First-In-Man PARP1-Selective Inhibitor in Lethal Prostate Cancer: Mechanisms of Action and Biomarkers of Therapeutic Response

Principal Investigators: Harveer Dev, MD, PhD (University of Cambridge), Simon Pacey, MD, PhD (University of Cambridge), Charlie Massie, PhD (University of Cambridge)

Co-Investigators: Hisham Mohammed, PhD (Knight Cancer Institute)

Description:

• PARP-inhibitors are a new class of treatments that are approved for patients with metastatic castration resistant prostate cancer (mCRPC) with alterations in certain DNA repair genes, and are under investigation in broader patient groups and in combination with other therapies.
• Recent phase 3 clinical trials found that the combination of a PARP-inhibitor with next generation hormonal agents were efficacious in mCRPC patients regardless of whether they had DNA repair gene alterations.However, not all patients responded to this combination. It remains unclear how this combination therapy works in genomically ‘DNA repair proficient’ tumors and how to identify the patients most likely to benefit.
• Harveer Dev and team are studying the mechanisms of action of combining PARP-inhibitors with anti-androgen therapy in mCRPC.
• In this project, Dr. Dev and team will determine whether epigenetic patterns in tumor cell DNA can serve as biomarkers of response to PARP-inhibitor + anti-androgen combination therapy.  Whether these biomarkers can be detected in circulating tumor DNA will be determined, and the team aims to ultimately develop a liquid biopsy-based biomarker test to select patients for this treatment.
• Prostate cancer models will be used to determine the role of various DNA repair genes in response to various doses and timings of PARP-inhibitor + anti-androgen combinations, in order to identify optimal personalized treatment dosing strategies.
• Samples from patients treated with PARP-inhibitor + anti-androgens in clinical trials will be studied to determine how the treatment impacts tumor and immune biology.
• If successful, this project will elucidate the mechanisms of action of PARP-inhibitor + anti-androgen combination therapy, and result in the development of a blood-based biomarker test that can identify patients most likely to benefit from this treatment.

What this means to patients:  The combination of a PARP-inhibitor with anti-androgen therapy is a promising new treatment strategy for patients with mCRPC, that is currently under FDA-evaluation for approval.  Dr. Dev’s project will elucidate the biology of this treatment combination and develop a blood test to select which patients are most likely benefit from this therapy.