Maarten van der Doelen

Chapter 7

Table 2. Outcomes of radium-223 therapy.

Complete cohort N = 93

Group DDR - N = 65

Group DDR + N = 28

P

Number of injections, median (range)

6 (1-6)

6 (1-6)

6 (3-6)

0.034

Completion of radium-223 therapy, n (%)

59 (63.4)

37 (56.9)

22 (78.6)

0.047

PSA decline >30%, n (%)

15 (16.1)

12 (18.5)

3 (10.7)

0.540

PSA decline >50%, n (%)

7 (7.5)

5 (7.7)

2 (7.1)

1.000

ALP decline >30%, n (%)

57 (61.3)

39 (60.0)

18 (64.3)

0.697

ALP decline >50%, n (%)

25 (26.9)

18 (27.7)

7 (25.0)

0.788

ALP normalization a , n (%)

28 (57.1)

20 (55.6)

8 (61.5)

0.709

ALP, alkaline phosphatase; DDR, DNA damage repair; PSA, prostate-specific antigen. a If elevated alkaline phosphatase according to institutional upper limit of normal (e.g. ≥ 115 U/l) at baseline.

DISCUSSION This retrospective collaborative study investigated in 93 molecularly profiled mCRPC patients whether presence of deleterious aberrations in pre-defined DDR genes was associated with an improved outcome to radium-223 therapy. We show that patients with pathogenic DDR alterations, including BRCA1 and BRCA2 , and additional genes with indirect involvement in HR, appear to benefit from radium-223 therapy. A remarkable nineteen month longer median OS was identified, whilst no clear imbalance was found in baseline characteristics between both groups, nor did subsequent therapies clearly influence outcome. The proportion of patients that completed six radium-223 injections was higher in the DDR+ compared to the DDR- group. Secondary endpoints favoured the DDR+ group with a numerically longer TAP and TST. Previous case reports hinted towards a beneficial response to radium-223 in patients with DDR alterations. (9-11) In the study of Isaacsson Velho et al. a trend towards an OS benefit was seen in the DDR+ group (median OS 36.9 vs. 19.0 months; HR 3.3; P = 0.11), which is in line with the OS benefit seen in our study. (11) The recently presented interim analysis of the enrolling prospective PRORADIUM study (NCT02925702) also showed a trend towards prolonged OS in patients with germline HR mutations (median OS 14.4 versus 10.6 months, P = 0.066). (15)

It is mechanistically still largely unclear how radium-223 translates to survival benefit. Abou et al. showed in a metastatic prostate cancer model that radium-223 localizes

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