(UroToday.com) The 2025 ASCO annual meeting featured a prostate cancer session and a presentation by Dr. Maha Hussain discussing the clinical, environmental, genetic, and genomic profile of patients with rapid progression to metastatic castration resistant prostate cancer (mCRPC). Patients 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.
This multisite pilot study evaluated patients with mHSPC who progressed within 14 months of initiation of ADT ± docetaxel or androgen receptor targeted therapy. Data were collected to define clinical, environmental, and genetic profiles, including exome and transcriptome sequencing.
There were 22 men with progressive mCRPC enrolled, the median age at enrollment was 66 years (range 52-80), the median PSA at original diagnosis was 82 ng/mL (range 5-3,648), 55% had a Gleason score 9-10 disease, and 73% had de novo high volume mHSPC. The most frequent metastatic sites were bone (86%) and lymph nodes (59%).
Overall, 41% received local therapy, and the most common systemic therapy was ADT + docetaxel (50%). The clinical data, including biochemical exposures, were similar to prior studies evaluating patients of all ages: 9% of patients 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), and 27% had a family history of prostate cancer. The median progression free survival from study enrollment was 15.8 months.
Genetic data were available for 19 patients. Clinically significant germline mutations were found in 10.5% (n = 2) (ATM (n = 1), BRCA2 (n = 1). The most common clinically significant somatic mutations were TP53 (42%), NY-ESO-1 (21%), PTEN, ERBB2, and AR (each 16%). Among patients with TP53 mutations, co-occurring mutations in PTEN were identified in 57%, making this the most common co-mutation. Clinically significant somatic mutations were identified in 51 genes, with the most common somatic mutations regardless of clinical significance being TP53 (42%), PTEN and TTN (26% each), and ERBB3 and NY-ESO-1 (21% each).
Dr. Hussain concluded her presentation discussing the clinical, environmental, genetic, and genomic profile of patients with rapid progression to mCRPC with the following take home points:
- This cohort study focused on the clinical and genetic factors associated with early progression to mCRPC despite intensive therapy for mHSPC
- Enrolled patients had evidence of aggressive disease at the time of diagnosis (ex. de novo mHSPC, high Gleason score, and PSA), howeve,r there were no clear indicators of increased risk based on personal exposures or family history
- Rates of clinically significant 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 patient population, thus, further work is needed to identify underlying critical risk factors
Presented by: Maha Hussain, MD, Northwestern University, Chicago, IL
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting, Chicago, IL, Fri, May 30 – Tues, Jun 3, 2025.
Related content: Genomic and Clinical Profiles of Rapidly Progressing mCRPC Patients - Maha Hussain