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2023 Durden Foundation-PCF Challenge Award

Characterizing Imaging, Genomic and Immune Predictors of 177Lu-PSMA (Lu-PSMA) and Olaparib Response in Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC)

Principal Investigators: Shahneen Sandhu, MBBS (The University of Melbourne), Belinda Parker, PhD (University of Melbourne)

Co-Investigators: Michael Hofman, MBBS (University of Melbourne), Nicole Haynes, PhD (University of Melbourne), David Quigley, PhD (University of California San Francisco), Alexander Wyatt, PhD (University of British Columbia), Anna Trigos, PhD (University of Melbourne), Louise Emmett, MD (St Vincent’s Hospital), Anis Hamid, MBBS (Peter MacCallum Cancer Centre), Ramyar Molania, PhD (University of Melbourne), Anthony Joshua, MBBS, PhD (St Vincent’s Hospital), Andrei Gafita, MD, PhD (Johns Hopkins University), Felix Feng, MD (University of California San Francisco), William Chen, MD (University of California San Francisco), Paul Neeson, PhD (University of Melbourne)

Young Investigator: Richard Rebello, PhD (University of Melbourne)

Description:

  • LuPSMA (177Lu-PSMA-617) and olaparib are standard therapies for certain patients with metastatic castration resistant prostate cancer (mCRPC) that can significantly extend patient survival. However, even among eligible patients, not all will benefit from these treatments, and they are not curative. New ways to improve efficacy and better identify which patients will benefit are urgently needed.
  • Dr. Shahneen Sandhu is leading the phase 1b LuPARP trial, which is testing the combination of LuPSMA and olaparib in patients with mCRPC. The rationale for this trial is based on knowledge that LuPSMA delivers DNA-damaging radiation to tumor cells, while olaparib prevents DNA repair, thus combining these may deliver therapeutic synergy, as tumor cells that receive extensive DNA damage but cannot repair it are more likely to die.
  • In this project, Dr. Sandhu will leverage patient samples and data from the LuPARP trial to define imaging and molecular biomarkers that predict response vs. resistance to LuPSMA + Olaparib and to understand the mechanisms of action of this treatment.
  • The performance of PSMA PET imaging, circulating tumor DNA, and circulating tumor cell numbers for measuring treatment efficacy and disease burden will be investigated.
  • How the treatment combination impacts the molecular and genomic evolution of the tumor will be investigated.
  • Whether and how this treatment combination changes the tumor microenvironment, including anti-tumor immune responses will be studied. These data may help to uncover novel strategies to increase the efficacy of LuPSMA-based therapy by targeting the altered tumor immune microenvironment.
  • If successful, this project will characterize the tumor and immune impacts of LuPSMA + Olaparib combination treatment, and will define biomarkers to guide selection of patients who will most benefit from this combination.

What this means to patients: LuPSMA and Olaparib are two new treatments for certain patients with mCRPC that may work even better when combined. Dr. Sandhu and team are leading a clinical trial to test this combination. In this project, the team will develop biomarkers to measure combination treatment efficacy and help to select patients who will most benefit from. The team will also define the biological impacts of this combination, which will help to refine how best to use these treatments for maximal efficacy.