Clinically node positive newly diagnosed prostate cancer · 2019-09-05 · Clinically node positive newly diagnosed prostate cancer ... James N, De Bono JS, Spears M, et al: Adding

Clinically node positive newly diagnosed prostate cancer

Nicholas James @Prof_Nick_James

1

Disclosures• Trial funding from:

• Cancer Research UK• Medical Research Council• Astellas• Janssen• Novartis• Pfizer• Sanofi-Aventis

• Speaking fees and Advisory Boards• Astellas, Janssen, Novartis, Pfizer, Sanofi-Aventis, Bayer, Clovis, Merck,

Ferring, Astra Zeneca

Focus of talk• I will focus on newly diagnosed clinically node

positive (cN+) hormone sensitive prostate cancer (mHSPC) with no prior therapy

• Treatment of the primary• Which treatments can we combine?

cN+ HSPC: what do we know?• Androgen deprivation therapy remains a fixed part

of therapy• Radiotherapy improves survival in low volume

TxNxM1 and TxN0M0 disease implying benefit in N+M0

Which combinations in M0 HSPC?• Combinations with good evidence• ADT + RT• ADT + docetaxel• ADT + abiraterone

• Combinations with limited evidence• ADT + docetaxel + RT• ADT + abiraterone + RT

• Combinations with no evidence• ADT + docetaxel + androgen receptor targeting (ART)

+ RT

TREATING THE PRIMARY

MRC CTU at UCL31-Aug-19

7

Radiotherapy as a Standard of Care

MRC CTU at UCL

The effect is consistent with HORRAD

Boeve et al. Eur Urol (2018)

Overall survival

MRC CTU at UCL

Summary

u Prostate radiotherapy did not improve survival for unselected patients (HR=0·92, 95%CI 0·80-1·06; p=0.266)

u Prostate radiotherapy did improve survival (from 73% to 81% at 3 years) in those with a low metastatic burden (HR=0·68, 95%CI 0·52-0·90; p=0·007). Test for interaction: p=0.0098

u Mirrors benefit seen in HORRAD trialu Implies potential benefit in cN+M0 disease taken with known survival gain

with radiotherapy in N0M0 diseaseBurdett S, Boeve LM, Ingleby FC, et al: Prostate Radiotherapy for Metastatic Hormone-sensitive Prostate Cancer: A STOPCAP Systematic Review and Meta-analysis. Eur Urol, 2019Parker CC, James ND, Brawley CD, et al: Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet 392:2353-2366, 2018

WHAT WE KNOW ABOUT M0 HSPC -DOCETAXEL

What is the current evidence for docetaxel or bisphosphonates in men with hormone sensitive prostate cancer?

A systematic review and meta-analysesClaire Vale MRC Clinical Trials Unit at UCL

Systemic Treatment Options for Cancer of the ProstateWorking Group: Rydzewska LH, Tierney JF, Albiges L, Clarke NW, Fisher D, Fizazi K, James ND, Mason MD, Parmar MKB, Sweeney CJ, Sydes MR, Tombal B and Burdett S

Vale CL, Burdett S, Rydzewska LH, et al: Lancet Oncol 17:243-56, 2016

M1 docetaxel: Failure-free survival

Favours SOC + docetaxel Favours SOC

Trial name

OverallSTAMPEDE (SOC+ZA +/- Doc)STAMPEDE (SOC +/- Doc)GETUG-15CHAARTED

HR=0.64 (0.58, 0.70); p<0.00011 2.5

Heterogeneity:c2=1.66, df=3, p=0.646, I2=0%

Results based on 2993 men / 2198 events

15% absolute reduction in failure (from 80% to 65%) at 4 years


M0 docetaxel: Failure free survival

Results based on 2348 men / 842 events

Trial name

OverallTAX 3501 (Delayed ADT)TAX 3501 (Immediate ADT)STAMPEDE (SOC+ZA +/- Doc)STAMPEDE (SOC +/- Doc) RTOG 0521GETUG 12

HR=0.70 (0.61, 0.81), p<0.0001.5 1 2

8% absolute reduction in failure (from 70% to 62%) at 4 years

Favours SOC + docetaxel Favours SOC

Heterogeneity:c2=2.63, df=5, p=0.757, I2=0%


M1 docetaxel: SurvivalResults based on 2993 men / 1254 deaths

10% absolute improvement in survival (from 40% to 50%) at 4 years

Trial name

OverallSTAMPEDE (SOC+ZA +/- Doc)STAMPEDE (SOC +/- Doc)GETUG15CHAARTED

HR=0.77 (0.68, 0.87) p<0.0001.5 1 2

Heterogeneity:c2=4.80, df=3, p=0.187, I2 = 37.5%Favours SOC + docetaxel Favours SOC


