Maarten van der Doelen

Impact of DNA damage repair defects on response to radium-223 therapy in mCRPC patients

FANCL, FANCM, MRE11A, MUTYH, NBN, NUDT1, PALB2, PARP1, PARP2, PARP3, PPP2R2A, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, RPA1, TP53BP1, XRCC2, and XRCC3. The pathogenicity of the alterations was assessed by two clinical molecular biologists within the molecular tumor board, according to the guidelines for the interpretation of sequence variants. Variants that were likely pathogenic or pathogenic in nature were selected for further associations with response and outcome. In addition to this pre-defined broad panel, two less inclusive panels of genes directly or indirectly linked to HR were used for exploratory analysis. One analysis explored the BRCA1 and BRCA2 genes. The other panel, defined as HRD+, consisted of ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCG, FANCI, PALB2, RAD51B , and RAD51C . Study endpoints Primary study endpoint was OS, defined as time between initiation of radium-223 therapy and date of death from any cause or date of last follow-up. Secondary endpoints included biochemical (prostate-specific antigen (PSA) and ALP) responses, time to ALP progression (TAP), the number of administered radium-223 injections, time to first skeletal-related event (TSRE), and time to subsequent treatment (TST) initiation following radium-223 therapy. Changes in PSA and ALP were calculated as maximal decline during therapy from baseline, with cut-offs of 50% and 30%, according to Prostate Cancer Working Group 3 (PCWG3) criteria. (14) Biochemical responses were confirmed by a second value. ALP progression was defined as an increase of ≥25% from baseline in patients with no decrease from baseline, or as an increase of ≥25% above the nadir, according to the ALSYMPCA study criteria (2). In case a next systemic therapy was started prior to ≥25% increase of ALP above the nadir, no ALP progression was documented and patients were censored. According to institutional upper limit of normal, normalization of ALP was defined as an ALP level below 115 U/L in patients with elevated ALP levels at baseline. Skeletal-related events (SREs) were defined according to PCWG3 criteria. (14) Statistical analyses To characterize the cohort, descriptive statistical methods were used. In case of missing data, valid percentages were calculated. Baseline characteristics between the defined DDR+ and DDR- groups were compared using the chi-square test or the Fisher’s exact test for categorical variables and the Mann-Whitney U test for continuous variables. Kaplan-Meier curves were used to visualize time-to-event data. Univariate and multivariate Cox proportional hazards models were used to compare time-to-event

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