Metastatic castration-resistant prostate cancer (mCRPC) with bone metastases — EORTC (European Organisation for Research and Treatment of Cancer); collaborators Bayer, Astellas
Metastatic castration-resistant prostate cancer (mCRPC) with bone metastasesXtandi + XofigoASCO GU 2026 (#GU26)
[Slide 1]
Background
Abiraterone and enzalutamide are standard of care options for 1st line treatment of patients with
metastatic castration-resistant prostate cancer (mCRPC) progressing on androgen deprivation
therapy (ADT) (1,2)
No combination so far has been proven to increase radiological progression-free survival
(rPFS) and overall survival (OS) in first line mCRPC
Radium-223 dichloride (Ra223) is an alpha particle-emitting calcium mimetic that selectively
targets bone metastases and induces double-stranded DNA-breaks(3)
In the ALSYMPCA trial, Ra223 has been shown to increase OS (HR: 0.7), in an era before the
introduction of abiraterone and enzalutamide(4)
The ERA-223 trial tested the combination of abiraterone plus Ra223 versus abiraterone plus
placebo. The combination did not show a benefit in symptomatic skeletal event-free survival or
OS and was associated with an increase in fractures(5)
(1) Ryan CJ et al. N Engl J Med 2013; (2) Beer TM et al N Engl J Med 2014; (3) Morris MJ et al. Nat Rev Urol 2019; (4) Parker C et al. N Engl J Med 2013;
(5) Smith M et al. Lancet Oncol 2019
BARCELONA
congress
2024
ESMO
---
[Slide 2]
EORTC-GUCG 1333 (PEACE-3)
Ra223
Study population
55 kBq/kg iv every 4 weeks
for 6 cycles plus
Primary endpoint
Patients with mCRPC
rPFS
and bone metastases
N=446**
Enzalutamide 160 mg od
Asymptomatic or
Key secondary
mildly symptomatic*
Stratification factors
endpoints
WHO PS of 0 or 1
Country
Safety
1:1
No prior treatment
Baseline pain (BPI worst pain 0-1 vs 2-3)
Randomisation
Overall Survival
with enzalutamide or
Prior docetaxel (yes vs no)
Use of bone protecting agents
Time to next treatment
Ra223
Prior abiraterone (yes vs no)
Time to pain progression
No known visceral
Time to first SSE
metastases
(symptomatic skeletal
Ongoing ADT
Enzalutamide 160 mg od
event)
"defined as brief pain inventory WP24 score <4
" original target accrual N=560, adapted for slow accrual
Use of bone protecting agents (BPA) made mandatory
BARCELONA
congress
2024
ESMO
(after inclusion of 119 patients)
---
[Slide 3]
Overall Survival at interim analysis (80% of OS events)
Arm
n/N
Median (95%CI)
100
90
Enzalutamide
110/222
Ra223
42.3 (36.8-49.1) mo
80
Enzalutamide + Ra223
70
Enzalutamide
129/224
35.0 (28.8-38.9) mo
Overall Survival (%)
60
HR (95%CI)
0.69 (0.52-0.90)
50
40
Enzalutamide
Log-Rank p-
0.0031
<0.0034
value
30
20
Pre-set level of significance for interim analysis
10
was s 0.0034
Due to non-proportional hazards plus lack of
0
unequivocal significance for RMST (restricted
0
6
12
18
24
30
36
42
48
54
60
66
72
mean survival time) sensitivity analysis, study will
Time in months
continue to final OS analysis
Patients-at-Risk (No. Cumulative Events)
Enza-
224(0)
206 (15)
107 (64)
58 (90)
30 (112)
14 (123)
1 (129)
Enza+Ra223-
222(0)
194 (21)
114(53)
71 (73)
43(90)
23 (101)
12 (105)
BARCELONA
congress
2024
ESMO
---
[Slide 4]
Conclusions
Combination of enzalutamide and 6 cycles of Ra223 shows a statistically significant
improvement in rPFS
HR of 0.69 (p=0.0009)
Median rPFS increased from 16.4 months with enzalutamide to 19.4 months with the
combination
Improvement in rPFS supported by a significantly improved OS (HR 0.69, p=0.0031)
Due to non-proportional hazards this will be tested further in the final OS analysis to
confirm and further characterise the result
Improvement in rPFS is also supported by a statistically significant improvement in time to
next systemic treatment (HR 0.57, p<0.0001)
Drug related ≥ grade 3 adverse events increased from 19% to 28% in the combination arm
[Slide 1]
16:30 - 18:15 Presidential Symposium I: Practice-changing trials
CHAIRS: ANDRES CERVANTES, KARIN JORDAN
Primary endpoint: rPFS
100
90
Arm
n/N
