Homologous recombination (HR) deficiency (HRD), particularly from biallelic mutational loss of BRCA1/BRCA2/ATM (BRCA/ATM), is significantly enriched in men with metastatic castration-resistant prostate cancer (mCRPC). Such patients have multiple FDA-approved systemic life-prolonging therapies to choose from, including abiraterone, enzalutamide, and taxane chemotherapies, as well as the possibility of poly(ADP- ribose) polymerase (PARP) inhibitor therapy which currently remains investigational. A few recent studies suggest that patients with germline and/or somatic HRD mutations may respond better (and for longer durations of time) to novel hormonal therapies than their HRD-negative counterparts. These studies suggest that in addition to PARP inhibition, potent AR suppression is also ?synthetic lethal? with HRD in mCRPC. However, the genetic/genomic determinants of HRD and their role in treatment selection remain unknown. We propose a resource-driven, patient-centered study to determine the genetic/genomic drivers of HRD predicting ?deep? response to abiraterone and enzalutamide. We hypothesize that mCRPC patients can be categorized into three groups according to HRD status defined by deleterious mutations in HRD genes: 1) germline/somatic HRD; 2) somatic-only HRD; 3) negative HRD; and that these groups are molecularly distinct, and have different clinical implications as predictive markers of response to AR-targeting therapies and taxane chemotherapies. To address the overall hypothesis, it is necessary to establish clinical and tumor/normal specimen cohorts that enable detailed molecular and clinical characterization of HRD in men with mCRPC.
In Specific Aim 1, we will seek to ascertain the HRD mutations status, both somatic and germline, in three existing advanced/lethal prostate cancer cohorts enriched for HRD using blood-based assays.
In Specific Aim 2, we will determine the association of HRD status defined by blood-based assays with treatment response to first-line AR-directed therapy (abiraterone/enzalutamide) and taxane chemotherapies in mCRPC patients by comparing treatment outcomes of men in these three groups.
In Specific Aim 3, we seek to determine the expression correlates of HRD status defined by blood-based assays and further ascertained by tissue-based assays, by performing RNA-Seq in surgical specimens from men with lethal prostate cancer with: 1) germline/somatic HRD; 2) somatic-only HRD; and 3) negative HRD. The proposed work addresses an unmet need due to focus on liquid biopsy markers in a vulnerable patient population facing difficult treatment decisions. Also, our effort in defining the clinical and functional implications of HRD status in established cohorts of mCRPC patients will directly lead to treatment selection strategies to improve clinical management as well as patient selection strategies for clinical trials.

Public Health Relevance

We propose a resource-driven, patient-centered study to determine the genetic/genomic drivers of homologous recombination deficiency and their role as treatment selection markers for lethal prostate cancer. The focus on liquid biopsies in a vulnerable patient population facing difficult treatment decisions will directly lead to treatment selection strategies to improve clinical management as well as patient selection strategies for clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA238284-02
Application #
10064615
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Daee, Danielle L
Project Start
2019-12-03
Project End
2024-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Urology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218