Trattamento della malattia ormonosensibile

Dott. G. Di Lorenzo

Metastatic hormone-sensitive

prostate cancer

JCO 2019

mHSPC 2018: Radiotherapy in oligometastatic disease mHSPC 2019: Addition of Enzalutamide to ADT

mHSPC 2019: Addition of Apalutamide to ADT

CRPC M0 2019: Darolutamide, Enzalutamide, Apalutamide

8 YEARS OF PROGRESS IN PROSTATE CANCER

Clinical decision making

in a rapidly evolving landscape of life-prolonging therapy…

JCO 2019

2015

TAX327 (DOC/P ‒ mCRPC): 2.7 mo² TROPIC (DOC/P  CAB/P ‒ mCRPC): 2.4 mo^3-4 COU-AA-301 (DOC/P  ABI/P ‒ mCRPC): 4.6 mo⁵ COU-AA-302 (ABI/P pre-DOC ‒ mCRPC): 4.4 mo⁶ PREVAIL (ENZA pre-DOC ‒ mCRPC): 4.0 mo⁷

STAMPEDE ‒ M1 (DOC/P + ADT ‒ mHSPC): 15.0 mo⁸

CHAARTED – M1 De Novo (DOC/P + ADT – mHSPC): 16.8 mo⁹ LATITUDE De Novo (ABI/P+ADT-mHSPC) 16.8 mo¹⁰

STAMPEDE (ABI/P +ADT –mHSPC): not yet reached

PROSPER – M0 CRPC (ENZA) not yet reached

SPARTAN –M0 CRPC (ABI/P) not yet reached TITAN: HSPC: APALUTAMIDE

HR: 0.67

ENZAMET: HSPC: ENZALUTAMIDE HR: 0.67

1. Kantoff PW. J Clin Oncol. 1999;7:2506–13; 2. Tannock IF. N Engl J Med. 2004;351:1502–12; 3. de Bono JS et al. Lancet.

2010;376:1147–54; 4. Sartor O. J Clin Oncol. 2011;29(S15):abstract 4525 (podium presentation); 5. Fizazi K . Lancet Oncol.

2012;13:983–92 (supplementary appendix); 6. Ryan CJ. Lancet Oncol. 2015;16:152–60; 7. Beer TM. Eur Urol. 2017;71:151–54; 8.

James ND et al. Lancet. 2016;387:1163–77; 9. Sweeney C et al. Ann Oncol. 2016;27(suppl 6):10 .Final Analysis of atitude ASCO GU 2019 Fizazi et al.Abstr. 141

2004 2010

2013 2011

2014 2015 2016 2017 2018

2019

History:

OS gain in prostate cancer

6

years

Local therapy

Androgen deprivation therapy (ADT)

Therapies after ADT

Death

ADT

mCRPC post- docetaxel

mCRPC

Asymptomatic or mildly symptomatic

M+

Hormone sensitive

ADT + Abiraterone

Enzalutamide

Abiraterone Abiraterone

Docetaxel Cabazitaxel

Enzalutamide

ADT + Docetaxel

tempo

Carico di malattia

Ca prostatico: uno scenario in evoluzione

RT+

OT/Docetaxel

CRPC M0

RADIUM 223

enzalutamide

Apalutamide

Darolutamide

RADIUM 223

ADT + Enza

ADT + Apalutam

.

Topics to discuss

Hormone-sensitive disease

-High volume/high risk

-Low volume/low risk

-Future perspectives

Abiraterone or Docetaxel:

this is the question... ^.

Overall Efficacy comparison

Subgroup Efficacy comparison

-Tumor burden

-Disease presentation

Toxicity

Quality of life

Costs and treatment duration

Vale et Al. Lancet Oncol 2016

Overall Survival in M1

Failure-free Survival in M1

Rydzewska et Al. Eur J Canc 2017

Overall Survival in M1

Progression-free survival in M1 (clin/radiol)

Kyriakoupulos et Al. JCO 2018

Overall Survival High-volume Overall Survival Low-volume

Kyriakoupulos et Al. JCO 2018 OS High-volume De novo M OS Low-volume De novo M

OS High-volume prior local Ther OS Low-volume prior local Ther

Clear Benefit

Likely to Benefit

No

Benefit

Hormone Sensitive Prostate Cancer

17

Latitude study

N Engl J Med. 2017 June 4 [Epub ahead of print]

Stampede study

N Engl J Med. 2017 June 3

[Epub ahead of print]

Internal Use Only

18

High risk – definition from LATITUDE

 High-risk prognosis is defined as having at least 2 ^{of the}

following 3 risk factors ^: (1) Gleason score of ≥8

(2) Presence of 3 or more lesions on bone scan (3) Presence of visceral metastasis

 The high-risk prognostic factor of Gleason score ≥8 was selected based on data from the SWOG 9346 study – Gleason score ≥8: strong predictor for risk of death (HR=1.58 and p <0.0001)

 The second and third high-risk prognostic factors are both related to high volume disease (defined as 3 or more lesions by bone scan or involvement of viscera).

