Neoplasie della prostata

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Innovazione e

personalizzazione: come i nuovi farmaci cambiano la

strategia terapeutica

Neoplasie della prostata

Chiara Porcu

UO Oncologia Ospedale San Francesco

Nuoro

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Outline

• M1 Hormone Sensitive Disease

• M0 Castration Resistent Disease

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Outline

• M1 Hormone Sensitive Disease

• M0 Castration Resistent Disease

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(5)

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High volume

Visceral metastases

≥4 bone lesions with ≥1 beyond the vertebral or bodies and pelvis

High risk :

Gleason score >8

or

Visceral metastases

>3 bone lesions or

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DOCETAXEL ABIRATERONE

ENZALUTAMIDE APALUTAMIDE

2015 2017 2019

TREATMENT OPTIONS IN mHSPC

CHARTEED

STAMPEDE

LATITUDE

STAMPEDE

ARCHES ENZAMET

TITAN

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ARCHES Trial

Armstrong et al., Abstract N° 687, ASCO GU 2019

ADT, androgen deprivation therapy; CT, computerised tomography; ECOG, eastern cooperative oncology group; mHSPC, metastatic hormone sensitive prostate cancer; MRI, magnetic resonance imaging; OS, overall survival, rPFS, radiographic progression free survival

Key eligibility criteria:

• mHSPC (confirmed by bone scan, CT, or MRI), histologically confirmed adenocarcinoma

• ECOG Performance Status 0 to 1

• Current ADT duration ≤3 months unless prior docetaxel, then

≤6 months

Stratification factors:

• Volume of disease (low vs. high)

• Prior docetaxel therapy for mHSPC (none, 1–5, or 6 cycles)

Enzalutamide 160 mg/day + ADT

Placebo + ADT

Key discontinuation criteria Radiographic progression, unacceptable toxicity, or initiation of an investigational

agent or new therapy for prostate cancer

First patient enrolled March 21,

2016

October 14, 2018

rPFS final analysis Overall survival (OS)

interim analysis

OS final analysis N=1150

R

1:1

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PRIMARY ENDPOINT: rPFS

Armstrong et al., Abstract N° 687, ASCO GU 2019

61% reduction in risk of rPFS or death

(10)

SUBGROUP ANALYSIS OF rPFS

Armstrong et al., Abstract N° 687, ASCO GU 2019

Excellent results observed on rPFS across all pre-specified subgroups

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ENZAMET Trial

Christopher Sweeney, ASCO 2019

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ENZAMET

Primary endpoint: Overall survival

Christopher Sweeney, ASCO 2019

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ENZAMET – Concurrent Docetaxel

Christopher Sweeney , ASCO 2019

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TITAN Trial

Kim et al, ASCO2019

mCSPC Patient Eligibility

Distant metastatic disease by ≥ 1 lesion on bone scan

Castration sensitive ECOG PS 0 or 1

On-Study Requirement Continuous ADT

Stratifications

Gleason score at diagnosis (≤ 7 vs ≥ 8) Region (North America and EU vs all other countries

Prior docetaxel (yes vs no)

Permitted Prior docetaxel

ADT ≤ 6 mo for mCSPC or ≤ 3 yr for local disease Local treatment completed ≥ 1 yr prior

Apalutamide 240 mg daily + ADT

(n = 525)

Placebo + ADT (n = 527)

Dual primary end points

• OS

• rPFS

Secondary end points

• Time to cytotoxic chemotherapy

• Time to pain progression

• Time to chronic opioid use

• Time to skelet al-related event

1:1 R A ND O MIZ A TION

N = 1052

“ All-comer” patient population

Exploratory end points

• Time to PSA progression

• Second progression-free survival (PFS2)

• Time to symptomatic progression

ECOG, Eastern Cooperative Oncology Group performance status;

PSA, prostate-specific antigen; rPFS, radiographic progression-free survival.

Kim N. Chi, MD

Dec 2015 – Jul 2017

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TITAN OS: Apalutamide Significantly Reduced the Risk of Death by 33%

15

Kim N. Chi, MD

CI, confidence interval; NE, not evaluable.