M0 docetaxel: SurvivalResults based on 2120 men / 346 deaths

5% potential improvement in survival (from 80 to 85%) at 4 years

Trial name

OverallSTAMPEDE (SOC+ZA +/- Doc)STAMPEDE (SOC +/- Doc) RTOG 0521GETUG 12

HR= 0.87 (0.69, 1.09) p=0.218.5 1 2

Heterogeneity:c2=1.80, df=3, p=0.614, I2=0%Favours SOC + docetaxel Favours SOC


Conclusions – docetaxel in M0 disease

• Consistent effect on failure free survival with docetaxel –hazard ratio around 0.7

• Individual trials underpowered with respect to overall survival

• Trend to an OS benefit seen in the meta-analysis – HR 0.87 (CI: 0.69-1.09)


Question: docetaxel in M0 disease

• What is the interaction with radiotherapy and docetaxel – is there dual benefit?

The Lancet 2016 387, 1163-1177DOI: (10.1016/S0140-6736(15)01037-5)

STAMPEDE docetaxel subgroup analysis

Docetaxel and radiotherapy in M0

• Suggests interaction between RT and docetaxel – only benefit in patients notgetting radiotherapy

Docetaxel and radiotherapy and survival in M0 HSPC

• Suggests interaction between RT and docetaxel – only benefit in patients notgetting radiotherapy

• Further data to be presented at ESMO 2019

ADT + RT + ABIRATERONE

Abiraterone in high-risk M0 prostate cancer• Prognosis of newly-diagnosed high-risk M0 disease

• Cohort selection:

Non-metastaticN=915

MetastaticN=1002

N+M0N=384

N0M0N=530

Randomised by Jan-2014N=1,917

No RTN=70

RTN=314

RTN=519

James N, De Bono JS, Spears M, et al: Adding abiraterone for patients (pts) with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT):

Outcomes in non-metastatic (M0) patients from STAMPEDE (NCT00268476). Proc ESMO Annals of Oncology, 2017

Failure-free survival Events535 Control | 248 Abiraterone

No good evidence of heterogeneity by

stratification factors

status

Mets

Overall

M1

M0

Dths/N

SOC-only

218/502

44/455

Dths/N

SOC+AAP

150/500

34/460

(95% CI)

Haz. Ratio

0.63 (0.52, 0.76)

0.61 (0.49, 0.75)

0.75 (0.48, 1.18)

Favours: abiraterone SOC-only

.2 .4 .6 .8 1 1.2 1.4

SOC vs SOC+AAP

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)


.2 .4 .6 .8 1 1.2 1.4

SOC vs SOC+AAP

Mets * treatment interaction P-value = 0.085

James N, De Bono JS, Spears M, et al: Adding abiraterone for patients (pts) with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Outcomes in non-metastatic (M0) patients from STAMPEDE (NCT00268476). Proc ESMO Annals of Oncology, 2017

Failure-free survival

status

Mets

Overall

M1

M0

Dths/N

SOC-only

218/502

44/455

Dths/N

SOC+AAP

150/500

34/460

(95% CI)

Haz. Ratio

0.63 (0.52, 0.76)

0.61 (0.49, 0.75)

0.75 (0.48, 1.18)


.2 .4 .6 .8 1 1.2 1.4

SOC vs SOC+AAP

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)


.2 .4 .6 .8 1 1.2 1.4

SOC vs SOC+AAP

Time period (co-recruiting arms)

Recurrent disease

Is radiotherapy planned?

NSAID/Aspirin use

WHO PS 0 vs 1-2

Age at randomisation (cats)

Gleason Sum Score (cats)

Nodal status

Mets status

Subgroup

Overall

A-----GH--ABC-E-GH--ABC-E-G---

YesNo

RT plannedNo RT planned

Uses eitherNo use

1-20

70 or overUnder 70

unknown8-10<=7

NXN+N0

M1M0

FFS/NSOC-only

290/58031/49

214/328

21/38514/919

110/396425/561

141/239394/718

133/213402/744

174/361361/596

11/13417/721107/223

28/36323/483184/438

393/502142/455

FFS/NSOC+AAP

126/58312/47

110/330

15/60233/900

24/396224/564

69/246179/714

58/215190/745

83/357165/603

9/24199/71540/221

19/42160/48469/434

210/50038/460

p-valueInteraction

0.34

0.49

0.023

0.29

0.25

0.042

0.73

0.35

0.085

(95% CI)Haz. Ratio

0.29 (0.25, 0.34)

