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