Dua George Systemic Therapy for Men with ... - Duke University

Systemic Therapy for Men with Metastatic Prostate Cancer in 2018

Daniel George, MD Professor of Medicine and Surgery

Director of GU Oncology Duke Cancer Institute

Metastatic

Local Therapy

Castration Hormone Therapy

Tum

or V

olum

e an

d Ac

tivity

Sipuleucel-T

Time NONMETASTATIC

Asymptomatic Symptomatic

Docetaxel Cabazitaxel

Enzalutamide Radium-223

Natural History of Lethal Prostate Cancer and Treatment Options

Nonmetastatic

Abiraterone or Enzalutamide Radium-223

Men who Present with Metastatic Disease Have a Truncated Natural History (HSPC)

Symptomatic Time

Tum

or V

olum

e &

Act

ivity

Hormone-Sensitive Castrate-Resistant

Asymptomatic or Symptomatic

Death

Cabazitaxel Radium-223

Enzalutamide, Abiraterone, Sipuleucel-T

Androgen Deprivation +/- Docetaxel +/- Abiraterone

Metastatic

3 Key Trials: STAMPEDE, LATTITUDE, and CHAARTED

LATITUDE: Randomized Phase 3 study of abiraterone acetate in mCSPC

Fizazi K et al, NEJM, 2017

• Metastatic CSPC • ECOG PS 0-2 • Measurable/ evaluable disease • Two of three:

• Gleason >8 • >3 bone

lesions • Visceral mets

R A N D O M I Z A T I O N

ADT + Abiraterone Prednisone 5 mg daily

Co-primary endpoints: OS

rPFS

Secondary endpoints: Next SRE

Time to next treatment Time to chemo

Time to pain progression

ADT + double placebo

N=1199

LATITUDE: Overall Survival


Median OS NR vs 34.7 months

Median PFS 33 mos vs 14.8 months

LATITUDE: Secondary Endpoints


OS benefit consistently favorable across subgroups

Presented By Karim Fizazi at 2017 ASCO Annual Meeting

Statistically significant improvement in all secondary end points


Subsequent life-prolonging therapy for prostate cancer


LATITUDE: Adverse Events


E3805 – CHAARTED Treatment

STRATIFICATION Extent of Mets -High vs Low Age ≥70 vs < 70yo ECOG PS - 0-1 vs 2 CAB> 30 days -Yes vs No SRE Prevention -Yes vs No Prior Adjuvant ADT ≤12 vs > 12 months

RANDOMIZE

ARM A: ADT + Docetaxel 75mg/m2 every 21 days for maximum 6 cycles

ARM B: ADT (androgen deprivation therapy alone)

Evaluate every 3 weeks while receiving docetaxel and at week 24 then every 12 weeks

Evaluate every 12 weeks

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

• ADT allowed up to 120 days prior to randomization. • Intermittent ADT dosing was not allowed • Standard dexamethasone premedication but no daily prednisone

Primary endpoint: Overall survival

HR=0.61 (0.47-0.80) p=0.0003 Median OS: ADT + D: 57.6 months ADT alone: 44.0 months

Presented by: Christopher J. Sweeney, MBBS

In patients with high volume metastatic disease, there is a 17 month improvement in median overall survival from 32.2 months to 49.2 months

OS by extent of metastatic disease at start of ADT High volume Low volume

p=0.0006 HR=0.60 (0.45-0.81) Median OS: ADT + D: 49.2 months ADT alone: 32.2 months

p=0.1398 HR=0.63 (0.34-1.17) Median OS: ADT + D: Not reached ADT alone: Not reached

Presented by: Christopher J. Sweeney, MBBS

14

Adding abiraterone acetate plus prednisolone (AAP) or docetaxel for patients (pts) with high-risk

prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT):

directly randomised data from STAMPEDE

Matthew Sydes Statistician, Reader in Clinical Trials

MRC Clinical Trials Unit at UCL Institute of Clinical Trials and Methodology UCL, London, UK

