Maarten van der Doelen

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Chapter 2

A A 10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100 C C 10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100

B B 10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100 D D 10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100

A A 10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100 C C 10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100

B B 10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100 D D 10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100

Prior RLT No prior Prior RLT No prior

Prior RLT No prior RLT Prior RLT No prior RLT

Survival (%)

0 3 6 9 12 15 18 21 24 27 30 33 36 0 0 3 6 9 12 15 18 21 24 27 30 33 36 0 13 11 8 6 6 4 3 2 2 2 1 1 0 Months since start of 225 Ac-PSMA RLT

0 3 6 9 12 15 18 21 24 27 30 33 0 0 3 6 9 12 15 18 21 24 27 30 33 0 2 1 0 0 0 0 0 0 0 0 0 0 11 10 8 6 6 4 3 2 2 2 1 1 Months since start of 225 Ac-PSMA RLT 2 1 0 0 0 0 0 0 0 0 0 0 11 10 8 6 6 4 3 2 2 2 1 1 Months since start of 225 Ac-PSMA RLT

0 3 6 9 12 15 18 21 24 27 30 33 36 0 No. at risk 0 3 6 9 12 15 18 21 24 27 30 33 36 0 13 11 8 6 6 4 3 2 2 2 1 1 0 Months since start of 225 Ac-PSMA RLT

No. at risk Prior RLT No prior RLT No. at risk Prior RLT No prior RLT 0 3 6 9 12 15 18 21 24 27 30 33 36 0 0 3 6 9 12 15 18 21 24 27 30 33 36 0 2 1 0 0 0 0 0 0 0 0 0 11 10 8 6 6 4 3 2 2 2 1 1 0 Months since s art of 225 Ac-PSMA RLT 2 1 0 0 0 0 0 0 0 0 0 0 11 10 8 6 6 4 3 2 2 2 1 1 0 Months since s art of 225 Ac-PSMA RLT

No. at risk Prior RLT No prior RLT No. at risk Prior RLT No prior RLT

Months since start of 225 Ac-PSMA RLT

No. at risk

13 11 8 6 6 4 3 2 2 2 1 1 0

PSMA expression H score >200 PSMA expression H score <200 PSMA expression H score >200 PSMA expression H score <200

DD DD DD DD

DDR + DDR - DDR + DDR -

Survival (%)

0 3 6 9 12 15 18 21 24 27 30 33 36 0 0 3 6 9 12 15 18 21 24 27 30 33 36 0 11 10 8 6 6 4 3 2 2 2 1 1 0 2 1 0 0 0 0 0 0 0 0 0 0 0 Months since start of 225 Ac-PSMA RLT 11 10 8 6 6 4 3 2 2 2 1 1 0 2 1 0 0 0 0 0 0 0 0 0 0 0 Months since start of 225 Ac-PSMA RLT

0 3 6 9 12 15 18 21 24 27 30 33 0 0 3 6 9 12 15 18 21 24 27 30 33 0 2 2 2 1 1 1 1 0 0 11 9 6 4 4 2 2 1 1 1 1 1 Months since start of 225 Ac-PSMA RLT 2 2 2 2 2 2 1 1 1 1 0 0 11 9 6 4 4 2 2 1 1 1 1 1 Months since start of 225 Ac-PSMA RLT 2 2

No. at risk H score >200 H score <200 No. at risk H score >200 H score <200 0 3 6 9 12 15 18 21 24 27 30 33 36 0 0 3 6 9 12 15 18 21 24 27 30 33 36 0 11 10 8 6 6 4 3 2 2 2 1 1 0 2 1 0 0 0 0 0 0 0 0 0 Months since s art of 225 Ac-PSMA RLT 11 10 8 6 6 4 3 2 2 2 1 1 0 2 1 0 0 0 0 0 0 0 0 0 0 Months since s art of 225 Ac-PSMA RLT

No. at risk DDR + DDR - No. at risk DDR + DDR - 0 3 6 9 12 15 18 21 24 27 30 33 36 0 0 3 6 9 12 15 18 21 24 27 30 33 36 0 2 2 2 2 2 1 1 1 1 0 0 0 11 9 6 4 4 2 2 1 1 1 1 1 0 Months since s art of 225 Ac-PSMA RLT 2 2 2 2 2 2 1 1 1 1 0 0 0 11 9 6 4 4 2 2 1 1 1 1 1 0 Months since s art of 225 Ac-PSMA RLT

k 200 200 k 200 200

No. at risk DDR + DDR - No. at risk DDR + DDR -

Figure 1. Kaplan-Meier estimates of overall survival in patients with metastatic castration-resistant prostate cancer treated with 225 Ac-PSMA-617 targeted alpha-radiation therapy. A . Survival estimate for the total cohort. B . Survival stratified by prior 177 Lu-PSMA-617 radioligand therapy. C . Survival stratified by immunohistochemical prostate-specific membrane antigen expression. D . Survival stratified by DNA damage response mutation status. DDR, DNA damage repair; PSMA, prostate-specific membrane antigen; RLT, radioligand therapy. Efficacy Patients received a median of three 225 Ac-PSMATAT cycles. Nine (69%) patients achieved ≥50% PSA decrease and six (46%) patients showed ≥90% PSA decline (Figure 2A and Supplementary figure 1). The median best PSA decline following the first cycle was 68% and median best PSA decline at any time during therapy was 88% from baseline. Median time from TAT initiation to PSA nadir was 3.9 months. All patients achieved ALP decline in response to therapy, with a median best ALP decline of 48% (Figure 2B). Eight (62%) patients showed ≥30% ALP decline, and six (46%) patients had ≥50% ALP decline.

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