Precision care and comprehensive research strategy for ovarian cancer patients: Beyond PARP inhibitors

Aim/goals:

To use molecular based tests (in the form of HRD tests using NGS) for treatment decision-making for all patients with advanced stage ovarian cancer following response to initial chemotherapy +/- surgery.  Second aim identify the HRP (high unmet need) group for further study.

1. BRCA testing - BRCA positive - offer olaparib +/- biosimilar bevacizumab.
2. BRCA negative patients: HRD testing + counselling:
   1. HRD - offer niraparib +/- biosimilar bevacizumab.
   2. HRP - patients will be offered a Patient Decision Aid (PtDA) to help them decide if a small (2.7 month in disease progression compared with placebo) benefit from niraparib, although it is approved if they choose.
3. HRP patients - finding treatment options for these patients is the goal of this project
   1. Whole genomic and transcriptomic sequencing of all patient tumors and matched normal blood will be used to identify somatic mutations, CNV, gene expression changes. Bioinformatics analyses will identify the most frequently observed pathway alterations and match each patient with treatments for any clinically actionable targets.
   2. Cell line and organoid models will be generated to investigate if treatment response can be inferred from patient derived organoids. Establishment of organoids will be correlated with tumor aggressiveness, with the intent of developing phenotype-specific therapies.

Genome-wide CRISPR/Cas9 screens, FDA-approved drug library screens and epigenetic compounds to identify targetable vulnerabilities specific to molecular contexts/mutations revealed by the sequencing and bioinformatics analyses.

 

High-grade serous ovarian carcinoma (HGSOC) is the most common and lethal type of ovarian cancer, accounting for 90% of patients with advanced stage disease and 70% of patients overall. The most promising treatment advance in recent years is the success of a new group of drugs called PARP inhibitors.  Two PARPi’s, olaparib and niraparib, are now approved for patients who show response to initial therapy with chemotherapy /- surgery.   This represents about 75% of all patients.  The side effect profile of each PARPi is different; niraparib is substantially more toxic than olaparib but approvals for each of these drugs are different and we cannot substitute one PARPi for another.

There is strong evidence in support of using molecular tumour testing to select the patients who will benefit most from PARP inhibitors. Despite this fact, tumor testing is not yet standard of care.  We are able to test for certain mutations (i.e. BRCA1/2) that account for about 15% of all patients with ovarian cancers.  The presence of BRCA 1/2 confers substantial sensitivity to PARP inhibition with olaparib (delay time to progression of cancer by 36 months). A further 35% of patients with ovarian cancer have genetic changes, called homologous recombination deficiency (HRD) that also effectively predict sensitivity to treatment with niraparib (delay time to progression of cancer by 11.4 months).  Taken together HRD and BRCA 1/2 represent 50% of patients.  The other fifty percent of patients with ovarian cancer have tumors that do not have genetic changes predictive of response to either PARPi; we call these homologous recombinant proficient (HRP) tumors. Tumors that are HRP do not respond well to any known chemotherapy treatments and patients have shorter survival time, especially compared to patients with tumors that are HRD.  Tumors that are HRP also do not respond well to PARPi, time to progression of cancer is prolonged by only 2.7 months; yet niraparib is approved for use in this setting.  The majority of side effects from niraparib are experienced in the first 6 weeks of treatment and generally dissipate by 3 months. Given this fact, most oncologists feel uncertain about the benefit in the HRP setting.  If we could identify patients with HRP tumors using tumor testing, patients could make a better decision about whether niraparib is right for them.  

In this study, we will implement HRD testing for ovarian cancer patients in response to their initial treatment. This information will provide personalized and precision estimates about the amount of benefit that can be expected from taking a PARPi.  More significantly, we will identify patients with HRP tumors, who are in desperate need of finding new targeted and effective therapies. We will also be able to develop clinical trial protocols that are specifically designed for HRP patients.  This is the only way we can improve outcomes for patients with HRP tumors, a group of patients with the highest unmet need in ovarian cancer.