P ati e n ts Who W e re A liv e ( % )

100

75

50

25

0 No. at risk Apalutamide Placebo 525

527 513 509

490 473

410 387

165 142

14 16

0 0

0 6 12 18 24 30 36

Months

Apalutamide + ADT

Placebo + ADT

Apalutamide

(n = 525)

Placebo (n = 527) Median, mo (95% CI) NE (NE-NE) NE (NE-NE)

HR (95% CI) 0.67 (0.51-0.89)

P value 0.0053

82%

74%

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Overall Survival in M1 CSPC trials (from best to worse HR)

Trial HR for OS LP treatment Follow-up (mo)

STAMPEDE Abi 0.61 (0.49-0.75) 310/957 (32%) 40

LATITUDE 0.66 (0.56-0.78) 345/602 (57%) 52

TITAN 0.67 (0.51-0.89) 165/527 (31%) 23

ENZAMET 0.67 (0.52-0.86) 271/562 (48%) 34

CHAARTED 0.72 (0.59-0.89) 187/393 (48%) 54

STAMPEDE Doc+ZA 0.79 (0.66-0.96) 372/1184 (31%) 43

ARCHES 0.81 (0.53-1.25) <133/576 (<23%) 14

STAMPEDE Doc 0.81 (0.69-0.95) 372/1184 (31%) ?

GETUG-15 0.88 (0.68-1.14) 127/193 (66%) 84

Kyriakopoulos CE, J Clin Oncol 2018; Gravis G, Eur Urol 2015; Clarke N/James N, ESMO 2019, James N, Lancet 2016, Fizazi K, Lancet Oncol 2019, James N, NEJM 2019 Armstrong AJ, J Clin Oncol 2019, Chi K, NEJM 2019, Davis I, NEJM 2019

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Next generation AR targeting improve OS regardless of low/high burden

STAMPEDE (Abi)

TITAN (Apa)

ENZAMET (Enza)

Hoyle A, ESMO 2018; Chi K, NEJM 2019, Davis I, NEJM 2019

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Take home message

• Nella mHSPC l’ ADT da sola non puo piu rappresentare lo standard terapeutico

• ARTA possono offrire un vantaggio maggiore di DOC nella popolazione all camers

Come selezionare il paziente?

Ci sono pazienti che possono essere trattati con sola ADT?

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Outline

• M1 Hormone Sensitive Disease

• M0 Castration Resistent Disease

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Chi è il paziente nmCRPC?

Biochemical progression while

on ADT

PSA ≥ 2 ng/dl

+

Serum testosterone levels below 50

ng/mL

+

evidence of ^No metastasis

By CT/bone scan

PSA DT <10 months M0 CRPC:

• Patients with high- risk nmCRPC have a shorter PSADT and a higher risk of metastasis

^4,5

High Risk

1. Paller CJ et al. Clin Adv Hematol Oncol. 2013;11(1):14-23;

2. Arlen PM, et al. J Urol. 2008 Jun;179(6):2181-5; 3. Smith MR, et al. J Clin Oncol. 2013 Oct 20;31(30):3800-6; 4.

Freedland SJ, et al. J Clin Oncol. 2007 May 1;25(13):1765-71;

5. Howard LE et al. BJU Int. 2017 Nov;120(5B):E80-E86.

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Enzalutamide

SPARTAN

PROSPER ARAMIS

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Phase III randomized trials in High-Risk nmCRPC

Similar trials with Enzalutamide (PROSPER)¹, Apalutamide (SPARTAN)², Darolutamide (ARAMIS)³

1

Hussain, NEJM 2018;

²

Matthew, NJM 2018;

³

Fizazi, NEJM 2019

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SPARTAN

Smith MR, et al. N Engl J Med. 2018;378:1408-18.

Hussain M, et al. N Engl J Med. 2018;378:2465-74.

Fizazi K et al. N Engl J Med. 2019;380:1235–1246

HR 0.28 p < 0.0001

ENZA, 36.6 mo (median)

PBO, 14.7 mo (median)

PROSPER ARAMIS

SPARTAN, PROSPER, and ARAMIS:

primary endpoint – MFS

HR 0.29 p < 0.001

HR 0.41

p < 0.001

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Apalutamide SPARTAN

Enzalutamide PROSPER

Darolutamide ARAMIS

TTPP NR vs. 3.7 mo

HR 0.06

(95% CI 0.05 – 0.08)

37.2 mo vs. 3.9 mo HR 0.07

(95% CI 0.05 – 0.08)

33.2 mo vs. 7.3 mo HR 0.13

(95% CI 0.11–

0.16)

PFS 40.5 vs. 14.7 mo

HR 0.29

(95% CI 0.24 – 0.36)

Not reported 36.8 vs. 14.8 mo HR 0.38

(0.32–0.45)

Time to symptom.

progression

NR fav. apalutamide HR 0.45

(0.32–0.63)

