Maarten van der Doelen
Chapter 7
A
B
B
100
100
100
A
B
B
90
90
90
DDR + DDR -
DDR + DDR -
DDR + DDR -
DDR + DDR -
100 80
100 80
100 80
90 70
90 70
90 70
DDR + DDR -
DDR + DDR -
DDR + DDR -
DDR + DDR -
80 60
80 60
80 60
70 5
70 5
70 5
60 40
60 40
60 40
50 30
50 30
50 30
Overall survival (%)
ALP progression (%)
ALP progression (%)
40 20
40 20
40 20
30 10
30 10
30 10
Overall survival (%)
ALP progression (%)
ALP progression (%)
20 0
20 0
20 0
0
6
12
18
0 24
6 30
12
36
18
42
24
48
30
36
42
48
0
3
6
9
0
12
3
15
6
18
9
21
12
15
18
10
10
10
Months
Months
Months
Months
risk
Patients at risk DDR + DDR - 28 65 11 12 Patients at risk DDR + DDR - 28 65 11 12 0 24 0
Patients at risk DDR + DDR - 28 65 Patients at risk DDR + DDR - 28 65 0 0
Patients at risk DDR + DDR - 28 65 5 5 Patients at risk DDR + DDR - 28 65 5 5 0 0 9
26 51
6 25 14
3
26 51
1
6 25 14
1
5 5
0
3
1
1
8 5
28 53
23 36
19 23
28 53 6
23 36 6
19 23 2
48 11 12
6
6
2
1
0
6
12
18
6 30 6
12
36 3
18
42 0
24 0
30 6
36 3
42 0
48 0
3
12 2
3
15 1
18 0
9
21 0
12 2
15 1
18 0
Months
Months
Months
Months
risk
26 51
14 25
3 2
26 51
1 1
14 25
1 0
5 5
0 0
3 2
1 1
1 0
8 5
28 53
23 36
19 23
28 53 6 6
23 36 6 3
19 23 2 0
11 12 0
6 6
6 3
2 0
1 0
C
D
D
100
100
100
C
D
D
90
90
90
DDR + DDR -
DDR + DDR -
DDR + DDR -
DDR + DDR -
100 80
100 80
100 80
90 70
90 70
90 70
DDR + DDR -
DDR + DDR -
DDR + DDR -
DDR + DDR -
80 60
80 60
80 60
70 50
70 5
70 5
60 40
60 40
60 40
50 30 Next therapy (%)
50 30
50 30
Skeletal-related event (%)
Skeletal-related event (%)
40 2
40 2
40 2
30 Next therapy (%)
30 10
30 10
10
Skeletal-related event (%)
Skeletal-related event (%)
20 0
20 0
20 0
0
3
6
9
0
12
3
15
6
18
9
21
12
15
18
21
0
6
12
18
0 24
6 30
12
36
18
42
24
48
30
36
42
10
10
10
Months
Months
Months
Months
risk
Patients at risk DDR + DDR - 28 65 11 11 Patients at risk DDR + DDR - 28 65 11 11 0 0 9
Patients at risk DDR + DDR - 28 65 Patients at risk DDR + DDR - 28 65 0 0
Patients at risk DDR + DDR - 28 65 9 5 4 Patients at risk DDR + DDR - 28 65 9 5 4 0 24 0
8 5
28 58
6 38 22
6
28 58
2
6 38 22
2
9 11 11
1
6
2
2
1
21 47
14 28
21 47 3
14 28 3
1
9
5 0
3
3
1
0
3
12 3
3
15 1
18 1
21 1
12 3
15 1
18 1
21 1
6
12
18
6 30 1
12
36 1
18
42 0
24 4 0
48
30 1
36 1
42 0
12
12
Months
Months
Months
Months
risk
8 5
28 58
22 38
6 3
28 58
2 1
22 38
2 1
11 11
1 1
6 3
2 1
2 1
1 1
21 47
14 28
21 47 3 1
14 28 3 1
1
9
5 4 0 0
3 1
3 1
1 0
12 0 Figure 2. Kaplan-Meier curves, stratified by DNA damage response (DDR) mutation status. A. Overall survival. B. Time to alkaline phosphatase (ALP) progression. C. Time to initiation of next systemic therapy. D. Time to first skeletal-related event. 12
Patients with DDR alterations more frequently completed all six radium-223 injections compared to patients without these alterations (78.6% vs 56.9%; P = 0.047; median number of injections 6 vs. 6; P = 0.034) (Table 2 and Supplementary table 2). Despite the longer survival benefit, biochemical responses did not differ significantly between the DDR+ and DDR- groups; PSA response: median 29.4% vs. 34.6% ( P = 0.508) and ALP response: median -33.0% vs. -35.0% ( P = 0.639). In total, 57 (61.3%) patients showed an ALP decline of ≥30% (Figure 3).
DDR+ patients received significantly more subsequent therapies when compared to the DDR- patients, including PARP inhibitors (Supplementary table 3). The proportion of
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