0.27 (0.22, 0.34)0.21 (0.11, 0.43)0.33 (0.26, 0.41)

0.32 (0.16, 0.65)0.29 (0.25, 0.34)

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

0.33 (0.25, 0.45)0.27 (0.23, 0.32)

0.25 (0.18, 0.34)0.30 (0.25, 0.36)

0.36 (0.28, 0.47)0.26 (0.22, 0.32)

0.15 (0.05, 0.48)0.29 (0.25, 0.35)0.26 (0.18, 0.38)

0.44 (0.24, 0.80)0.29 (0.24, 0.36)0.26 (0.20, 0.35)

0.31 (0.26, 0.37)0.21 (0.15, 0.31)


.2 .4 .6 .8 1 1.21.4

SOC vs SOC+AAP

Time period (co-recruiting arms)

Recurrent disease

Is radiotherapy planned?

NSAID/Aspirin use

WHO PS 0 vs 1-2

Age at randomisation (cats)

Gleason Sum Score (cats)

Nodal status

Mets status

Subgroup

Overall

A-----GH--ABC-E-GH--ABC-E-G---

YesNo

RT plannedNo RT planned

Uses eitherNo use

1-20

70 or overUnder 70

unknown8-10<=7

NXN+N0

M1M0

FFS/NSOC-only

290/58031/49

214/328

21/38514/919

110/396425/561

141/239394/718

133/213402/744

174/361361/596

11/13417/721107/223

28/36323/483184/438

393/502142/455

FFS/NSOC+AAP

126/58312/47

110/330

15/60233/900

24/396224/564

69/246179/714

58/215190/745

83/357165/603

9/24199/71540/221

19/42160/48469/434

210/50038/460

p-valueInteraction

0.34

0.49

0.023

0.29

0.25

0.042

0.73

0.35

0.085

(95% CI)Haz. Ratio

0.29 (0.25, 0.34)

0.27 (0.22, 0.34)0.21 (0.11, 0.43)0.33 (0.26, 0.41)

0.32 (0.16, 0.65)0.29 (0.25, 0.34)

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

0.33 (0.25, 0.45)0.27 (0.23, 0.32)

0.25 (0.18, 0.34)0.30 (0.25, 0.36)

0.36 (0.28, 0.47)0.26 (0.22, 0.32)

0.15 (0.05, 0.48)0.29 (0.25, 0.35)0.26 (0.18, 0.38)

0.44 (0.24, 0.80)0.29 (0.24, 0.36)0.26 (0.20, 0.35)

0.31 (0.26, 0.37)0.21 (0.15, 0.31)


.2 .4 .6 .8 1 1.21.4

SOC vs SOC+AAP



Failure-free survival in M0 subgroup

ADT +/- Abi


Metastasis-free survival in M0 subgroup

ADT +/- Abi


Overall survival in M0 subgroup

ADT +/- Abi


Abiraterone in M0 HSPC

• Evidence of failure free and metastasis free survival benefit from ADT + abiraterone vs. ADT alone for 2 years

• Strong suggestion of synergy with radiotherapy



CAN WE CHOOSE BETWEEN DOCETAXEL AND ART?

STAMPEDE: SOC+DocP vs SOC

HR (95%CI) 0.78 (0.66, 0.93)P-value 0.006

SOC

SOC+DOC

Recruitment: Oct-2005 to Mar-2013

Reported: ASCO 2015Published: Lancet 2016

Patients: 1184 SOC592 SOC+DocP

Allocation ratio: 2:1

STAMPEDE: SOC+AAP vs SOC

SOC

SOC+AAP

HR (95%CI) 0.63 (0.52, 0.76)P-value 0.00000115

Recruitment: Nov-2011 to Jan-2014

Reported: ASCO 2017Published: NEJM 2017

Patients: 957 SOC960 SOC+AAP

Allocation ratio: 1:1

STAMPEDE: SOC+AAP vs SOC+DocP

AAP and DocP may work

in quite different ways

Evidence about whether

to give both is pending

ESMO

2017

Recruitment: Nov-2011 to Mar-2013

Reported: ESMO 2017

Published: Sydes et al, Annals of Oncology, 2018

Patients: 189 SOC+DocP

377 SOC+AAP566 patients randomised

contemporaneously to either

research armSydes MR, Spears MR, Mason MD, et al: Adding abiraterone or docetaxel to long-term hormone

therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol 29:1235-1248, 2018

Summary

Strong evidence favouring AAP

Toxicity profiles quite different and well known

Weak evidence favouring AAP

No good evidence of a differenceCause-specific

survival

Head-to-head data in 566 pts (Nov-2011 to Mar-2013)

