Chemotherapy-naïve 1:1
Key secondary endpoints:
No requirement for
steroids Bicalutamide • Time to PSA progression
Ongoing ADT 50 mg QD • PSA response
No prior progression on (n=198) • rPFS (M1 population only)
bicalutamide
ADT=androgen-deprivation therapy; M0=non-metastatic; M1=metastatic; mCRPC=metastatic castration-resistant prostate cancer;
PFS=progression-free survival; PSA=prostate-specific antigen; QD=once daily; R=randomised; rPFS=radiographic progression-
free survival.
Penson D, et al. JCO 2016. DOI: 10.1200/JCO.2015.64.9285Penson et al. Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial. Published online ahead of print at www.jco.org on January 25, 2016. DOI: 10.1200/JCO.2015.64.9285
Penson et al. Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial. Published online ahead of print at www.jco.org on January 25, 2016. DOI: 10.1200/JCO.2015.64.9285
STRIVE: CONCLUSIONS
• Enzalutamide plus ADT was more efficacious than bicalutamide
plus ADT in men with either M0 or M1 CRPC, as evidenced by:
– A 76% reduction in the risk of disease progression (pEFFICACY AND SAFETY OF ENZALUTAMIDE VERSUS BICALUTAMIDE
FOR PATIENTS WITH METASTATIC PROSTATE CANCER (TERRAIN):
A RANDOMISED, DOUBLE-BLIND, PHASE 2 STUDY.
NEAL D. STORE ET. AL. 2016
TERRAIN PHASE 2
ENZALUTAMIDE vs BICALUTAMIDE
ASYMPTOMATIC/MINIMALLY• A randomised, double-blind, Phase 2, efficacy and safety study of enzalutamide versus
bicalutamide in castrate men with mCRPC
Primary endpoint:
Patient population
Enzalutamide • PFS
375 men with
progressive mCRPC 160 mg QD – Radiographic
who have progressed (n=184) progression
on LHRHa therapy or (central review)
after bilateral R – Skeletal-related event
orchiectomy – Change in new
1:1
Asymptomatic/ antineoplastic therapy
mildly symptomatic –
Bicalutamide Death
Chemotherapy-naïve 50 mg QD Secondary endpoints:
No requirement for (n=191) • PSA response
steroids
• Time to PSA progression
• LHRHa=luteinizing hormone-releasing hormone analogue; mCRPC=metastatic castration-resistant prostate cancer;
PFS=progression-free survival; PSA=prostate-specific antigen; QD=once daily; R=randomised.
• Heidenreich A, et al. EAU 2015; Oral presentation LBA3.TERRAIN: CONCLUSIONS
• Treatment with enzalutamide plus ADT, compared with bicalutamide plus ADT, is
associated with:
– A 56% reduction in the risk of disease progression (pSEIZURE RATES IN ENZALUTAMIDE-TREATED MEN WITH METASTATIC CASTRATION-RESISTANT
PROSTATE CANCER ATINCREASED RISK OF SEIZURE: THE UPWARD STUDY.
Slovin SF, Clark W., et al. J. Clin Oncol 35, 2017 (suppl 6S; anstract 147. poster F1)
UPWARD PHASE 4 ENZALUTAMIDE
SECURITYUPWARD
UPWARD: CONCLUSSIONS
• Enzalutamide was generally well tolerated in this study and analyses of the
UPWARD adverse event data are consistent with enzalutamide´s known safety
profile .
• The results of the UPWARD study suggest that enzalutamide did not increase
the risk of seizures in men with mCRPC known to have potential risk factors for
seizure.
• The observed incidence of all confirmed seizures, as of data cut-off, was
comparable with that in men with mCRPC and similar potential risk factors with
no exposure to enzalutamide (data on file, TRUVEN Health Report 2013)THE DISEASE CONTINUUM IN PROSTATE CANCER
Localised Castration Anti- Chemotherapy
therapy* androgens
PSA tumor volume
M0 BCR M0 CRPC
EMBARK PROSPER
P3 study P3 study
Chemo-naïve
Ongoing Ongoing PREVAIL
P3 study Post-chemo
M1 HSPC
AFFIRM
ARCHES
P3 study
P3 study†
Ongoing
Asymptomatic Symptoms
Non-metastatic
Non-Metastatic Metastatic
Metastatic
Castration Resistant
Time
*Radiotherapy, prostatectomy;†Metastatic at time of diagnosis. M0 BCR=non-metastatic biochemical recurrence; M0 CRPC=non-metastatic castration-
resistant prostate cancer; M1 HSPC=metastatic hormone sensitive prostrate cancer; PSA=prostate-specific antigen.
