cou-aa-302 version 10oncocare.org.br/aulas/27/tarde/apc_overview_recife_27.04.2019.pdf · • no...
TRANSCRIPT
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Advanced Prostate Cancer
Diogo Assed BastosGenitourinary Oncology
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Agenda Epidemiology in Brazil
Clinical States
Current treatment paradigm
mCSPC: treatment options
mCRPC: the sequencing dillema
Novel approaches
Biomarkers
Molecular Subtypes
Promising therapies
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3
Prostate Cancer Epidemiology in Brazil
• INCA 2018-2019:
• 68.220 new cases/year
• Risk: 66 new cases/100,000 men
• Around 14,000 deaths due to prostate
cancer yearly in Brazil – ascending curve
http://www2.inca.gov.brhttps://mortalidade.inca.gov.br
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Clinical States and Available Therapies
Adapted, Prostate Cancer Working Group 3, J Clin Oncol, 2016
• Prostatectomy
• Radiation
• ADT
• Active surveillance
•Watchful waiting
• Radiation
• ADT
• Observation • ADT alone
• ADT + Apalutamide
• ADT + Enzalutamide
• ADT + Darolutamide
• ADT alone
• ADT + Abiraterone
• ADT + Enzalutamide
• ADT + Docetaxel
•ADT plus:
o Abiraterone
o Enzalutamide
o Docetaxel
o Cabazitaxel
o Radium-223
o Sipuleucel T
•Radiation for mets
•Pembrolizumab for MSI-H
•Platinum (DDR+)
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Case Presentation
• 64-year-old man
• No significant comorbidities or family history of cancer
• July 2017 with a palpable left neck mass and urinary symptoms.
• Digital rectal examination: right firm nodule in the prostate.
Laboratory results – July 2017:
Prostate Specific Antigen (PSA) 1512.0 ng/mL
Lactate Dehydrogenase (LDH) 357 U/L
Alkaline Phosphatase 126 U/L
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Imaging
– Multiple bone lesions in the axial and appendicular skeleton
– Left supraclavicular lymph node (LN) mass (red arrows)– Extensive pelvic and retroperitoneal lymphadenopathy
(orange arrows)– Large infiltrating prostatic lesion (blue arrow)
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Diagnosis
US-guided percutaneous biopsy: metastatic adenocarcinoma consistent with prostatic origin: – IHC Positive markers: PSA, prostate specific membrane antigen (PSMA),
prostate specific acid phosphatase (PSAP)
– IHC Negative markers: CK7, CK20, TTF-1, CDX-2, CD56, Chromogranin, Synaptophysin
PSA PSMA PSAP
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Initial Therapy for CSPC• Androgen Deprivation / Castration
– Mainstay of treatment
– Goal: supress gonadal androgen (Testosterone < 50ng/dL)
– High efficacy
• PSA decline in > 90% of patients.
• Symptom improvement also in the majority of patients.
• Objective response in > 80% of patients.
Despite high efficacy, most patients will progress to CRPC and eventually
die from disease
Median Overall Survival ~ 4 years
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CHAARTED1: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer.
STAMPEDE2,3: Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy: a multi-stage multi-arm randomised controlled trial.
LATITUDE4: A phase 3, double-blind, randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebo in newly diagnosed high-risk metastatic hormone-naïve prostate cancer patients.
ARCHES: Phase 3 study of androgen deprivation therapy with enzalutamide or placebo in metastatic hormone-sensitive prostate cancer. 2019 GU ASCO
ENZAMET: A randomized, phase III trial evaluating the impact of adding enzalutamide to standard initial treatment for metastatic hormone-sensitive prostate cancer. (2019 ASCO Annual Meeting, Abstract LBA2, Plenary Session)
TITAN: phase III double-blind, randomized study of apalutamide versus placebo in patients with metastatic castration-sensitive prostate cancer receiving androgen deprivation therapy. 2019 ASCO Annual Meeting, abstract 5006
ARASENS: A phase 3 trial of darolutamide in combination with docetaxel for men with metastatic hormone-sensitive prostate cancer. Ongoing trial; results pending
Phase III trials in CSPC
1. N Engl J Med. 2015 Aug 20;373(8):737-46.2. Lancet 2016 Mar 19;387(10024):1163-77.3. N Engl J Med. 2017 Jul 27;377(4):338-351.4. N Engl J Med. 2017 Jul 27;377(4):352-360.