– A single-center study of 286 patients: OS was 3.1 years in those with high volume disease compared with 7.8 years in those with low volume disease

Clinicaltrials.gov: NCT01715285; Hussain M, et al. J Clin Oncol 2006;24:3984-3990;

Millikan RE, et al. J Clin Oncol 2008;26:5936-5942.

Statistically significant 38% risk reduction of death

0

0 6 12 18 24 30 36 42

20 40 60 80 100

Months

Overall Survival (%)

No. at risk

ADT + AA + P 597 565 529 479 388 233 93 9

602 564 504 432 332 172 57 2

Hazard ratio, 0.62 (95% CI, 0.51-0.76) P<0.0001

ADT + AA + P, not reached

ADT + placebo 34.7 mo

ADT + placebos

19 No. of events: 406 (48% of 852)

ADT + AA + P: 169 ADT + placebos: 237

Presented by: Karim Fizazi

Median follow-up:

30.4 months

Events

262 Control | 184 abiraterone plus prednisone

HR 0.63 95% CI 0.52 to 0.76 P-value 0.00000115

SOC SOC+AA P

OS – STAMPEDE “abiraterone plus prednisone comparison”

James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session

It represents a 37%

improvement in

survival

Kyriakoupulos et Al. JCO 2018 Fizazi et Al. NEJM 2017

High volume Disease CHAARTED

High risk Disease LATITUDE

vs

Patients selection according to Tumor Burden in phase III trials of mHSPC

Docetaxel Abiraterone

High Volume vs Low Volume mHSPC (prospectively stratified)

CHAARTED Criteria

• Visceral metastases

• ≥4 Bone lesions with ≥1 beyond the vertebral bodies and pelvis

High Risk de novo mHSPC (all randomized) LATITUDE Criteria

At least two of the following:

• Gleason Score ≥8

• ≥3 Bone lesions

•Visceral metastases

NEWS FROM ESMO 2018

Abiraterone : improved OS also stratifing for High volume

POST -HOC-ANALYSIS FROM STAMPEDE

Sydes et ESMO 2017

Sydes et ESMO 2017

Aim: The objective of this study was to

compare ITCs with AAP + ADT vs Doc + ADT on HRQoL and pain PROs in patients with mCNPC.

Mean Change in PRO Scores from Baseline for FACT-P (A) and BPI (B) from LATITUDE and CHAARTED

ASCO GU 2018

Indirect comparison showed that patients receiving AAP + ADT had improvements in HRQoL after 3 months, compared with Doc + ADT; these

effects were sustained up to 1 year after treatment.

Feyerabend S, et al. Poster presented at ASCO-GU 2018; abstract 200.

Indirect treatment comparison (ITC) of

AA + P and Doc on PROs in mCNPC

Docetaxel or Abiraterone Summary

Docetaxel Abiraterone

Efficacy FFS Probably better

Efficacy OS Equally appropiate Equally appropiate High Volume Dis.

Low Volume Dis.

Tollerability Preferred Often preferred

Duration 4 months 2 years

Costs More affordable Less affordable

Despite early Docetaxel or Abiraterone 20% of patients die to 24 months

Kyriakoupulos et Al. JCO 2018

CHAARTED

Overall Survival High-volume

LATITUDE

Overall Survival High-risk

James et Al. NEJM 2017

29

Evidence network

After ASCO 2019????????

NSAA+ADT

ENZAMET⁹

Apa+ADT

TITAN¹⁰

Enza+ADT ^ARCHES8

ADT alone

AA+P+ADT Doce+ADT

LATITUDE¹ STAMPEDE² (Arm G vs A)

CHAARTED⁴ GETUG-AFU15⁵

STAMPEDE (Arm C vs A)⁶ STAMPEDE³

(Arm C vs G)

Radiotherapy +ADT

STAMPEDE⁷ (Arm H vs A)

1. Fizazi K, et al. N Engl J Med. 2017 Jul 27;377(4):352-360; 2. James N, et al. N Engl J Med. 2017 Jul 27;377(4):338-351; 3. Sydes MR, et al. Ann Oncol. 2018 May 1;29(5):1235-1248; 4. Sweeney et al. N Eng J Med 2015; 378(8): 737-746; 5. Gravis G, et al. Eur Urol. 2016 Aug;70(2):256-62; 6.

