> Our Work > The Work We Fund

2023 PCF Challenge Award

Personalizing Treatment Decisions Through Composite Next Generation Imaging and Liquid Biomarker Development Within a Phase II Randomised Trial of Enzalutamide (+/-177Lu-PSMA-617) (ENZAp)

Principal Investigator: Louise Emmett, MD, MBBS (St Vincent’s Hospital Sydney, Australia)

Young Investigators: Edmond Kwan, MBBS, PhD (University of British Columbia), Megan Crumbaker, MD, PhD (St Vincent’s Hospital Sydney), Andrei Gafita, MD (Johns Hopkins University), Narjess Ayati, MD (St Vincent’s Hospital Sydney)

Co-Investigators: Michael Hofman, MBBS (Peter MacCallum Cancer Centre), Ian Davis, MBBS, PhD (Monash University), Alexander Wyatt, PhD (University of British Columbia), Andrew Martin, PhD (University of Sydney), Shahneen Sandhu, MD, PhD (Peter MacCallum Cancer Centre), Martin Stockler, MBBS, PhD (University of Sydney), Felix Feng, MD (University of California, San Francisco), Martin Sjostrom, MD, PhD (University of California, San Francisco), Nathan Papa, MBBS, PhD (Garvan Institute of Medical Research)

Description:

  • LuPSMA (Pluvicto®; 177Lu-PSMA-617 is a new life-extending treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). LuPSMA works by targeting radiation to prostate cancer cells, which uniquely express the PSMA protein. However, this treatment remains non-curative. How to overcome treatment resistance and increase efficacy is of critical importance.
  • The efficacy of LuPSMA requires sufficient levels of PSMA on the surface of prostate cancer cells. PSMA levels are regulated by the androgen receptor (AR), and can be increased by AR-targeted therapies such as enzalutamide. These data suggest that therapeutic synergy may be achieved by combining LuPSMA with enzalutamide.
  • Louise Emmett is leading the ENZA-p trial, a fully recruited randomized phase II trial testing LuPSMA plus enzalutamide versus enzalutamide alone as first-line therapy in patients with mCRPC.
  • In this project, Dr. Emmett and team will utilize data and samples from the ENZA-p trial to investigate whether enzalutamide can impact PSMA levels, determine mechanisms of synergy of LuPSMA + enzalutamide, and develop biomarkers to determine whether individual patients are more likely to benefit from enzalutamide alone vs. with LuPSMA.
  • Patients on the trial will undergo serial PSMA PET imaging before, during and after treatment. These images will be studied to determine how PSMA PET levels are changed by enzalutamide, and whether sites of resistance to enzalutamide can be identified by PSMA PET.
  • Combined PSMA PET and blood-based tests will be developed to better predict patients most likely to benefit from enzalutamide monotherapy vs. combination therapy.
  • Circulating tumor DNA from blood will be used to study tumor genomics and identify mechanisms of response and resistance to the different therapy options.
  • Finally PSMA SPECT, a molecular imaging technique that can directly visualize LuPSMA in the body, will be investigated as a method to evaluate and predict the efficacy of LuPSMA treatment.
  • If successful, this project will answer key questions about how to use imaging and molecular biomarkers to improve personalization of treatment decisions in patients with mCRPC being considered for enzalutamide +/- LuPSMA.

What this means to patients: Several treatments are now available for patients with mCRPC, including AR-targeted therapies and LuPSMA. However, none of these are curative alone, and how to sequence and combine them to optimize efficacy is of critical importance. Dr. Emmett and team are leading a phase 2 trial testing LuPSMA plus enzalutamide versus enzalutamide alone as first-line therapy in patients with mCRPC. In this project, the team will study molecular imaging and liquid biopsy biomarkers from patients on this trial, to understand mechanisms of synergy and resistance, and develop optimal biomarkers to guide individual treatment selection decisions for patients with mCRPC.