à Proportionately different time spent in each disease state

FavoursSOC+AAP

FavoursSOC+DocP

Hazard ratio

Metastatic progression-free

survival

Progression-free survival

Failure-free survival

Symptomatic skeletal eventsCause-specific

survival

Overall survival

Sydes MR, Spears MR, Mason MD, et al: Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol29:1235-1248, 2018

Docetaxel vs. AR therapy in mHSPC• No evidence of survival difference in STAMPEDE• Upfront abiraterone gives longer failure free and

metastasis free benefit than docetaxel• but shorter castrate refractory phase

• Effects on failure free survival may be more important in M0 disease as lower risk of prostate cancer death

Sydes MR, Spears MR, Mason MD, et al: Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol 29:1235-1248, 2018

DOES FAILURE FREE SURVIVAL MATTER?

Addition of docetaxel to first-line long-termhormone therapy in prostate cancer (STAMPEDE): long-term survival, quality-adjusted survival and

cost-effectiveness analysis.Nicholas James

on behalf of Beth Woods, Eleftherios Sideris, Matthew Sydes,

Melissa Spears, Mark Sculpher and the STAMPEDE Investigators

36

Impact of docetaxel on Quality Adjusted Life Years (QALYs)

• All groups show a QALY gain• Driven by reduction in relapse therapy and skeletal events

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

M1 Q1 M1 Q2 M1 Q3 M1 Q4 M0 Q1 M0 Q2 M0 Q3 M0 Q4

Increm

ental

QAL

Ys (DO

C+SO

C vs. S

OC)

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80


Increm

ental

QAL

Ys (DO

C+SO

C vs. S

OC)

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80


Increm

ental

QAL

Ys (DO

C+SO

C vs. S

OC)

Non-metastatic Metastatic

Woods BS, Sideris E, Sydes MR, et al: Addition of Docetaxel to First-line Long-term Hormone Therapy in Prostate Cancer (STAMPEDE): Modelling to Estimate Long-term Survival, Quality-adjusted Survival, and Cost-effectiveness. Eur Urol Oncol 1:449-458, 2018

Conclusion• ADT plus 1 drug therapy improves failure free survival &

increases QALYs in M0 HSPC • ADT + radiotherapy improves survival in low volume M1

HSPC and TxN0M0 HSPC• Available data suggest an either/or effect with docetaxel

and radiotherapy• Available data suggest a synergistic effect with

abiraterone and radiotherapy• Overall supports ADT + RT + 2 years abiraterone in cN+

prostate cancer

Key references1. Vale CL, Burdett S, Rydzewska LH, et al: Addition of docetaxel or bisphosphonates to standard of care in men with

localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data. Lancet Oncol 17:243-56, 2016

2. James ND, Sydes MR, Clarke NW, et al: Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 387:1163-77, 2016

3. James ND, de Bono JS, Spears MR, et al: Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med 377:338-351, 2017

4. James N, De Bono JS, Spears M, et al: Adding abiraterone for patients (pts) with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Outcomes in non-metastatic (M0) patients from STAMPEDE (NCT00268476). Annals of Oncology, 2017

5. Burdett S, Boeve LM, Ingleby FC, et al: Prostate Radiotherapy for Metastatic Hormone-sensitive Prostate Cancer: A STOPCAP Systematic Review and Meta-analysis. Eur Urol, 2019

6. Parker CC, James ND, Brawley CD, et al: Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet 392:2353-2366, 2018

7. Woods BS, Sideris E, Sydes MR, et al: Addition of Docetaxel to First-line Long-term Hormone Therapy in Prostate Cancer (STAMPEDE): Modelling to Estimate Long-term Survival, Quality-adjusted Survival, and Cost-effectiveness. Eur Urol Oncol 1:449-458, 2018

8. Sydes MR, Spears MR, Mason MD, et al: Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol29:1235-1248, 2018

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Clinically node positive newly diagnosed prostate cancer · 2019-09-05 · Clinically node positive newly diagnosed prostate cancer ... James N, De Bono JS, Spears M, et al: Adding