Systemic treatment for men with high-risk and locally ... · 1. High-risk localised (T3/4, PSA >40...

Systemic treatment for men with

high-risk and locally-advanced

prostate cancer treated with

curative intent

Nicholas James

@Prof_Nick_James

1

Disclosures Receipt of grants/research supports:

•Merck (Europe), Janssen, Astellas, Sanofi, Novartis, Pfizer, Bayer, Algeta, Oncogenix

Receipt of honoraria or consultation fees:

•Merck (US), Janssen, Astellas, Sanofi, Pfizer, Bayer, Algeta, Oncogenix, Pierre Fabre

Participation in a company sponsored speaker’s bureau:

•Janssen, Astellas, Sanofi, Bayer, Pierre Fabre, Ferring

Stock shareholder:

•Nothing to declare

“High risk”disease

• Defined in terms of T-stage, N-stage

Gleason, PSA

• No single definition

– High risk for surgery ≠ High risk for

radiotherapy

High risk outcomes

Tombal B, Alcaraz A, James N, Valdagni R, Irani J. Can we improve the definition of high-risk, hormone naive,

non-metastatic prostate cancer? BJU international. 2014;113(2):189-99

Combining RT and ADT

• RT + ADT better than RT alone – Bolla M, et al. External irradiation with or without long-term androgen suppression for prostate

cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol.

2010;11(11):1066-73

• RT + ADT better than ADT alone – Widmark A, Klepp O, Solberg A, Damber JE, Angelsen A, Fransson P, et al. Endocrine

treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3):

an open randomised phase III trial. Lancet. 2009;373(9660):301-8

– Warde P, Mason M, Ding K, Kirkbride P, Brundage M, Cowan R, et al. Combined androgen

deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised,

phase 3 trial. Lancet. 2011;378(9809):2104-11

• No randomised studies in N+ disease

STAMPEDE

• Recruits men from 4 groups starting long-term ADT:

1. High-risk localised (T3/4, PSA >40 or Gleason 8-10)

2. Node-positive (N+) prostate cancer

3. Newly-diagnosed metastatic (M1)

4. High risk recurrence post surgery or RT

• Radical radiotherapy in standard care:

– N+M0 patients; optional

– N0M0 patients; optional Oct 2005 – Nov 2011, mandatory

from Nov-2011

7

www.stampedetrial.org

63.3 (IQR 26.4-NR)

0.00

0.25

0.50

0.75

1.00

Pro

port

ion e

vent-

free

721 392(7) 273(10) 173(6) 108(6) 46(9) 24(2) 8(0)Death721 345(74) 219(32) 128(18) 69(14) 35(6) 18(3) 3(2)FFS Event

N(risk)

0 12 24 36 48 60 72 84

Time from randomisation (Months)

FFS Event Death

Survival & failure free survival

outcomes – M0 cohort

James ND, Spears MR, Clarke NW, Dearnaley DP, Mason MD, et al: Failure-Free Survival and

Radiotherapy in Patients With Newly Diagnosed Nonmetastatic Prostate Cancer: Data From Patients in the

Control Arm of the STAMPEDE Trial. JAMA Oncol 2:348-57, 2016

Failure free survival: Node-negative cohort

62% (95% CI 48-73)

87% (95% CI 79-92)

0.00

0.25

0.50

0.75

1.00

121 112(5) 101(3) 61(6) 37(5) 19(2) 8(0) 0(0)+RT59 48(11) 39(8) 29(3) 13(4) 4(3) 2(1) 2(0)-RT

N(risk)

0 12 24 36 48 60 72 84Time from randomisation (months)

-RT +RT

N0 Planned radical RT status




FFS by RT status: Node-positive cohort

47% (95% CI 33-59)

71% (95% CI 58-81)

0.00

0.25

0.50

0.75

1.00

98 75(14) 42(4) 23(4) 10(2) 7(1) 4(2) 0(0)+RT80 54(18) 29(13) 15(4) 9(3) 5(0) 4(0) 1(2)-RT

N(risk)

0 12 24 36 48 60 72 84Time from randomisation (months)

-RT +RT

N+ Planned radical RT status




• Effect of RT in N0M0 patients consistent with effect seen

in previous large RCTs

• Effect of RT in N+ patients similar to effect in N0

patients

• Strongly supports routine use RT in node-positive

prostate cancer

James ND, Spears MR, Clarke NW, Dearnaley DP, Mason MD, et al: Failure-Free Survival and Radiotherapy in

