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Advanced Prostate Cancer

Diogo Assed BastosGenitourinary Oncology

Agenda Epidemiology in Brazil

Clinical States

Current treatment paradigm

mCSPC: treatment options

mCRPC: the sequencing dillema

Novel approaches

Biomarkers

Molecular Subtypes

Promising therapies

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

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+)

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

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)

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

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

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.

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..

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

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

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.

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.

– 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

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.

STAMPEDE: Abiraterona

N Engl J Med. 2017 Jul 27;377(4):338-351.

Doença metastática

Doença não metastática

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

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

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

• 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

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

Câncer de Próstata Resistente à Castração

(CPRC)

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

Int Braz J Urol. 2017 May-Jun;43(3):407-415.Braz J Clin Oncol, under submission

Treatment Sequencing Strategies

and

Current Role of Biomarkers

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

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

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

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

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

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

Potential Decision Schema

Sprenger, Uo, Plymate. Annals of Oncology 2015; 26: 1805-7

• 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

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

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

Oncotarget. 2016 Aug 16;7(33):52810-52817

KEYNOTE-199: Pembrolizumab for docetaxel-refractory mCRPC

De Bono J, et al. ASCO 2018, abstract#5007

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%)

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)

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

Obrigado!!

Diogo Assed Bastos

diogo.bastos@hsl.org.br

@DiogoAssed