James et al. Lancet 2016; 387(10024):1163-77; 7. Parker CC, et al. Ann Oncol 2018;29(Suppl 8):LBA5_PR; 8. Armstrong AJ, et al. ASCO-GU 2019.

Poster and oral presentation (Abstract 687); 9. NCT02446405; 10. NCT02489318

June, 2019

TITAN Study Design

3 1

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 skeletal-related event

1:1 RANDOMIZATION

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

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

33

Kim N. Chi, MD

CI, confidence interval; NE, not evaluable.

Patients Who Were Alive (%)

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%

First Subsequent Therapy for Prostate Cancer

34

Proportion of Patients receiving subsequent therapy Apalutamide + ADT Placebo + ADT

Patients who discontinued treatment for any reason^a and remained alive, n 170 271

Patients receiving subsequent systemic prostate cancer therapy at data cutoff,^c n (%) 87 (51.2) 190 (70.1)

Distribution of reported subsequent therapy n = 87 n = 190

Hormonal therapy, n (%) 44 (50.6) 98 (51.6)

Abiraterone acetate plus prednisone 21 (24.1) 45 (23.7)

Bicalutamide 16 (18.4) 31 (16.3)

Enzalutamide 3 (3.4) 17 (8.9)

Chemotherapy, n (%) 35 (40.2) 73 (38.4)

Docetaxel 29 (33.3) 67 (35.3)

Cabazitaxel 1 (0.4) 2 (1.1)

Other therapy, n (%) 8 (9.2) 19 (0.1)

Radium-223 2 (2.3) 4 (2.1)

Sipuleucel-T 2 (2.3) 5 (2.6)

aReasons for discontinuation were disease progression, adverse event, withdrawal by patient, death, physician decision, and protocol violation.

Kim N. Chi, MD

35

TITAN & SPARTAN – safety profile

STUDY TITAN¹ SPARTAN²

POPULATION mHSPC “all comers” High risk nmCRPC

Apalutamide + ADT

(n = 524) Placebo + ADT

(n = 527) Apalutamide + ADT

(n = 803) Placebo + ADT (n = 398)

Any AE 507 (96.8) 509 (96.6) 775 (96.5) 371 (93.2)

Grade 3 or 4 AEs 221 (42.2) 215 (40.8) 362 (45.1) 136 (34.2)

Any SAE 104 (19.8) 107 (20.3) 199 (24.8) 92 (23.1)

Any AE leading to

treatment discontinuation 42 (8.0) 28 (5.3) 85 (10.6) 28 (7.0)

AE leading to death 10 (1.9) 16 (3.0) 10 (1.2) 1 (0.3)

Adverse Event, n (%) All Grades Grade ≥ 3 All Grades Grade ≥ 3 All Grades Grade ≥ 3 All Grades Grade ≥ 3

Rash 142 (27.1) 33 (6.3) 45 (8.5) 3 (0.6) 191 (23.8) 42 (5.2) 22 (5.5) 1 (0.3)

Fatigue 103 (19.7) 8 (1.5) 88 (16.7) 6 (1.1) 244 (30.4) 7 (0.9) 84 (21.1) 1 (0.3)

Fall 39 (7.4) 4 (0.8) 37 (7.0) 4 (0.8) 125 (15.6) 14 (1.7) 36 (9.0) 3 (0.8)

Hypothyroidism 34 (6.5) 0 6 (1.1) 0 65 (8.1) 0 8 (2.0) 0

Fracture 33 (6.3) 7 (1.3) 24 (4.6) 4 (0.8) 94 (11.7) 22 (2.7) 26 (6.5) 3 (0.8)

Seizure 3 (0.6) 1 (0.2) 2 (0.4) 0 2 (0.2) 0 0 0

1. Chi K, et al. ASCO 2019. Oral presentation (abstract 5006); 2. Smith MR, et al. N Engl J Med. 2018 Apr 12;378(15):1408-1418

Not head-to-head trials

June, 2019

June, 2019

ENZAMET Treatment

STRATIFICATION

Volume of metastases*

-High vs Low

Planned Early Docetaxel Yes vs No

ECOG PS - 0-1 vs 2

Anti-resorptive therapy -Yes vs No

Comorbidities ACE-27**: 0-1 vs 2-3 Study Site

R A N D O M I Z E

ARM A:

Testosterone Suppression + standard NSAA

ARM B:

Testosterone Suppression + Enzalutamide (160 mg/d)

Evaluate every 12 weeks

Evaluate every 12 weeks

CRPC therapy at investigator’s discretion at progression Follow for time to progression and overall survival

• Prior to randomization testosterone suppression up to 12 weeks and 2 cycles of docetaxel was allowed.