Median (95%CI)
80
Enzalutamide + Ra223
Enzalutamide + Ra223
139/222
19.4 (17.1-25.3) mo
Radiological Progression Free Survival (%)
70
Enzalutamide
160/224
16.4 (13.8-19.2) mo
60
congress
24mo rPFS:
50
36% vs. 45%
HR (95%CI)
0.69 (0.54-0.87)
Log-Rank p-value
0.0009
40
Silke Gillessen
30
Assumption of proportional hazard achieved
Enzalutamide
A randomized multicenter open label phase . trial comparing
20
enzalutamide vs a combination of Radium-223 (Ra223) and
10
enzalutamide in asymptomatic or mildly symptomatic
patients with bone metastatic clastration-resistant prostate
0
0
6
12
18
24
30
36
42
48
54
60
66
72
cancer (mCRPC) First
Time in months
Patients-at-Risk (No. Cumulative Events)
Enza-
224(0)
122(84)
52 (128)
13(150)
7(155)
3 (158)
0 (160)
Enza+Ra223-
222(0)
138(65)
64 (107)
32(123)
19(131)
9(135)
3 (137)
BARCELONIA
congress
ESMO
BARCELONA
congress
2024
ESMO
Barcelona Auditorium - Hall 2
BARCELONA SPAIN 13-17 SEPTEMBER 2024
---
[Slide 2]
16:30 18:15 Presidential Symposium I: Practice-changing trials
CHAIRS: ANDRES CERVANTES, KARIN JORDAN
Overall Survival at interim analysis (80% of os events)
Arm
n/N
Median (95%CI)
100
Enzalutamide
90
110/222
42.3 (36.8-49.1) mo
+ Ra223
80
Enzalutamide + Ra223
70
Enzalutamide 129/224 35.0 (28.8-38.9) mo
Overall Survival (%)
ESMO
60
HR (95%CI)
0.69 (0.52-0.90)
50
40
Enzalutamide
Log-Rank
0.0031
<0.0034
Silke Gillessen
value
30
A randomized multicenter open label phase a trial comparing
20
Pre-set level of significance for interim analysis
enzalutamide vs a combination of Radium-223 Ra223) and
was S 0.0034
10
enzalutamide in asymptomatic or midly symptomatic
Due to non-proportional hazards plus lack of
patients with bone metastatic clastration-resistant prostate
0
unequivocal significance for RMST (restricted
0
6
12
18
24
30
36
42
48
54
60
66
72
cancer (mCRPC) First
mean survival time) sensitivity analysis, study will
Time in months
continue to final OS analysis
Patients-at-Risk (No. Cumulative Events)
Enza-
224(0)
206(15)
107(64)
58(90)
30
(112)
14
(123)
1
(129)
Enza+Ra223.
222(0)
194(21)
114(53)
71(73)
43(90)
23 (101)
12 (105)
BARCELONA
congress
ESMO
BARCELONA
congress
LIVE
2024
ESMO
Barcelona Auditorium - Hall 2
BARCELONA SPAIN 13-17 SEPTEMBER 2024
+
---
[Slide 3]
16:30 - 18:15 Presidential Symposium I: Practice-changing trials
CHAIRS ANDRES CERVANTES, KARIN JORDAN
EORTC-GUCG 1333 (PEACE-3)
Ra223
Study population
55 kBq/kg iv every 4 weeks
Patients with mCRPC
for 6 cycles plus
Primary endpoint
rPFS
and bone metastases
N=446**
Enzalutamide 160 mg od
Asymptomatic or
Key secondary
ESMO
mildly symptomatic*
Stratification factors
endpoints
WHO PS of 0 or 1
Country
Safety
1:1
No prior treatment
Baseline pain (BPI worst pain 0-1 vs 2-3)
Randomisation
Overall Survival
Silke Gillessen
with enzalutamide or
Prior docetaxel (yes vs no)
Use of bone protecting agents
Time to next treatment
Ra223
A randomized multicenter open label phase a trial comparing
Prior abiraterone (yes vs no)
Time to pain progression
No known visceral
Time to first SSE
enzalutamide vs a combination of Radium-223 Ra223) and
metastases
(symptomatic skeletal
enzalutamide in asymptomatic or midly symptomatic
Ongoing ADT
Enzalutamide 160 mg od
event)
patients with bone metastatic castration-resistant prostate
cancer (mCRPC) First
"defined as brief pain inventory WP24 score < 4
** original target accrual N=560, adapted for slow accrual
congress
ESMO
BARCELONA
congress
2024
ESMO
Barcelona Auditorium - Hall 2
BARCELONA SPAIN 13-17 SEPTEMBER 2024
---
[Slide 4]
16:30 - 18:15 Presidential Symposium I: Practice-changing trials
CHAIRS: ANDRES CERVANTES, KARIN JORDAN
Conclusion: Radium-223 after PEACE-3
Combining Enzalutamide and Radium-223 improves rPFS (HR 0.69) and probably also OS (HR 0.69) in
(mostly ARPI-naive) mCRPC and predominant bone metastases
ESMO
If this combination is used, a Bone-Protecting Agent is mandatory (mostly Denosumab)
Karim Fizazi
Baseline symptomatic bone disease is not needed to benefit from Enza+Ra-223 !
