Clinical, environmental, genetic, and genomic profile of patients with rapid progression to metastatic castration resistant prostate cancer (mCRPC).

e17053 Background: Patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC) that develop rapid progression to castration resistance following initiation of systemic therapy frequently have inferior outcomes. However, the clinical, environmental, and genetic drivers of disease in this population have not been well characterized. Methods: This multisite pilot study evaluated pts with mHSPC who progressed within 14 months of initiation of androgen deprivation therapy (ADT) ± docetaxel or androgen receptor targeted therapy. Data were collected to define clinical, environmental, and genetic profiles, including exome and transcriptome sequencing xE. Standard descriptive statistics were used. Results: 22 men with progressive metastatic castration resistant prostate cancer (mCRPC) were enrolled, median age at enrollment was 66 (range 52-80 years), median PSA at original diagnosis was 82 (range 5-3,648 ng/mL), 55% had a Gleason score 9-10, and 73% had de novo high volume mHSPC. The most frequent metastatic sites were bone (86%) and lymph nodes (59%). 41% received local therapy, the most common systemic therapy was ADT + docetaxel (50%). The Clinical data including biochemical exposures were similar to prior studies evaluating pts of all ages. 9% of pts served in the U.S. Armed Forces and all denied Agent Orange exposure, 86% reported a family history of cancer (ex. breast and colon cancer), 27% had family history of PCa. Median PFS from study enrollment was 15.8 months. Genetic data is available for 19 pts. Clinically significant (CS) germline mutations were found in 10.5% (N=2) (ATM (N=1), BRCA2 (N=1). The most common CS somatic mutations were TP53 (42%), NY-ESO-1 (21%), PTEN, ERBB2 and AR (each 16%). Among pts with TP53 mutations, co-occurring mutations in PTEN were identified in 57%, making this the most common co-mutation. CS somatic mutations were identified in 51 genes. The most common somatic mutations regardless of CS were TP53 (42%), PTEN and TTN (26% each) and ERBB3 and NY-ESO-1 (21% each). Conclusions: This cohort study focused on the clinical and genetic factors associated with early progression to mCRPC despite intensive therapy for mHSPC. Enrolled pts had evidence of aggressive disease at the time of diagnosis (ex. de novo mHSPC, high Gleason score and PSA), however there were no clear indicators of increased risk based on personal exposures or family history. Rates of CS germline and somatic mutations were similar to published data, although full interpretation of these findings is limited by the small patient numbers enrolled in the trial. No clear signal was identified in this analysis of the clinical, environmental and genetic contributors of disease in this pt population, thus further work is needed to identify underlying critical risk factors.