Prostate Cancer Advances: Opaganib Trial, Age-Mortality Link, and AI Detection Tools

New research is reshaping prostate cancer care through advances in detection, combination treatment for advanced disease, and refined prognostic insight. A Phase 2 trial tested the experimental drug opaganib alongside standard therapies in men with metastatic castration-resistant prostate cancer, while a SEER database study of over 11,000 patients showed that older age independently increases cancer-specific mortality in bone-only metastatic prostate cancer. Additional studies assessed artificial intelligence for pathology workflows and polygenic risk scores for MRI triage.

The multi-institutional Phase 2 trial, led by researchers at the Medical University of South Carolina (MUSC) and Emory University and published in Cancer Medicine, focused on 66 patients whose cancer had already progressed on standard hormone therapies. Patients received opaganib in combination with either abiraterone or enzalutamide. About 15% of patients taking opaganib with abiraterone and 9% taking it with enzalutamide experienced disease control at 16 weeks, which was short of the study's primary goal. However, a subset of patients showed clear biological signs of response, including drops in prostate-specific antigen (PSA) levels and periods of disease stabilization. The combination treatment was generally manageable, with most side effects mild to moderate; some patients experienced more serious side effects, but most improved when the drug dose was reduced or stopped. Opaganib, a first-in-class therapy, blocks a pathway involved in sphingolipid metabolism rather than targeting hormones. The researchers now plan to look for biomarkers in blood samples that could predict response.

In a retrospective, population-based cohort study using SEER data from 2010 to 2022, researchers evaluated 11,098 men diagnosed with bone-only metastatic prostate cancer, 48.2% of whom were aged 70 years or older. Five-year cancer-specific mortality increased stepwise with advancing age, from 50.2% in patients younger than 50 years to 64.8% in those aged 80 years or older (p < 0.001). At multivariate analysis, older age remained independently associated with higher cancer-specific mortality (≥80 years: subdistribution hazard ratio 1.78, 95% CI 1.45–2.19). Non-Hispanic Black race/ethnicity, single marital status, elevated PSA, and a higher International Society of Urological Pathology (ISUP) grade emerged as adverse predictors. Radical prostatectomy was associated with lower cancer-specific mortality, while radiotherapy and chemotherapy were associated with higher cancer-specific mortality in the overall cohort. The authors concluded that tumor burden, pathological grade, and treatment allocation jointly affect age-related survival disparities.

Two artificial intelligence studies reported practical diagnostic improvements. In a retrospective study spanning three European centres, a task-specific AI model tested on standard H&E slides that had previously required basal cell immunohistochemistry (IHC) for clarification achieved area under the curve values up to 0.993, and when sensitivity-prioritised thresholds were applied, no false negatives occurred. Overall IHC use dropped by 20 to 44%, with reductions reaching as high as 81% among benign cases. A separate study presented the first comprehensively validated AI system for automated cribriform morphology detection in prostate cancer. The model achieved an area under the curve of 0.97 internally and 0.90 externally, and in head-to-head comparison against nine expert uropathologists, the algorithm showed the highest mean pairwise agreement. Cribriform morphology defines a lethal prostate cancer phenotype that excludes patients from active surveillance.

A prospective study followed 386 men of Western European descent to assess whether polygenic risk scores could refine triage before MRI. The prostate cancer polygenic risk score showed a significant association with positive MRI findings, with an odds ratio of 1.56, while PSA alone did not. When age was combined with the polygenic risk score, the proportion of men showing suspicious findings rose from 46% to 60% compared with PSA-based selection alone.

The prospective IMPACT study followed 3063 men aged 40 to 69 through five annual screening rounds. Among BRCA2 carriers, the incidence of clinically significant prostate cancer was notably higher than in noncarriers, at 3.1% versus 1.3%. Notably, BRCA1 carriers showed a much greater proportion of intermediate unfavourable or high-risk tumours, 56% compared with 18%, despite similar overall incidence rates. Grade upgrading at radical prostatectomy occurred only in carriers. These results suggest BRCA1 carriers should also be considered for systematic screening. Another study found that pathogenic genomic alterations in circulating tumor DNA predict overall survival in men with metastatic castrate-resistant prostate cancer.