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Wnt-pathway activating mutations are associated with resistance to first-line abiraterone and enzalutamide in castration-resistant prostate cancer

  • Pedro Isaacsson Velho,
  • Wei Fu,
  • Hao Wang,
  • Nooshin Mirkheshti,
  • Fahad Qazi,
  • Fabiola A.S. Lima,
  • Farah Shaukat,
  • Michael A. Carducci,
  • Samuel R. Denmeade,
  • Channing J. Paller,
  • Mark C. Markowski,
  • Catherine H. Marshall,
  • Mario A. Eisenberger,
  • Emmanuel S. Antonarakis


Wnt signaling is a cellular pathway involved in embryogenesis, development, and neoplasia. Wnt-pathway activation may accelerate prostate cancer androgen-independent growth and mediate antiandrogen resistance. Since 10–20% of advanced prostate cancers
harbor Wnt-activating mutations, we aimed to characterize the clinical features and response to novel antiandrogens in such patients.

To determine whether men with metastatic castration-resistant prostate cancer (mCRPC) who harbor Wnt-pathway mutations have poorer responses to first-line novel hormonal therapies: abiraterone/enzalutamide.

Design, setting, and participants
Patients with mCRPC who received first-line abiraterone or enzalutamide were retrospectively evaluated. Using tumor DNA analyses, we queried for activating mutations in CTNNB1 or inactivating mutations
in APC or RNF43, all of which are predicted to stimulate Wnt signaling. Presence or absence of at least one Wnt-activating alteration was correlated with clinical-pathologic characteristics and treatment outcomes.

Outcome measurements and statistical analysis
Time to prostate-specific antigen (PSA) progression, overall survival (OS), and PSA response were measured. Cox regression models were used to test associations between Wnt status and clinical-pathologic
outcomes; Kaplan-Meier and log-rank analyses were used to compare time-to-event endpoints.

Results and limitations
Of 137 patients evaluated, 11% (n = 15) had tumor DNA analysis showing at least one Wnt-stimulating alteration. Patients with Wnt-activating mutations had numerically fewer T3/T4 tumors than Wnt wild-type patients
(31% vs 51%), but were otherwise generally balanced. Median time to PSA progression on first-line abiraterone/enzalutamide was shorter in Wnt-activated patients (6.5 vs 9.6 mo, hazard ratio [HR] 2.34, p = 0.003), as was OS (23.6 vs 27.7 mo, HR 2.28,
p = 0.01). PSA responses were numerically worse in Wnt-activated patients (53% vs 75%, p = 0.12). Presence of Wnt-activating alterations (adjusted HR [aHR] 2.33, p = 0.007) and use of previous chemotherapy (aHR 1.83, p = 0.004) were both independently
associated with increased hazard of progression.

Patients with somatic Wnt-pathway activating mutations have worse outcomes to first-line abiraterone/enzalutamide than Wnt wild-type patients. Our data suggest that additional genomically informed therapies are needed for
this relevant subset of mCRPC patients.

Patient summary
In this report, we retrospectively examined outcomes of metastatic prostate cancer patients with or without Wnt-pathway mutations who received abiraterone or enzalutamide for the first time, in order to examine whether
these mutations affect the prognosis. Our study suggested that patients who have Wnt-pathway activating mutations derived less benefit from abiraterone and enzalutamide when compared to patients without these mutations. We conclude that Wnt-pathway
mutations might decrease the effectiveness of abiraterone and enzalutamide, and we propose that the Wnt pathway might be a good therapeutic target for these patients, in order to potentially reverse or prolong resistance to abiraterone and enzalutamide
in men with Wnt mutations.