Figure adapted from George D. Urology – The Gold Journal 2013. Available at: http://education.goldjournal.net/path.php?1396:bxvcs.
Last accessed February 2016. Confidential and proprietary. For non-promotional use only. Do not copy or distribute.THE BIGGEST WAVES EVER SEEN
PROSPER: CPRC M0
• PROSPER es un estudio fase 3, Evaluaciones planeadas
randomizado, doble ciego, controlado con • Supervivencia libre de metástasis
placebo • SG
• Objetivo principal: Supervivencia libre de
• Tiempo hasta progresión del dolor
metástasis
• Tiempo hasta el uso de opiáceos para
n=1560 el dolor de CaP
• Tiempo hasta la primera quimioterapia
CPRC no Enzalutamida
metastásico (M0) • Tiempo hasta el primer tratamiento
160 mg QD antineoplásico
Testosterona
≤50 ng/dL R • Tiempo hasta progresión de PSA
2:1 • Tasa de respuestas PSA
En progresión con
tratamiento DA • QoL
Placebo
Asintomático QD
Tiempos
PSADT ≤10 meses
• Se estima terminar el estudio en
agosto 2017
En reclutamiento
ADT=androgen-deprivation therapy; CRPC=castration-resistant prostate cancer; OS=overall survival; PSA=prostate-specific
antigen;
PSADT=PSA doubling time; QD=once daily; QoL=quality of life; R=randomisation.
NCT02003924. Available at http://clinicaltrials.gov. Last accessed: May 2015.EMBARK: CaP M0 alto riesgo en progresión bioquímica
• Estudio fase 3, randomizado, doble ciego, Evaluaciones Planeadas
controlado con placebo • Supervivencia libre de metástasis
• Objetivo principal: Supervivencia libre de • SG
metástasis • Proporción de pacientes por grupo sin
tratamiento después de 2 años de la
n=1.860 Enzalutamida finalización de la medicación de
160 mg QD + estudio
CaP No
leuprolide • Tiempo hasta la resistencia a la
metastásico
12-weekly castración
Hormono-
• Supervivenvia cáncer específica
sensible
R Enzalutamida • Tiempo hasta el primer SRE
Alto riesgo 1:1:1 160 mg QD sintomático
Progresión • Seguridad (AAs, signos vitales,
después de Placebo + evaluaciones de laboratorio)
radioterapia, leuprolide
PR... 12-weekly Tiempos:
• Estudio completado diciembre 2020
Reclutamiento
AE=adverse event; BCR=biochemical relapse; QD=once daily; OS=overall survival; R=randomisation; SRE=skeletal-related event.
NCT02319837. Available at http://clinicaltrials.gov. Last accessed: May 2015.ARCHES: CaP metastásico hormonosensible
•Docetaxel treatment for mHSPC will be permitted in both arms
•Primary objective: rPFSTHE DISEASE CONTINUUM IN PROSTATE CANCER
Localised Castration Anti- Chemotherapy
therapy* androgens
PSA tumor volume
M0 BCR M0 CRPC
EMBARK PROSPER
P3 study P3 study
Chemo-naïve
Ongoing Ongoing PREVAIL
P3 study Post-chemo
M1 HSPC
AFFIRM
ARCHES
P3 study
P3 study†
Ongoing
Asymptomatic Symptoms
Non-metastatic
Non-Metastatic Metastatic
Metastatic
Castration Resistant
Time
*Radiotherapy, prostatectomy;†Metastatic at time of diagnosis. M0 BCR=non-metastatic biochemical recurrence; M0 CRPC=non-metastatic castration-
resistant prostate cancer; M1 HSPC=metastatic hormone sensitive prostrate cancer; PSA=prostate-specific antigen.
Figure adapted from George D. Urology – The Gold Journal 2013. Available at: http://education.goldjournal.net/path.php?1396:bxvcs.
Last accessed February 2016. Confidential and proprietary. For non-promotional use only. Do not copy or distribute.GUÍAS NCCN 2017 V1 - TDA
TO BE THE BEST THANK VERY MUCH
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