Neoadjuvant Antiandrogen Therapy With or Without MEK or SRC Inhibition for Unfavorable-risk Prostate Cancer: A Phase 2 Randomized Clinical Trial

BACKGROUND AND OBJECTIVE: It is thought that androgen deprivation therapy (ADT) resistance and subsequent prostate cancer progression via epithelial-mesenchymal transition (EMT) is induced by the SRC and MEK pathways. We hypothesized that inhibition of these pathways could reduce EMT. METHODS: In this phase 2 trial, 45 patients undergoing prostatectomy for International Society of Urological Pathology grade group ≥3, prostate-specific antigen >20ng/ml, and/or stage ≥cT3a localized prostate adenocarcinoma were randomized 1:1:1 to receive 6-8wk of neoadjuvant ADT (enzalutamide+degarelix) alone or in combination with either an SRC inhibitor (dasatinib) or MEK inhibitor (trametinib). The primary endpoint was the abundance of EMT markers (N-cadherin and vimentin) on immunohistochemistry (IHC) after prostatectomy. Secondary outcomes included clinicopathologic outcomes, changes in EMT markers between biopsy and prostatectomy according to IHC and RNA abundance, and safety. KEY FINDINGS AND LIMITATIONS: IHC results for N-cadherin and vimentin after treatment did not differ by arm. No differences were observed in time to biochemical recurrence, time to testosterone recovery, or pathologic minimal residual disease. MAP2K1, MAP2K2, and SRC RNA abundance decreased significantly in all three arms. No patients experienced a grade ≥3 treatment-related adverse event. CONCLUSIONS AND CLINICAL IMPLICATIONS: Neoadjuvant SRC or MEK inhibition does not appear to mitigate the EMT response to ADT or influence clinical or pathological outcomes.