Patients With Newly Diagnosed Nonmetastatic Prostate Cancer: Data From Patients in the Control Arm of the

STAMPEDE Trial. JAMA Oncol 2:348-57, 2016

Impact of RT

11

Relevant trials of peri-RT

chemotherapy

• RTOG 0512

• GETUG-12

• STAMPEDE

• MRCCTU Meta-analysis

RTOG 0521

Stage Gleason score PSA

Any T stage

≥9 <150

7-8 ≥20-150

≥T2 8 <20

Arm 1

Androgen Suppression (24 mos)

+ External RT (8 wks)

High Risk

R a n d o m i z e

Arm 2

Androgen Suppression (24 mos)

+ External RT (8 wks)

+ Docetaxel beginning 4 wks after RT

(6 cycles)

RTOG 0512: Overall Survival

4 yr OS 93% vs. 89%

HR 0.70 (90%CI: 0.51-0.98)

RTOG 0512: Disease-Free

Survival

6 yr DFS 65% vs.

55%

HR 0.76 (95%CI:

0.58-0.99)

RTOG 0512: Cause of Death*

AS+RT

(n=59)

AS+RT+CT

(n=43)

Death due to cancer under study 23 16

Death due to protocol treatment 0 2

Death due to other cause 24 16

Death due to second primary 12 5

Unknown cause of death 0 4

*Based on central review blinded to treatment arm

GETUG-12

Karim Fizazi, et al, Lancet Oncology, Volume 16, Issue 7, 2015, 787–794. http://dx.doi.org/10.1016/S1470-2045(15)00011-X

ADT + docetaxel & estramustine vs. ADT alone for

high-risk localised prostate cancer (GETUG 12)

Karim Fizazi, et al, Lancet Oncology, Volume 16, Issue 7, 2015, 787–794. http://dx.doi.org/10.1016/S1470-2045(15)00011-X

GETUG 12 – relapse free survival

STAMPEDE M0

Treatment effect by metastatic status: FFS

+ZA

+Doc

+ZA+Doc

Pre-planned analysis

+ZA

+Doc

+ZA+Doc

Pre-planned analysis

Treatment effect by metastatic status: Overall survival

SOC 328 SSE events SOC+Doc 112 SSE events

HR (95%CI) 0.60 (0.48, 0.74) P-value 0.00000127

Non-PH p-value 0.0001

Restricted mean SSE time SOC 61.4m SOC+Doc 68.0m Diff (95%CI) 6.6m (3.6, 9.6m)

Docetaxel: Skeletal events All patients

Excluding ONJ SOC 0 reports SOC+Doc 0 reports

SOC 65 deaths SOC+Doc 31 deaths HR (95%CI) 0.95 (0.62, 1.47)

Docetaxel: M0

STOPCaP Comparison 2: SOC versus SOC + Docetaxel

Non-Metastatic (M0) setting

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

M0 docetaxel: Failure free survival

Results based on 2348 men / 842 events

Trial name

Overall TAX 3501 (Delayed ADT) TAX 3501 (Immediate ADT) STAMPEDE (SOC+ZA +/- Doc) STAMPEDE (SOC +/- Doc) RTOG 0521 GETUG 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:2=2.63, df=5, p=0.757, I2=0%


M0 docetaxel: Survival

Results based on 2120 men / 346 deaths

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

Trial name

Overall

STAMPEDE (SOC+ZA +/- Doc)

STAMPEDE (SOC +/- Doc)

RTOG 0521

GETUG 12

HR= 0.87 (0.69, 1.09) p=0.218

.5 1 2

Heterogeneity:2=1.80, df=3, p=0.614, I2=0%

Favours SOC + docetaxel Favours SOC


Effects of docetaxel on survival in

hormone sensitive prostate cancer

• Consistent effect in M1 HSPC

• Consistent effect on progression free

survival in M0 and M1

• No proven OS effect in M0 disease at

present


Non- survival benefits of

docetaxel

• Progression free survival gain of 40%

• Effect on symptomatic skeletal events

– Secondary outcome in STAMPEDE

Conclusions

• Strong evidence for combining RT and

ADT in locally advanced prostate cancer

• Good evidence that docetaxel prolongs FFS

• Weaker evidence that docetaxel improves

overall survival

Systemic treatment for men with high-risk and locally ... · 1. High-risk localised (T3/4, PSA >40...

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