• Intermittent ADT and cyproterone were not allowed

• NSAA: bicalutamide; nilutamide; flutamide

• *High volume: visceral metastases and/or 4 or more bone metastases (at least 1 beyond pelvis and vertebral column)

• **Adult Co-morbidity Evaluation-27

Primary endpoint: Overall survival

Proportion alive at 36 months (95% CI)

NSAA Enzalutamide

0.72 (0.68 to 0.76) 0.80 (0.75 to 0.83)

Concurrent Docetaxel: Prespecified Subgroup of Interest (Biology and Treatment Implications)

Presented by: Christopher J. Sweeney, MBBS

Clinical Progression-Free Survival Overall Survival Testosterone

Suppression +

Docetaxel N=503

(71% High Volume) Testosterone

Suppression +

No Docetaxel N=622

(37% High Volume)

JCO 2019

Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer

(STAMPEDE): a randomised controlled phase 3 trial

•Christopher C Parker, MD

•Prof Nicholas D James, PhD

•Christopher D Brawley, MSc

• Prof Noel W Clarke, ChM

•Alex P Hoyle, MRCS

• Adnan Ali, MBBS

Lancet 2018, Oct.

Charteed Criteria:

Low volume:

until 3 lesions

TAKE HOME MESSAGES (1)

● Several agents have improved OS in mHSPC;

●

Patient and study characteristics: differences among the studies…..

Not head-to-head comparison studies

Docetaxel AAP+ADT ENZA+ADT APA+ADT

GETUG-15 CHAARTED STAMPEDE

(Arm C) LATITUDE STAMPEDE

(Arm G) ARCHES ENZAMET TITAN Study population

Total sample size, n 385 790 1776 1199 1917 1150 1125 1052

Patients with

mHSPC 100% 100% 61% 100% 52% 100% 100% 100%

Patient subtypes M1 all comers M1 all comers M0 M1 all

comers M1 de-novo

high-risk M0 M1 all

comers M1 all comers M1 all comers M1 all comers

Patients with high-risk/high

volume mHSPC 47.5% (183) 65 % (513) NE HR: 100% For M1 pts:

HR: 52.5%

HV: 55.4% HV: 63% HV: 52% HV: 63%

Patients with de

novo M1 71% 72.8% 58% 100% 49% 67%

61%

(61.7% ENZA and 59.5%

NSAA)

81%

(78.3% APA and 83.7%

PBO) Treatment

Median follow up 83.9 months 53.7 months 43 months 51.8^# 40 months 14.4 months 34 months 22.7 months Study arm treatment

duration, median 8 cycles 86% received 6 cycles

77% received 6

cycles 25.8 months^# 33.2 months* 12.8 months NA 20.5 months

Prior docetaxel

for mHSPC Exclusion Exclusion Exclusion Exclusion Exclusion 18% 16% 10.7%

Concurrent docetaxel for

mHSPC Not allowed Not allowed Not allowed Not allowed Not allowed Not

allowed 45% Not allowed

TAKE HOME MESSAGES (1)

● Although no level 1 evidence it is reasonable to consider in low volume oligom:

-ADT (few met, long history)

ADT + ARPi (de novo M. or aggressive disease);

-RT to prostate;

In high volume: Doc

TAKE HOME MESSAGES (2)

● Therapy in HSPC influences CRPC-therapy

What are the first-line systemic options in castration-resistant prostate cancer

after first-line treatment in the castration-sensitive setting?

Efficacy of docetaxel in CRPC seems impaired after docetaxel in CSPC

With prior docetaxel

Open questions (1)

● Best drug in HSPC?

Consider efficacy and toxicity (Abi/enza/apa/doc)

● Combination or sequence? Sequence (ENZAMET

trial)(PEACE 1 and ARASENS trials waiting)

Open questions (2)

How do we best personalize therapy on the basis of clinical subgroups?

(histologies other than adenocarcinoma, poor PS, recent cardiac events, prior seizures)

What is the role of focal therapy in the setting of effective sistemic therapy?

( RT on prostate or also on metastases…Platon trial)

How should we incorporate molecular characteristics into management?

(PTEN, RB, p53)

RB

Open questions (3)

The evolution of imaging is a major confounding factor

M1 disease by conventional imaging and those with M0

disease but M1 disease on next generetion imaging (PSMA- PET)

Trials to date have not incorporated next generation imaging

Future trials should seek to refine subgroup definitions by

incorporating newer imaging techniques

Open questions (4)

If the patient achieves an undetectable PSA with durable control (more than 2 years):

Is It reasonable to halt systemic therapy especially if adverse events that are metabolic and QoL

impairing emerge and observe until biochemical

Progression?

All Eligible Patients should benefit of all proven and effective treatments………

But

Decision based on:

-Balance risks/benefits -Comorbidities

-Emerging data

-Patients preferences

My Personal View and Hope …

Thanks