# Project 1: Genomic Predictors of Clinical Outcomes and Response to Targeted Therapy in Advanced Prostate Cancer

> **NIH NIH P50** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $177,336

## Abstract

SUMMARY/ABSTRACT
Clinical sequencing has only recently begun to inform the selection of FDA-approved therapies for individual
patients with prostate cancer. The recent FDA approvals of rucaparib and olaparib for men with metastatic
castration-resistant prostate cancers harboring alterations in DNA damage repair (DDR) genes and of
pembrolizumab for microsatellite instability–high (MSI-H) or mismatch repair deficient solid tumors dictate that
somatic and germline DNA profiling are now required for the optimal standard care of men with advanced
prostate cancer. However, among patients with BRCA and other DNA repair pathway gene mutations, only a
subset—half at best—respond to approved targeted therapies. Similarly, only a subset of patients with MSI-H
prostate cancers will responds to pembrolizumab. In this project, we will leverage an institutional-scale
prospective tumor and germline sequencing initiative to expand our understanding of the impact of genomic
alterations on clinical outcomes and response to targeted and immune-based therapies in men with prostate
cancer. Our overarching aims are to identify genomic alterations associated with progression to the lethal
metastatic phenotype and to refine molecularly targeted approaches to the treatment of locally advanced and
metastatic prostate cancer. We will accomplish these translational objectives through three broad approaches:
1) We will develop the largest clinical genomic data set of men with high-risk, localized prostate cancer and
test the association of genomic alterations with clinical outcomes in this disease state. With a recurrence rate
of at least 40%, high-risk, clinically localized prostate cancer represents an area of significant unmet need for
novel treatment approaches, including the introduction of targeted therapies and molecularly guided treatment
intensification to reduce the risk of recurrence. 2) We will identify molecular features of tumors with DDR
alterations that are more predictive of sensitivity or resistance to PARP inhibitors than DDR mutational status
alone. More specifically, we will use targeted and whole-genome sequencing analyses to explore the
associations between mutational zygosity, clonality, and the presence of structural variant signatures and
response to PARP inhibitor therapy. 3) We will determine the timing at which actionable DNA repair alterations
arise during prostate cancer disease progression and the impact of preexisting, intrapatient heterogeneity on
response to approved targeted and immunotherapies using sequential tumor and plasma sequencing. In sum,
on the basis of our institutional expertise in clinical molecular profiling, our ability to generate a prospective
data set of thousands of patients with prostate cancer treated with standard and investigational therapies, and
our experience in advancing the clinical development of targeted therapies in prostate cancer and other
malignancies, including leadership of the study that resulted in the ...

## Key facts

- **NIH application ID:** 10915671
- **Project number:** 5P50CA092629-23
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** David B. Solit
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $177,336
- **Award type:** 5
- **Project period:** 2001-09-14 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10915671

## Citation

> US National Institutes of Health, RePORTER application 10915671, Project 1: Genomic Predictors of Clinical Outcomes and Response to Targeted Therapy in Advanced Prostate Cancer (5P50CA092629-23). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10915671. Licensed CC0.

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