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Efficacy end points
Primary:– OSSecondary:– Time to clinical
progression– Time to castration
resistant prostate cancer
– Proportion of patients with PSA complete response (CR) at six months
– Proportion of patients with PSA CR at 12 months
– Quality of life change from baseline to three months
Androgen deprivation therapy (ADT) +
DOCETAXEL (N=397)
ADT ALONE(N=393)
Patients– Stratified according to:– Age (≥ 70 vs. < 70)– ECOG performance
status (0-1 vs. 2)– Combined androgen
blockade for > 30 days (yes vs. no)
– Duration of prior adjuvant hormonal therapy (> 12 months vs. ≤ 12 months
– Concurrent bisphosphonate use (yes vs. no)
– Volume of disease (low vs. high)
RANDOMIZED
1:1
790 PATIENTS RANDOMIZEDJULY 2006 – DECEMBER 2013
Estudo CHAARTED
N Engl J Med. 2015 Aug 20;373(8):737-46..
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Aumento de 13,6 meses na sobrevida global mediana com ADT + Docetaxel comparado com ADT monoterapia
N Engl J Med. 2015 Aug 20;373(8):737-46..
CHAARTED: sobrevida global
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Aumento de 17 meses na sobrevida com associação de docetaxel nos pacientes com alto volume de doença.
Não foi observado aumento na sobrevida em pacientes com baixo volume de doença, mesmo com maior tempo de seguimento mediano (53,7 meses).
N Engl J Med. 2015 Aug 20;373(8):737-46.J Clin Oncol 2018 Apr 10;36(11):1080-1087.
Alto volume:• ≥ 4 lesões
ósseas• ≥ 1 lesão
extra-axial OU • Doença
visceral
CHAARTED: análise de subgrupos
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Estudo STAMPEDE: câncer de próstata avançado
Lancet 2016 Mar 19;387(10024):1163-77.N Engl J Med. 2017 Jul 27;377(4):338-351.
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Eligibility:
– Newly diagnosed metastatic, or node positive, or locally advanced prostate cancer
– ≥ 2 of stage T3/4
– PSA≥ 40 ng/ml
– Gleason 8-10
– WHO performance status 0-2
Primary endpoint: Overall survivalSecondary endpoints: Failure-free survival (FFS), Toxicity, Quality of Life, Skeletal related events, Cost effectiveness
N=2,962
2:1:1:1
Stratification
– Prior Hormone therapy (no more than 12 months)
– PSA ≥ 4 ng/ml and rising with doubling time < six months
– PSA ≥ 20 ng/ml
– Patients relapsing with node positive or metastatic disease
RANDOMIZATION
SOC: (ADT +/-RT)Arm:A
SOC+ Zoledronate
Arm: B
SOC+ Docetaxel
Arm: C
SOC+ Zole +
DocetaxelArm: E
STAMPEDE (Braços A, B, C, and E)
Lancet 2016 Mar 19;387(10024):1163-77.
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– Aumento significativo da sobrevida livre de falha com TDA + Docetaxel comparado com TDA (37 meses vs. 21 meses, HR 0.62; p<0.0001)
– Aumento significativo da sobrevida global com TDA + Docetaxel comparado com TDA (81 meses vs. 71,3 meses, HR 0.78, 95% CI 0.66-0.93; p=0.006). Benefício aparentemente restrito a pacientes metastáticos (M1).
– Nenhum benefício da associação de ácido zoledrônico
STAMPEDE (Braços A, B, C, and E)
Lancet 2016 Mar 19;387(10024):1163-77.
Sobrevida Livre de Falha Sobrevida Global
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Efficacy end points
Primary:
– OS
Secondary:
– Failure-free survival (FFS)
– Toxicity
– Quality of life
– Skeletal-related events
– Cost effectiveness
ADT + abiraterone acetate
(1000 mg/d) + prednisolone (5 mg/d)
(n=960)
ADT alone(ADT ± RT)
(n=957)
Patients
Newly-diagnosed
Any of:– Metastatic– Node-positive– ≥ 2 of stage T3/4 PSA ≥
40ng/ml Gleason 8-10
Relapsing after previous RP or RT with ≥ 1 of:– PSA ≥ 4ng/ml and rising
with doubling time < 6m
– PSA ≥ 20ng/ml– Node-positive– Metastatic
RANDOMIZED
1:1
1,917 patients randomised November 2011 - January 2014
STAMPEDE (braço G): Abiraterona e Prednisolona
N Engl J Med. 2017 Jul 27;377(4):338-351.
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STAMPEDE: Abiraterona
N Engl J Med. 2017 Jul 27;377(4):338-351.
