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

Raag Agrawal1, Adam B Weiner2, Julie Livingstone1

  • 1Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California-Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA, USA.

European Urology Oncology
|November 9, 2025
PubMed
Abstract

Insights

Inhibition of SRC or MEK pathways did not reduce epithelial-mesenchymal transition (EMT) in prostate cancer patients receiving androgen deprivation therapy (ADT). This approach did not improve clinical or pathological outcomes, suggesting it is not effective for mitigating ADT resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Clinical Trials

Background:

  • Androgen deprivation therapy (ADT) resistance in prostate cancer is linked to epithelial-mesenchymal transition (EMT).
  • SRC and MEK pathways are implicated in driving ADT resistance and EMT.
  • Targeting these pathways is a potential strategy to overcome treatment resistance.

Purpose of the Study:

  • To investigate if inhibiting SRC or MEK pathways can reduce EMT in prostate cancer patients undergoing ADT.
  • To evaluate the impact of SRC or MEK inhibition on clinical and pathological outcomes in localized prostate adenocarcinoma.

Main Methods:

  • A phase 2 randomized trial involving 45 patients with high-risk prostate adenocarcinoma.
  • Patients received neoadjuvant ADT (enzalutamide + degarelix) alone or with an SRC inhibitor (dasatinib) or MEK inhibitor (trametinib).
  • Primary endpoint: abundance of EMT markers (N-cadherin, vimentin) via immunohistochemistry (IHC); secondary endpoints: clinicopathologic outcomes, safety.

Main Results:

  • No significant difference in N-cadherin and vimentin expression by IHC across treatment arms.
  • No improvement observed in time to biochemical recurrence, testosterone recovery, or minimal residual disease.
  • Significant decrease in MAP2K1, MAP2K2, and SRC RNA levels observed in all arms; no grade ≥3 adverse events.

Conclusions:

  • Neoadjuvant inhibition of SRC or MEK pathways does not mitigate the EMT response to ADT in prostate cancer.
  • This therapeutic strategy did not influence key clinical or pathological outcomes.
  • Targeting SRC/MEK pathways alongside ADT is not effective for improving outcomes in this patient population.
Keywords:
AgeAndrogen antagonistsAntineoplastic agentsDasatinibEpithelial-mesenchymal transitionGene expression regulationMAP kinase signalingNeoadjuvant therapyProstatectomyProstatic neoplasm

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