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2023 Igor Tulchinsky-PCF Challenge Award

ctDNA Determinants of Resistance to 177Lu-PSMA-617 versus Taxane-Based Chemotherapy

Principal Investigators: Alexander Wyatt, PhD (Vancouver Prostate Centre), Arun Azad, MD (Peter MacCallum Cancer), Kim Chi, MD (BC Cancer), Michael Hofman, MBBS (Peter MacCallum Cancer Centre)

Young Investigators: Heidi Fettke, PhD (Peter MacCallum Cancer Centre), Edmond Kwan, MBBS, PhD (University of British Columbia), Corinne Maurice-Dror, MD (BC Cancer), Martin Sjostrom, MD, PhD (University of California San Francisco)

Co-Investigators: Fred Saad, MD (University of Montreal Hospital Center), Francois Bernard, MD (BC Cancer), Ian Davis, MBBS, PhD (Monash University), Matti Annala, BS (Tampere University), Felix Feng, MD (University of California, San Francisco), Wendy Parulekar, MD (Queen’s University)

Description:

  • The prostate-specific membrane antigen (PSMA) radioligand therapy LuPSMA (177–Lutetium-PSMA-617; Pluvicto®) is a promising new treatment for metastatic castration-resistant prostate cancer (mCRPC).
  • However, it is unclear how to use LuPSMA in settings where taxane-based chemotherapy (docetaxel or cabazitaxel) is also a proven life-prolonging option. Importantly, neither treatment elicits benefit for all patients, and both can result in significant health and/or financial toxicity.
  • Alexander Wyatt and team have previously developed blood plasma circulating tumor DNA (ctDNA) tests that can track treatment response and disease progression.
  • In this project, they will develop ctDNA-based biomarker tests to determine differential responses of patients with mCRPC to LuPSMA versus taxane chemotherapy, and identify tumor subclones that drive acquired treatment resistance.
  • The team have assembled serial blood samples from over 600 patients enrolled in clinical trials testing LuPSMA versus docetaxel or cabazitaxel or receiving standard-of-care treatment with taxane chemotherapy or LuPSMA.
  • In this project, the team will perform genomic and epi-genomic sequencing on circulating tumor DNA from pre-treatment samples from all patients, and use custom computational and AI tools to identify genomic and epi-genomic tumor biomarkers that can predict probability of response and survival on each therapy.
  • The team will also analyze samples from patients at the time of disease progression on therapy to identify drivers of acquired resistance to LuPSMA versus taxane chemotherapy.
  • If successful, this project will identify new drivers of treatment resistance and provide new biomarkers to help guide treatment selection for patients with mCRPC, reducing the use of futile therapy, and improving quality and length of life.

What this means to patients: There are now several treatment options for patients with mCRPC, including LuPSMA and taxane chemotherapy. However, these treatments are not effective in all patients and can cause side effects that severely reduce patient quality of life. Biomarkers to predict which treatment a patient is likely to benefit more from are urgently needed. Dr. Wyatt and team will develop new blood-based biomarker tests that can predict how well individual patients with mCRPC will respond to LuPSMA vs taxane chemotherapy, and will also identify new mechanisms that drive treatment resistance. This will help to guide treatment selection and greatly improve patient outcomes.