Doença metastática
Doença não metastática
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Efficacy end points
Co-primary:
– OS
– rPFS
Secondary: time to
– Pain progression
– PSA progression
– Next symptomatic skeletal event
– Chemotherapy
– Subsequent PC therapy
ADT
+ Abiraterona 1000 mg/d
+ Prednisona 5 mg/d(n = 597)
ADT
+ placebos
(n = 602)
Patients
– Newly diagnosed adult men with high-risk* mCSPC
Stratification factors
– Presence of visceral disease (yes/no)
– ECOG PS (0, 1 vs 2)
RANDOMIZED
1:1
Estudo LATITUDE: Abiraterona e Prednisona
N Engl J Med. 2017 Jul 27;377(4):352-360.
* Alto risco: presença de ≥ 2 critérios:- Gleason ≥ 8- ≥ 3 lesões ósseas- Doença visceral
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N Engl J Med. 2017 Jul 27;377(4):352-360.
Estudo LATITUDE: Abiraterona e Prednisona
Sobrevida em 3 anos:ADT + AA + P: 66%ADT + placebos: 49%
33 meses14,8 meses
Sobrevida Global Sobrevida Livre de Progressão Radiográfica
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Docetaxel x 6 ciclos
Abiraterona + Prednisona
Duração mais curta de tratamento (18 semanas)
Tratamento mais longo (em geral, anos)
Menor custo Alto custo
Maior risco de toxicidade:- Mielosupressão- Neutropenia febril- Neuropatia- Fadiga significativa- etc
Tratamento bem tolerado, com eventos adversos infrequentes:- Hipertensão arterial- Edema- hipocalemia
Administração EV, com necessidade de visitas médicas frequentes
Tratamento oral, menor número de visitas médicas
Docetaxel vs. Abiraterona
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• TDA permanece como a base do tratamento do CPSC
• Abiraterona/prednisona OU Docetaxel devem ser oferecidos para pacientes com CPSC, especialmente em casos de doença de alto risco / alto volume.
• Comparação entre abiraterona e docetaxel (Stampede) sugere eficácia semelhante.
• Decisão entre docetaxel vs abiraterona deve levar em conta os custos, acesso às terapias, perfil de toxicidades e comorbidades do paciente.
• Cenário mudando rapidamente
• estudos de combinação
• novos agentes: apalutamida / darolutamida
Conclusões: CPSC
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Case Presentation
• 64-year-old man, ECOG 0.
• 07/2017: PSA 1512.0 ng/mL
• Imaging: multiple bone lesions, extensive lymphadenopathy.
• 07/2017: Degarelix + Abiraterone/prednisone
• 15/09/2017 - PSA 0,12 ng/mL
• 18/12/2018 - PSA 0,005 ng/mL
• 11/06/2018 - PSA < 0,003 ng/mL
• 23/04/2019 – PSA < 0,003 ng/mL
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Câncer de Próstata Resistente à Castração
(CPRC)
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Study Year Indication NPSA decline
>50%mPFS
(months)Overall Survival
Median HR P value
Docetaxel vs. mitoxantronea 2004 1st line
chemo 1,006 45% vs 32% NS 18.9 vs 16.5 0.76 0.009
Cabazitaxel vs. mitoxantronea
2010 Post docetaxel 755 39% vs 18% 2.8 vs 1.4 15.1 vs 12.7 0.70 <0.001
Abiraterona vs. placeboa 2012 Pre
docetaxel 1,088 62% vs 24% 16.5 vs 8.2 35.3 vs 30.1 0.79 0.0151
Enzalutamida vs. placebo
2014 Pre docetaxel 1,717 78% vs 3% NR vs 3.9 35.3 vs. 31.3 0.77 0.0002
Radium-223 vs. Placebo
2013 Pre and Post Docetaxel 921 16% vs 6% 15.6 vs 9.8b 14.9 vs 11.3 0.70 <0.001
N Engl J Med 2004; 351: 1502-1512 Lancet 2010; 376: 1147-1154Eur Urol 2014; 5:815-825 N Engl J Med 2014; 371: 424-433 N Engl J Med 2013; 369: 213-223
Life-prolonging agents for mCRPC available in Brazil
a. Prednisone in both armsb. PSA decline > 30%c. Time to 1st symptomatic skeletal
event
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Int Braz J Urol. 2017 May-Jun;43(3):407-415.Braz J Clin Oncol, under submission
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Treatment Sequencing Strategies
and
Current Role of Biomarkers
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PCWG 3
Adapted, Prostate Cancer Working Group 3, J Clin Oncol, 2016
How to sequence the available life-prolonging
agents?
