Biomarkers and pharmacogenomic evaluation
tumours, tumour, Tumour, prostate
TUMOURS, TUMOUR, TUMOUR, PROSTATE
Circulating and tissue markers were assessed for prognostic and predictive potential. In the Xe1000 + En160 arm, total circulating IGF-1 and IGF-2 concentrations increased after the start of xentuzumab treatment, reaching a plateau by the start of cycle 2; free IGF-1 and bioactive IGF decreased following xentuzumab treatment. While circulating biomarkers showed prognostic potential, e.g., high levels of IGF-1 and IGF-2 at baseline tended to be associated with better PFS and OS regardless of treatment (data not shown), none of the circulating biomarkers tested showed predictive potential for PFS or OS (Figs. Archival prostate tissue samples were analysed for PTEN expression by IHC in 90 patients, including 72 Phase II patients (36 per arm) and 18 patients from the Phase 1b expansion part. Median PTEN H-score was 177.5 in the Xe1000 + En160 arm, 100.0 in the En160 arm and 130 in all 90 patients. PTEN H-score was not prognostic for PFS or OS (data not shown). There was no OS difference in the Xe1000 + En160 versus En160 arms in patients whose tumours had PTEN H-score >80 (17.8 vs 17.4 months; HR 1.07, 95% CI 0.52–2.20) or >130 (17.8 vs 17.4 months; HR 1.18, 95% CI 0.55–2.53). However, there was a trend towards OS benefit with Xe1000 + En160 versus En160 in patients with tumours with PTEN H-score >220 (median OS 19.4 vs 12.7 months; HR 0.66 [95% CI 0.24–1.81]; Fig. Expression of IGF-pathway-related genes was determined in archival tissue samples from 55 patients (Xe1000 + En160, 29 patients; En160, 26 patients). Low expression of Tumour mutations were analysed in archival FFPE samples from 24 patients (Xe1000 + En160, 11 patients; En160, 13 patients). Median number of mutations per tumour was 14 in the Xe1000 + En160 arm and nine in the control arm. Assessment of prognostic potential showed that patients were more likely to stay progression free and alive if their tumour showed ≤10 mutations (>10 vs ≤10 mutations: HR 0.21 [95% CI 0.07–0.70]) or if their tumour had ≤9 short variants (>9 vs ≤9 short variants: HR 0.08 [95% CI 0.02–0.39]). Patients were more likely to stay alive for a longer period of time if their tumour had ≤9 short variants (>9 vs ≤9 short variants; HR 0.135 [95% CI 0.040–0.459]). Mutational status by cfDNA showed that the mean (standard deviation [SD]) number of mutations at baseline was similar in both treatment groups (Xe1000 + En160: 2.2 [1.5], 