Background: Wnt signaling is a cellular pathway responsible for embryogenesis and neoplasm. When activated, in about 10-20% of mCRPC, the WNT signaling pathway may cause androgen-independent growth and consequently antiandrogen resistance. To further characterize the clinical features and biology of this subtype of mCRPC, we studied mutations in genes of this pathway, including APC, CTNNB1, RNF43, ZNRF3 and RSPO2, in patients who received treatment at Johns Hopkins Hospital (JHH). Methods: Patients with CRPC who received first-line antiandrogen (abiraterone or enzalutamide) therapy for CRPC at JHH were retrospectively studied. Pathological staging, extension of primary disease, tumor somatic genomic data by Next Generation Sequencing (NGS) were correlated with clinical outcomes such as time to PSA progression, PSA response and overall survival (OS). Cox regression was used to test associations between variables and clinical outcomes and Kaplan-Meier method was used for time-to-event data. Results: Of 137 pts who received first-line antiandrogen therapy for CRPC, 10.9% (15 pts) had NGS with at least one activating WNT pathway alteration, including mutations in APC (6 pts), CTNNB1 (8 pts) and RNF43 (3 pts). Patients with WNT mutations had fewer T3/T4 tumors (30.8% vs. 51.4%, p = 0.24), but were balanced in other aspects. The median time to PSA progression in WNT activated patients was 6.5 months vs. 9.6 months in WNT negative patients (HR 2.3, 95% CI 1.3 - 4.1, p = 0.003). The presence of WNT mutations (HR 2.3, 95% CI 1.2 - 4.3, p = 0.007) and previous chemotherapy (HR 1.8, 95% CI 1.2 – 2.7, p = 0.003) were independently associated with shorter time to PSA progression. PSA50 response was numerically worse in WNT activated patients (53% vs 75%, p = 0.12). The OS in patients with WNT mutations was 23.6 months vs 27.7 months in patients without WNT mutations (HR 2.2, 95% CI 1.1 - 4.5, p = 0.01). Conclusions: Patients with WNT pathway mutations may have worse outcomes to first-line abi/enza compared to patients without these aberrations. Time to PSA progression and OS were inferior in WNT activated population. Our data reinforce the necessity to develop effective WNT pathway inhibitors to test in clinical trials for WNT activated patients.