Discussion
DLTs, fatigue, toxicity, mCRPC, prostate cancers
DISEASE, PROSTATE CANCER, DELETION
Xentuzumab in combination with enzalutamide demonstrated a manageable safety profile across all three parts of the study. No DLTs were reported in the first cycle during the Phase Ib dose escalation phase and the MTD/RP2D was determined to be Xe1000 + En160. The most common AEs across all parts of the study were fatigue and decreased appetite. There were no notable differences in safety profile between the xentuzumab plus enzalutamide and enzalutamide alone arms in the Phase II part. No new safety signals were observed, and the AE profile was as expected based on previous xentuzumab monotherapy trials [The exploratory dose expansion phase suggested that xentuzumab did not have antitumour activity in combination with enzalutamide in patients with mCRPC with rising PSA levels on enzalutamide. Addition of xentuzumab to enzalutamide in the Phase II part did not prolong PFS versus enzalutamide alone in patients with mCRPC after previous treatment with docetaxel and abiraterone. The groups were imbalanced with respect to baseline characteristics, with more adverse factors (ECOG PS, Gleason score, mutation burden) in the Xen1000 + En160 arm, although the outcomes with respect to PFS and OS were not altered after correction for PFS and Gleason score. Thus, while there is a strong preclinical rationale for targeting of IGF in prostate cancer, this did not translate to clinical efficacy in this study. This finding is consistent with other trials of IGF-1R inhibitory drugs in mCRPC patients. In a study of chemotherapy-naïve patients, addition of the IGF-1R inhibitory antibody, figitumumab, to docetaxel/prednisone did not significantly improve the PSA response rate above the null value of 45%, had a detrimental effect on PFS (4.9 vs 7.9 months) and substantially increased toxicity versus docetaxel/prednisone alone [Although the current and previous studies indicate that IGF or IGF-1R inhibition do not confer clinical benefit in unselected patients, certain patients with mCRPC appear to benefit. Therefore, there is a need to identify predictive biomarkers that might identify patients most likely to respond. As part of the current trial, there was an exploratory analysis of biomarkers to expand understanding of the disease and study treatment. PTEN is frequently downregulated by gene deletion or mutation as prostate cancers progress to mCRPC [Several IGF-pathway-related genes, including In conclusion, while xentuzumab and enzalutamide can be safely combined, the combination did not show antitumour activity in the overall population of patients with mCRPC. Further assessment of potential markers of response or resistance is required to enable selection of patients who may benefit from this combination.