Invited Discussant LBA1
Blood pressure should be monitored when using Enzalutamide (+/- Radium-223)
More data needed in PEACE-3 (ONJ, QoL, long-term OS, etc)
With more Radium-223 phase 3 trials maturing, we'll need to optimize the use of Radium-223 VS Lu-PSMA
(and hopefully soon other radio-pharmaceuticals)
BARCELONA
congress
2024
ESMO
Barcelona Auditorium - Hall 2
BARCELONA SPAIN 13-17 SEPTEMBER 2024
[Slide 1]
4
Methods — Study design
Statistical design
Primary analysis:
283 rPFS event
Enzalutamide 160 mg od
Study population
+
Key secondary endpoints
Primary endpoint
Patients with mCRPC
Ra223 55 kBq/kg iv
rPFS
tested semi-hierarchically.
and bone metastases
N=446**
every 4 weeks for 6 cycles
OS tested at 1-sided
Asymptomatic or
Key secondary
mildly symptomatic*
Overall Survival
a = 0.0034 due to interim
Stratification factors
WHO PS of 0 or 1
1:1
Country
Time to next treatment
testing (239 events).
No prior treatment
Randomisation
Baseline pain (BPI worst pain 0-1 vs 2-3)
Time to pain progression
with enzalutamide or
Prior docetaxel (yes vs no)
Time to first SSE
Use of bone protecting agents
Ra223
Prior abiraterone (yes vs no)
(symptomatic skeletal
Final OS analysis:
No known visceral
event)
317 OS events
metastases
Safety
Ongoing ADT
Enzalutamide 160 mg od
Treatment emergent
(target = 299)
CTCAE
OS tested at 1-sided
*defined as brief pain inventory WP24 score < 4
a = 0.0248
** original target accrual N=560, adapted for slow accrual
70% power to detect
IDMC recommendation (Sep 2024):
HR=0.75
Use of bone protecting agents (BPA) made mandatory
OS at primary analysis considered
(March 2018 after inclusion of 119 patients)
significant but conducts a final OS
OS tested on the ITT set (ie all randomized
patients) - stratified for baseline pain, prior
analysis to confirm the magnitude of
docetaxel and use of BPA.
benefit.