Co-authors Malcolm D Mason, Melissa R Spears, Noel W Clarke, David P Dearnaley, Alastair WS Ritchie, J Martin Russell, Clare Gilson, Rob Jones, Johann S de Bono, Silke Gillessen, Robin Millman, Shaun Tolan, John Wagstaff, Simon Chowdhury, Jason Lester, Denise Sheehan, Joanna Gale, Mahesh KB Parmar and Nicholas D James and the STAMPEDE Investigators

Trial registration: NCT00268476

STAMPEDE: Multigroup study of prostate cancer in UK Analysis of ADT+ abiraterone vs ADT alone in CSPC

• WHO PS 0-2 • Histologic evidence of PCa • New diagnosis and

metastatic • OR high risk locally

advanced (2 of 3): • T3/T4 • Gleason 8-10 • PSA>40

• OR high risk relapse: • PSA>4 & PSADT<6

months • PSA>20 • <6 months ADT

R A N D O M I Z A T I O N

ADT + Abiraterone Prednisone

for 2 years or progression

Primary endpoint: OS

Secondary endpoints:

Time to next treatment Time to chemo

Time to pain progression ADT alone

N=1917

James N et al, NEJM, 2017

STAMPEDE: SOC+AAP vs SOC+DocP

ESMO 2017

Recruitment: Nov-2011 to Mar-2013 Reported: ESMO 2017 Published: (paper in development)

Patients: 189 SOC+DocP 377 SOC+AAP 566 patients randomised

contemporaneously to either research arm

Underpowered but the only head-to-head data Last year of recruitment to “abiraterone comparison” overlap with a question of radiotherapy to the prostate in men with M1 disease

Sydes et al ESMO 2017


STAMPEDE: ADT + Abiraterone vs ADT alone in CSPC

STAMPEDE – OS (primary endpoint) (n=1,776) • 61% M1; 15% N1M0; 24% N0M0; median follow-up: 43 mo

HR=0.78 (95% CI: 0.66-0.93)

P=0.006

Time from randomization (months)

Ove

rall

surv

ival

1.0

0.8

0.6

0.4

0.2

0.0

0 12 24 36 48 60 72 84

SOC by Kaplan Meier SOC + DOC by Kaplan Meier SOC by flexible parametric model SOC + DOC by flexible parametric model

SOC Median 71 mo

SOC + DOC Median 81 mo

James, ND et al. Lancet. 2016;387:1163-77.

HR 0.61 (0.49-0.75)

HR 0.75 (0.48 -1.18)

STAMPEDE: ADT+ Abiraterone vs ADT alone in CSPC


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

(n=1,917)

HR 0.31 (0.26-0.37)

HR 0.21 (0.15-0.31)

STAMPEDE: ADT+ Abiraterone vs ADT alone in CSPC


Failure-free survival [driven by PSA failure]

HR (95%CI) P-val Interactn test

All 0.51 (0.39 to 0.67) <0.001

M0 0.34 (0.16 to 0.69) 0.003 0.17

M1 0.56 (0.42 to 0.75) <0.001

SOC+AAP

SOC+DocP

Key: HR<1 favours SOC+AAP HR>1 favours SOC+DocP Interactn = test for interaction (heterogeneity of treatment effect)

SOC+DocP SOC+AAP Events Pts Events Pts

All 97 189 122 377

M0 18 74 13 150

M1 79 115 109 227

HR (95%CI) P-val Interactn test

All 1.16 (0.82 to 1.65) 0.40

M0 1.51 (0.58 to 3.93) 0.40 0.69

M1 1.13 (0.77 to 1.66) 0.53

Key: HR<1 favours SOC+AAP HR>1 favours SOC+DocP Interactn = test for interaction (heterogeneity of treatment effect)

SOC+DocP SOC+AAP Events Pts Events Pts

All 44 189 105 377

M0 6 74 16 150

M1 38 115 89 227

SOC+AAP

SOC+DocP

Overall survival [primary outcome measure]

