Active Smoking Linked to Shorter Survival and Distinct Tumor Alterations in Advanced Prostate Cancer

Smoking has been associated with increased metastatic prostate cancer mortality, but the biological mechanisms driving this association are largely unknown. To investigate, a retrospective study published in the journal Prostate cancer and prostatic diseases in September 2026 analyzed patient characteristics, tumor genetics, and clinical outcomes.

The study utilized the Prostate Cancer Precision Medicine Multi-institutional Collaborative Effort (PROMISE) clinical genomic database for this retrospective analysis. The research team hypothesized that smoking increases the risk of genetic alterations associated with aggressive disease, the transformation to neuroendocrine prostate cancer (NEPC), or both.

To test this hypothesis, the researchers associated patient characteristics and tumor genetic data with smoking exposure at diagnosis—including current, former, never, and pack years—and with clinical outcomes. These clinical outcomes included overall survival (OS) from diagnosis, time to developing metastatic disease, and NEPC status.

The analysis identified 2,353 men with prostate cancer who had next-generation somatic tumor sequencing data evaluable for analysis in the PROMISE clinical genomic database. Within this study population, 8% were current smokers, 39% were former smokers, and 52% were never smokers.

Clinical Differences at Diagnosis

The clinical presentations across the patient groups demonstrated several clear differences at the time of diagnosis. Current smokers were more likely to be younger and more likely to present with metastatic (M1 or N1) disease at diagnosis. Additionally, current smokers were less likely to have received prior local therapy. Each of these findings was statistically significant, with a p-value of less than 0.001.

Survival Outcomes

The study identified a significant association between active smoking at diagnosis and shorter overall survival. Current smokers had an overall survival of 99.9 months, compared to 137.6 months in the comparison group. This association was represented by a hazard ratio (HR) of 1.42 (95% confidence interval [CI] 1.14–1.77). This association remained significant after the researchers adjusted for disease characteristics.

Overall, active smoking was associated with worse overall and prostate cancer-specific survival as compared to never or former smoking.

Genomic Alterations and Tumor Transformation

The study also explored the relationship between smoking status and specific genetic alterations. In patients with metastatic androgen pathway modulator sensitive prostate cancer (APMS), researchers found positive associations between smoking status and alterations in several genes, including SPOP, FGFR1, and ARID1A.

SPOP genetic alterations were identified in 15% of current smokers, 6.7% of former smokers, and 3.8% of never smokers (p = 0.018).

FGFR1 genetic alterations were identified in 10% of current smokers, 0.4% of former smokers, and 1.1% of never smokers (p = 0.001).

ARID1A genetic alterations were identified in 5.1% of current smokers, 2.2% of former smokers, and 0.4% of never smokers (p = 0.035).

However, the study found no difference in the percentage of NEPC at initial diagnosis or at any point between current, former, and never smokers (p = 0.8). Ultimately, while active smoking was associated with specific tumor genetic alterations, it was not associated with small cell or NEPC transformation.