AbirateroneAbiraterone
DocetaxelDocetaxel
CabazitaxelCabazitaxel
EnzalutamideEnzalutamide
Radium-223Radium-223
Predictive biomarkers for treatment selection are
urgently needed
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Examples• 65 yo male• Prostatectomy in 2013• Gleason 7 (4+3), pT3aN0• mCSPC S/P ADT started in Aug/2015• mCRPC Oct/17• PSA 88 ng/mL• Bone mets only (extensive disease)• Mild right hip pain• ECOG 1
• 69 yo male• Prostatectomy in 2013• Gleason 7 (4+3), pT3bN1• mCSPC S/P ADT started in Aug/2015• mCRPC Oct/17• PSA 115 ng/mL• Bone mets only (extensive disease)• Severe bilateral hip and sternal pain• ECOG 2
Which is the best treatment option??
o Abirateroneo Enzalutamideo Docetaxelo Radium-223
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Predictive• ARv7• AR mutations (?)• DDR gene alterations
(?)• MSI-H tumors• Rb1, TP53 (?)• CDK12• Others
• None (yet)
Biomarkers in Advanced Prostate Cancer
Prognostic• LDH• PSA• CTC count• Hemoglobin• Alkaline phosphatase• Albumin• Pain / Opioid use• ECOG PS• Sites of metastasis• Duration of ADT
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AR-V7 - Johns Hopkins Series Update (N= 202 pts)
J Clin Oncol 2017; 35: 2149-56
75.5% 52.2% 13.9%
11.3 vs 6.2 vs 2.1 monthsP<0.001
13.9 vs 7.7 vs 3.1 monthsP<0.001
28.7 mo
29.5 mo
11.2 mo
P<0.001
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Antonarakis ES, et al. JAMA Oncol 2015; 1: 582-591
AR-V7(+) : 7/17 = 41%
(95%CI: 18–67%)
AR-V7(–) : 13/20 = 65%
(95%CI: 41–85%)
P = 0.194
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ARV7(+) to ARV7(–) Transitions
Nakazawa M et al. Annals Oncol 2015; 26: 1859-65
58% (7/12) of AR-V7(+) patients converted to AR-V7(–) during treatment with taxane chemotherapy
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Potential Decision Schema
Sprenger, Uo, Plymate. Annals of Oncology 2015; 26: 1805-7
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• TOPARP-A Trial (phase II)• 50 pts with mCRPC• Treated with Olaparib 400 mg bid• Mandated tumor biopsies for NGS, exome and transcriptome analysis• Primary endpoints:
- RECIST response- PSA50 response- CTC conversion from > 5 to < 5 /7.5mL
N Engl J Med 373:1697-1708, 2015
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Overall response 33% (16/49 pts)PSA50 response: 22%
RECIST response: 19%CTC conversions: 29%
DNA repair defect
6% (2/33)88% (14/16)
Yes (33%) No (77%)
N Engl J Med 373:1697-1708, 2015
p<0.01
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Perspectives - Immunotherapy
Vaccines:- Sipuleucel-T: phase III trial – 4 months survival benefit- GVAX: 2 negative randomized trials- Prostvac: phase III study with no survival benefit
Immune Checkpoint Inhibitors- Ipilimumab: 2 phase III trials with no survival improvement over placebo- Small series with limited benefit from anti-PD-(L)1, but some significant
responses
Conclusions so far:- Modest benefit of immunotherapy for unselected patients – low mutational
burden- Need to identify subgroups that might derive benefit from checkpoint
blockade
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Oncotarget. 2016 Aug 16;7(33):52810-52817
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KEYNOTE-199: Pembrolizumab for docetaxel-refractory mCRPC
De Bono J, et al. ASCO 2018, abstract#5007
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mCRPC and Immunotherapy
• Potential subgroups that may benefit from anti-PD-(L)1 inhibitors– MSI-H (pembrolizumab approved in the US)– DNA repair gene alterations?– CDK12 inactivation?
Abida et al. ASCO 2018• 20/839 MSI-H (2,4%)
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Selected Ongoing Studies• Phase II
– Pembrolizumab + Olaparib vs Pembro + Docetaxel vs Pembro + Enzalutamide (Keynote-365; NCT 02861573)
– Checkmate 9Kd trial: mCRPC• Nivolumab + Rucaparib
• Nivolumab + Docetaxel
• Nivolumab + Enzalutamide
– Nivolumab monotherapy (DRD+ vs DRD- pts)
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CONCLUSIONS
• mCRPC is indeed an heterogeneous disease.
• Significant survival improvement with available therapies
• Currently, the decision on which therapy to start is based on clinical phenotype, symptoms, ECOG PS, PSA, histology…
• Major challenge is to identify biomarkers for treatment selection
• Treatment landscape is likely to change with incorporation of predictive biomarkers and identification of molecular / genomic subtypes