AA Failure free survival in M0 subgroup

status

Mets

Overall

M1

M0

FFS/N

SOC-only

393/502

142/455

FFS/N

SOC+AAP

210/500

38/460

(95% CI)

Haz. Ratio

0.29 (0.25, 0.34)

0.31 (0.26, 0.37)

0.21 (0.15, 0.31)

Favours: abiraterone SOC-only

.2 .4 .6 .8 1 1.2 1.4

SOC vs SOC+AAP

No difference in M0N0 for: OS MFS Based on n=530 underpowered subsets for N0 M0 and n=384 subset for N+M0

Is radiotherapy planned?

RT plannedNo RT planned

110/396425/561

24/396224/564 0.023

0.18 (0.12, 0.28)0.31 (0.26, 0.36)

Overall

0.29 (0.25, 0.34)

Favours: abiraterone SOC-only

.2 .4 .6 .8 1 1.2 1.4

James N et al LBA34 ESMO 2017

Safety population SOC+DocP SOC+AAP Patients included in adverse event analysis 172 (91%) 373 (>99%)

Grade 1+ AE 172 (100%) 370 (99%) Grade 3+ AE 86 (50%) 180 (48%)

Grade 3+ AEs by category (incl. expected AEs) Endocrine disorder (incl. hot flashes, impotence) 15 (9%) 49 (13%) Febrile neutropenia 29 (17%) 3 (1%) Neutropenia 22 (13%) 4 (1%) Musculoskeletal disorder: 9 (5%) 33 (9%) Cardiovascular disorder (incl. hypertension, MI, cardiac dysrhythmia): 6 (3%) 32 (9%) Gastrointestinal disorder: 9 (5%) 28 (8%) Hepatic disorder (incl. increased AST, increased ALT): 1 (1%) 32 (9%) General disorder (incl. fatigue, oedema): 18 (10%) 21 (6%) Respiratory disorder (incl. breathlessness): 12 (7%) 11 (3%) Renal disorder 5 (3%) 20 (5%) Lab abnormalities (incl. hypokalaemia): 9 (5%) 11 (3%)

Adverse events

Phase 3 Ongoing Combination Therapy Trials in HSPC

25

Study Identifier Study Drugs Pts (N) Primary End Point

Status/Read Out

LATITUDE NCT01715285 ADT ± AA 1209 rPFS, OS ASCO 2017

STAMPEDE (Arm G) NCT00268476 ADT ± AA 1800 OS LBA ASCO 2017

PEACE-1 NCT01957436 ADT ± DOC vs

ADT + AA ± DOC (± local RT)

916 PFS, OS Recruiting/2020

STAMPEDE (Arm J) NCT00268476 ADT ± AA + ENZ* 1800 OS Closed-will report in 2-

3 yrs

SWOG-1216 NCT01809691 ADT + TAK-700 vs

ADT + BIC 1304 OS Recruiting/2027

ENZAMET NCT02446405 ADT + ENZ vs ADT + antiandrogen 1100 OS Recruiting/2020

TITAN NCT02489318 ADT ± APA (ARN 509) 1000 rPFS, OS Recruiting/ 2021

ARCHES NCT02677896 ADT (+docetaxel in selected cases) ± ENZ* 1100 rPFS Recruiting/ 2021

ARASENS NCT02799602 ADT + DOC ± ODM-201 1300 OS Recruiting/2022

*Includes upfront Doc Modified from and courtesy of K. Fizazi

Summary

• ADT alone is suboptimal for mHSPC • Abiraterone is preferred in most patients because of tolerance and

lower SAE rates of fever/neutropenia. Docetaxel may be preferable for cost and shorter course of treatment.

• Remaining questions under study: • Is combination of AAP and Docetaxel better? • Is there a role for consolidative primary treatment? • Is there a role for SBRT in oligometastatic patients?

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