Not reported 40.3 vs. 25.4 mo HR 0.65

(0.53-0.79)

Time to subseq.

therapy

NR fav. apalutamide HR 0.44

(0.29–0.66)

39.6 vs. 17.7 mo HR 0.21

(0.17–0.26)

NR vs. 38.2 mo HR 0.43

(0.31–0.60)

OS

(Interim analysis)

NR vs. 39 mo HR 0.70, p = 0.07

NR fav. enza

HR 0.80 p = 0.15

NR fav. Darolut HR 0.71, p = 0.045

E ff ic ac y

SPARTAN, PROSPER, and ARAMIS:

Secondary endpoint

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Results: Apalutamide Was Associated With a 25%

Reduction in Risk of Death (SPARTAN)

The 4-year OS rates for APA and PBO were 72.1% and 64.7%, respectively

OBF, O’Brien-Fleming.

aAnalyses for the Kaplan-Meier plot were stratified log-rank test.

Secondary End Point:

Overall Survival At 41 months median follow-up 100

80

60

40

20

0 0

HR, 0.75 (95% CI, 0.59-0.96)

^a

P = 0.0197

OBF boundary = 0.0121

4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64

Months No. at risk

APA 806 791 774 758 739 716 689 645 592 462 350 249 143 61 25 4 0 PBO 401 390 383 371 356 336 325 300 266 200 144 105 57 28 9 2 0

APA, not reached

PBO, not reached

Patients Who Were Alive (%)

7

0.02 > 0.01  Non significant

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Apalutamide SPARTAN

Enzalutamide PROSPER

Darolutamide ARAMIS

AEs profile

SAEs: 24.8% vs. 23.1%

Discont. 10.6% vs. 7%

SAEs: 24% vs. 18%

Discont. 9% vs. 6%;

SAEs: 24.8% vs. 20%

Discont. 8.9% vs. 8.7%

Most frequent

3 AEs Hypert. 14.3% vs. 11.8%

Rash: 5.2% vs. 0.3%

Fracture: 2.7% vs. 0.8%

Falls: 1.7% vs. 0.8%

Mental disorders 0% vs 0%

Hypert.5% vs. 2%

Card. Ev. 4% vs. 2%

Fatigue: 3% vs. 1%

Mental disorders 1% vs 0,2%

Hypert. 3.1% vs. 2.2%

Coronary-disorders:

1.7% vs. 0.4%

Urinary retention 1,6% vs 2%

SPARTAN, PROSPER, and ARAMIS:

Safety

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Saad , Lancet Oncol 2018

Apalutamide

Impact on Health-related QoL FACT-P Score

Tombal , Lancet Oncol 2019

Enzalutamide

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Apalutamide Extended PFS2 Compared With Placebo



69% of PBO-treated patients and 40% of APA-treated patients received subsequent life-prolonging therapy



The most commonly received subsequent therapy was abiraterone acetate plus prednisone

*P value for PFS2 is nominal.

PFS2, secondary progression-free survival.

Exploratory End Point:

PFS2 100

80

60

40

20

0 0

APA, 55.6 mo (median)

PBO, 43.8 mo (median)

Patients Who Were Alive Without Second Progression (%)

No. at risk

Apalutamide 806 783 765 735 705 657 621 571 504 387 280 194 100 43 12 2 0

Placebo 401 387 365 335 299 265 226 184 148 113 77 56 24 12 1 0 0

HR, 0.55 (95% CI, 0.45-0.68) P < 0.0001*

4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64

Month

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Subsequent Approved Treatment

APA

(n = 803) PBO (n = 398)

Discontinued study treatment 412 (51%) 323 (81%)

Received approved therapy for mCRPC, n

(% of patients who dc’d study treatment) 247 (60%) 255 (79%)

First subsequent approved treatment

Abiraterone acetate + prednisone 183 (44%) 188 (58%)

Enzalutamide 27 33

Docetaxel 20 18

Cabazitaxel 0 1

Sipuleucel-T 4 9

Radium-223 1 0

*Subsequent approved treatment was defined as treatment with an agent associated with improved overall survival.

Small E, et al. Poster present at ASCO GU 2019. Abstract 144

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Take home message

• Nella nmCRPC il trattamento con ARTA aumenta la MFS a fronte di un profilo di tossicità accettabile

• Un follow up più lungo chiarirà il vantaggio in OS

Che ruolo hanno in questo setting le nuove tecniche di imaging (p.e. PET-PSMA)?

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