ASCO Genitourinary
#GU26
PRESENTED BY. Enrique Gallardo, MD
ASCO
AMERICAN SOCIETY OF
CONICAL
Cancers Symposium
Presentation a emperty of the author and ANCO required for muse; contact permissions@sco.org
KNOWLEDGE CONQUERS CANCER
---
[Slide 2]
7
Final OS results
Event/
Median (95%CI)
Hazard Ratio
1-sided P-
Total
(months)
(95% CI)2
value
100
Treatment
Treatment
Enza
Logrank:
Enza+RAD223
90
32.62
0.0096³
Enza
165/224
(29.31-38.24)
0.76
80
Permutation:
38.21
(0.60-0.96)
Enza+Ra223
152/222
0.0105
(33.08-44.75)
70
Kaplan-Meier method: 2Cox model; 3 Stratified Logrank test
60
Overall survival (%)
Enza+Ra223
Enza
50
(N=222)
(N=224)
40
(95% CI)
(95% CI)
6 mths
96.8 (93.5-98.5%)
99.1 (96.5-99.8%)
30
12 mths
90.5 (85.9-93.7%)
92.9 (88.6-95.6%)
20
18 mths
81.1 (75.3-85.6%)
80.8 (74.9-85.3%)
24 mths
10
71.1 (64.7-76.6%)
67.7 (61.2-73.4%)
36 mths
54.2 (47.1-60.6%)
47.4 (40.6-54.0%)
0
0
6
12
18
24
30
36
42
48
54
60
66
72
78
84
90
96
102
108
Time in months
Preset level of significance at final analysis: <0.0248
Patients-at-Risk
Enza- 224
209
151
84
35
20
6
3
0
Crossing of the curves (still) present at month 18
Enza+RAD223- 222
201
156
94
53
32
20
9
2
0
Only 3 patients censored < 24 months
Database locked on 12 January 2026 (cut off date: 01 May 2025)
ASCO Genitourinary
#GU26
PRESENTED BY: Enrique Gallardo, MD
ASCO
AMERICAN SOCIETY OF
CLINICAL ONCULOGY
Cancers Symposium
Presentation & property or the author and ASCO Parmission required for muse contact
KNOWLEDGE CONQUERS CANCER
---
[Slide 3]
Safety Summary: TEAE grade ≥3
Enza+RAD223
Enza
Nbr of patients (%) with grade 3-5
(N=218)
(N=224)
TEAE
Side effects of special interest:
N (%)
N (%)
1 MDS
All
151 (69.3%)
129 (57.6%)
1 AML
Hypertension
78 (35.8)
80 (35.7)
1 CML (drug-related)
Fatigue
12 (5.5)
4 (1.8)
All 3 in the combination arm
Fracture
12 (5.5)
3 (1.3)
17 osteonecrosis of the jaw:
Anemia
13 (6)
5 (2.2)
14 in the combo (5 grade 3)
Neutropenia
10 (4.6)
0
3 in the enza arm
Bone pain
13 (6)
12 (5.4)
Weight decreased
10 (4.6)
2 (0.9)
Spinal cord comprssn
7 (3.2)
8 (3.6)
No individual TEAE ≥ grade 3 has increased
Drug-related
63 (28.9%)
42 (18.8%)
by more than 5% in the combination
compared to the enzalutamide alone arm.
Hypertension
26 (11.9)
27 (12.1)
Fatigue
9 (4.1)
3 (1.3)
Anemia
Treatment-emergent AEs are all AEs arising from start of
6 (2.8)
0
treatment until 28 days after last dose of any study drug
Neutropenia
7 (3.2)
0
ASCO Genitourinary
#GU26
PRESENTED
BY: Enrique Gallardo, MD
ASCO
AMEXCAN SOCIETY OF
CUNICAL DSCULOGY
Cancers Symposium
Presentation & property of the author and AHCC Premission required for rouse contact
KNOWLEDGE CONQUERS CANCER
---
[Slide 4]
Event/
Median
Hazard Ratio
Updated rPFS analysis
Total
(95%CI) (months)
(95% CI)2
Treatment
100
Treatment
Enza
Enza+RAD223
16.43
90
Enza
176/224
Reference
(13.77-19.15)
80
19.19
0.71
Enza+Ra223
156/222
(16.92-24.57)
(0.57-0.89)
70
Radiological progression free survival (%)
'Kaplan-Meier method; 2Cox model;
60
50
Enza+RAD223
Enza
(N=222)
(N=224)
40
(95% CI)
(95% CI)
30
6 months
88.4 (83.3-92.0%)
84.6 (79.1-88.8%)
20
12 months
68.9 (62.2-74.7%)
60.6 (53.8-66.8%)
10
18 months
52.9 (45.9-59.4%)
44.5 (37.7-51.0%)
0
24 months
44.1 (37.2-50.7%)
37.2 (30.7-43.7%)
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
51
54
57
60
63
66
69
72
75
78
81
84
87
90
Time in months
Patients-at-Risk
Enza- 224
129
74
26
10
4
1
1
rPFS results confirmed with longer follow-up and
Enza+RAD223- 222
144
88
45
22
12
6
1
appear little changed from primary analysis.
Database locked on 12 January 2026 (cut off date: 01 May 2025)
ASCO Genitourinary
#GU26
PRESENTED BY: Enrique Gallardo, MD
ASCO
AMERICAN SOCIETY OF
CUNICAL ONCOLOGY
Cancers Symposium
Presentation & property of the author and ASCO Parmission required for ISSUED contact
KNOWLEDGE CONQUERS CANCER
[Slide 1]
congress
BARCELONA
2024
ESMO
3- PEACE-3: Safety data review
The ERA-223 Phase 3 trial
Fractures
N-806
Study population
56 k5g/hg every for cycles
The risk of fractures was strongly reduced
MORPC
factors
"
or
midy
I
Randomisation
by BPA in PEACE-3
for
UA)
90
I
go
and
Matching placebo
NO
Clear excess of fractures
ENZA+Ra-223 (no BPA)
in the Abiraterone + Radium-223
combination arm!
