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2021 John Paulson-PCF Young Investigator Award

Neoadjuvant Darolutamide and Abemaciclib in High-Risk Prostate Cancer

Praful Ravi, MD
Harvard: Dana-Farber Cancer Institute

Mentors: Mary-Ellen Taplin, MD, Heather Jacene, MD, Eliezer Van Allen, MD

Description:

  • Patients with high-risk localized prostate cancer have a significant risk for disease recurrence after radical prostatectomy (RP). Data from recent trials have suggested that neoadjuvant intense androgen receptor (AR)-targeted therapy prior to RP may improve outcomes, with 15-30% of patients achieving pathologic complete response or minimal residual disease.
  • Dr. Praful Ravi is investigating whether inhibitors of the cell cycle regulators CDK4 and CDK6 may synergize with AR-targeted agents as neoadjuvant therapy prior to RP.
  • In this project, Dr. Ravi will conduct a phase 2 neoadjuvant trial testing the addition of the CDK4/6 inhibitor abemaciclib to intense AR-targeted therapy (darolutamide + leuprolide) in men with high-risk prostate cancer prior to RP.
  • The safety, tolerability, and recommended phase 2 dose of this combination will be determined. Pathologic response rates will be evaluated in RP samples following neoadjuvant abemaciclib, darolutamide and leuprolide versus darolutamide and leuprolide alone.
  • Whether changes in disease extent as measured by PSMA-PET, or blood- and tissue-based biomarkers correlate with pathologic responses to the neoadjuvant therapy will be evaluated.
  • If successful, this project will determine whether the addition of CDK4/6 inhibitors to neoadjuvant intense AR-targeted therapy has the potential to improve outcomes for men with high-risk disease, and identify biomarkers of response and resistance.

What this means to patients: Neoadjuvant therapy with intense AR-targeted therapy is a promising experimental approach to improving outcomes in patients with high risk localized prostate cancer, who are otherwise at high risk for disease recurrence following radical prostatectomy. Dr. Ravi will conduct a clinical trial to test whether adding CDK4/6 inhibitors to neoadjuvant intense AR-targeted therapy has the potential to improve outcomes for men with high-risk disease. If this trial is positive, this could support further evaluation of this strategy in a larger phase 3 trial. The correlative studies embedded into the trial will improve understanding of high-risk prostate cancer and provide insights into the mechanisms of response and resistance to neoadjuvant therapy.