Project Duration: 2019-2025

MOHCCN Consortium: Marathon of Hope - Quebec

Investigators:  Fred Saad, Anne-Marie Mes-Masson, Jean-Baptiste Lattouf, Zineb Hamilou 

Partners: Centre de recherche du Centre hospitalier de l’Université de Montréal, Institut du cancer de Montréal 

Project goals:

In an initial retro cohort

1. Profile radical prostatectomy specimens from patients who received targeted therapy.
2. Determine the molecular and genomic aspects underlining the difference between the responders and non-responders

Going forward in a prospective cohort

1. Profile specimens of castrate-resistant prostate cancer (CRPC) responder and non-responder patients to provide a better stratification of patients and identify potential actionable targets.
2. Profile real world patients (n>30) to determine their eligibility for Poly (ADPribose) polymerase 1 inhibitors (PARPis) trials
3. Collect liquid biopsies and tissues from Aim 2) patients at progression or 12 months following the 1st treatment for patients who did not demonstrate signs of progression. Compare the responders and non-responders to better understand the resistance to PARPis in prostate cancer.

Summary:

Prostate cancer (PC) is the most frequently diagnosed cancer in Canadian men (1/7) and remains the third deadliest cancer behind lung and colon cancers. One in four PC patients will develop resistance to standard androgen deprivation therapy (ADT) and eventually progress to a metastatic castration-resistant (mCRPC) state. At this point, available treatments remain essentially palliative, and almost all mCRPC patients will die of their disease within three years.

During the recent years, new targeted therapeutics approaches were offered to metastatic and non-metastatic CRPC patients. These include the new generation of androgen receptor signalling inhibitors (ARSI) such as abiraterone, enzalutamide, apalutamide and darolutamide. While these therapies showed an improvement in patient progression free and overall survival of PC patient cohorts, resistance to these therapies will occur sooner or later. Understanding the molecular and genomic aspects underlining response and resistance to ARSI’s remains a priority.

Another class of molecules presently assessed in CRPC clinical trials are the PARP inhibitors (PARPi). Recent evidence shows that the highest PARPi sensitivity is achieved when two specific DNA repair pathways are both deficient in tumor cells. These pathways are composed of several proteins whose functionality and activity impact on patient response. Thus, there is a need to properly identify patients suitable to receive PARPis and who would benefit from them. More recent studies suggest that there may be benefit to combining both ARSI’s and PARPi’s in patients with mCRPC.

In this context, early identification of patients suitable and more likely to respond to these two targeted therapy regimens, alone or in combination, would better personalize care to the most efficient therapeutic options therefore maximizing benefit for those most likely to respond while decreasing the burden of ineffective and toxic treatments for those unlikely to benefit.