The Evaluation of Novel Therapeutics for Genitourinary Malignancies

Division Of Clinical Sciences - Nci

Investigators

Linked publications & trials

Abstract

1. Completed the first study to integrate targeted mpMRI biopsies spatially linked to prostatectomy specimens in men treated with intensive neoadjuvant hormonal therapy prior to surgery and provided the first evidence that a defined set of 4 genomic/histology features may help predict both outcome and genomic diversity. Prior studies of neoadjuvant therapy in prostate cancer have not used targeted biopsies or sequential mpMRI to evaluate changes in unique lesions. Utilizing the ability of the MIP to perform serial mpMRIs, the impact of therapy on targeted individual prostate tumors was evaluated for the first time both from an imaging perspective as well as genomically. Tumor response both per lesion and per patient could be reliably measured and was integrated with pathology. In addition, in my study the presence of 10q loss, intraductal carcinoma (IDC), nuclear ERG, and TP53 mutations distinguished exceptional responders (ERs) from the rest of the cohort and predicted tumor genomic diversity. 2. Demonstrated that the combination of durvalumab plus olaparib has greater than expected activity in prostate cancer patients with DNA damage response (DDR) abnormalities. My previously published data demonstrated that the combination of durvalumab plus olaparib had activity in an unselected population of men with mCRPC. Importantly, while on trial all patients had biopsies of metastatic lesions for genomic profiling. Further accrual demonstrated that much of the activity was driven by the BRCA2 and NBN populations, with 12 of the 13 patients in this cohort having a significant decline in prostate-specific antigen (PSA). In addition, both the median progression-free survival (PFS) (16.5 months) and overall survival (OS; not reached) appear to be very promising. Conversations are ongoing with the FDA and our industry partners on next steps. 3. Accrued 178 patients in my study (2019-2022) which prospectively uses mpMRI to screen a high-risk population of men with known germline genetic variants. As Principal Investigator (PI) I enrolled patients from 30-75 years of age with a germline variant (i.e., pathogenic/likely pathogenic) in prostate cancer risk-related genes as documented by a laboratory certified by the Clinical Laboratory Improvement Amendments: BRCA1 and BRCA2, MMR genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) associated with Lynch syndrome, as well as HOXB13, ATM, NBN, TP53, CHEK2, PALB2, RAD51D, BRIP1, or FANCA without a prior prostate cancer diagnosis. Sixteen patients had findings which led to a targeted biopsy, and 5 of those were found to have cancer (PSA range 0.69-2.49 ng/mL). This is the first study to prospectively screen men in this population using PSA as well as modern imaging. It would be difficult to conduct such a study outside of the NIH. 4. Completed a series of trials that are helping to define the role of molecular imaging in prostate cancer. One of the strengths of the NCI intramural program is the ability to study patients using molecular imaging. Since the last review, a series of studies have been completed which are defining the field for ferumoxytol, [18F] sodium fluoride PET/CT, and, more recently, PSMA-based PET/CTs. The work comparing [18F] sodium fluoride and PSMA PET/CT showing discordance in the same lesion, quantifying the ability of 18F-DCFPyL PET/CT to detect disease in biochemically recurrent prostate cancer and comparing 18F-DCFPyL PET/CT with mpMRI could not be done easily at other institutions and will have a very meaningful impact on the field.