ENZA (no BPA)
AAP
-
3
-
.
I
a
4
:
:
,
1
No
this
1235
5533
****
SSYS
****
****
****
***Y
:
***1
Smith M, ESMO 2018 and Smith M, Lancet Oncol 2019
Gillessen S, ASCO 2021
---
[Slide 2]
BARCELONA
2024
ESMOCongress
3- PEACE-3: Safety data review
Most common grade 3-5
Enza+Ra223
Enza
treatment emergent AE
(N=218)
(N=224)
N (%)
N (%)
All
Hypertension
73 (33.5)
77 (34.4)
Fatigue
12 (5.5)
4 (1.8)
Fracture
11 (5.1)
3 (1.3)
Anaemia
10 (4.6)
5 (2.2)
Neutropenia
10 (4.6)
0
Overall combination was well tolerated
But!
- High incidence of HTA in patients receiving Enzalutamide (>30%)
---
[Slide 3]
BARCELONA
congress
2024
ESMO
4- PEACE-3: Is this practice changing?
The concept of « rPFS + » ... Overall Survival?
100
Arm
n/N
Median (95%CI)
90
Enzalutamide
110/224
60
+ Ra223
42.3 (36.8-49.1) mo
70
Enzalutamide + Ra223
Enzalutamide 129/220 35.0 (28.8-38.9) mo
60
Overall Survival (%)
50
HR (95%CI)
0.69 (0.52-0.90)
40
Enzalutamide
30
20
10
0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
51
54
57
60
63
06
"
72
Time in months
Patients-at-Risk
Enta-
224
222
206
152
107
77
54
40
30
20
14
6
1
Enza+RAD23-
222
214
194
149
114
92
71
$7
43
36
23
18
12
---
[Slide 4]
BARCELONA
2024
ESMOCongress
Conclusion: Radium-223 after PEACE-3
Combining Enzalutamide and Radium-223 improves rPFS (HR 0.69) and probably also OS (HR 0.69) in
(mostly ARPI-naive) mCRPC and predominant bone metastases
If this combination is used, a Bone-Protecting Agent is mandatory (mostly Denosumab)
Baseline symptomatic bone disease is not needed to benefit from Enza+Ra-223 !
Blood pressure should be monitored when using Enzalutamide (+/- Radium-223)
More data needed in PEACE-3 (ONJ, QoL, long-term OS, etc)
With more Radium-223 phase 3 trials maturing, we'll need to optimize the use of Radium-223 VS Lu-PSMA
(and hopefully soon other radio-pharmaceuticals)
First phase 3 to demonstrate OS benefit combining radium-223 with a next-generation androgen receptor pathway inhibitor in mCRPC with bone mets. 5.6-month median OS improvement. Key caveat: mandatory bone-protective agents prevented the fracture excess seen in prior ERA-223 trial.
rPFS HR 0.69 (95% CI 0.54-0.87, P=0.0009) favoring enzalutamide + radium-223 over enzalutamide alone. First phase 3 combining radium-223 with a next-generation androgen receptor pathway inhibitor in mCRPC with bone metastases.
Final overall survival: HR 0.76 (95% CI 0.60-0.96, P=0.0096). Median OS benefit of 5.6 months with the combination. Median follow-up 58 months; 317 deaths at final analysis.
Grade ≥3 TEAEs: 69.3% with combination vs. 57.6% with enzalutamide alone. Grade ≥3 TRAEs: 28.9% vs. 18.8%. Most frequent G≥3 AE was hypertension. Mandatory bone-protective agents (denosumab / zoledronic acid) prevented the fracture excess seen in prior ERA-223 trial.
Fracture excess prevented with mandatory bone-protective agents
✅ Practice-informing OS benefit in mCRPC with bone mets. First phase 3 to demonstrate OS benefit combining radium-223 with a next-generation androgen receptor pathway inhibitor in mCRPC with bone mets. 5.6-month median OS improvement. Key caveat: mandatory bone-protective agents prevented the fracture excess seen in prior ERA-223 trial.
