Younger Men Face Higher Mortality Risk in Advanced Prostate Cancer: An Analysis of IRONMAN Registry Data

Younger age is generally associated with better health and longer life expectancy. However, new findings from the international IRONMAN registry suggest a different pattern in advanced prostate cancer: men diagnosed at age 55 or younger may have worse survival outcomes than those diagnosed at middle or older ages.

The analysis included 4,332 patients from 15 countries enrolled in the IRONMAN registry. Approximately 73% had metastatic hormone-sensitive prostate cancer (mHSPC), while the remaining patients had castration-resistant prostate cancer (CRPC). The median age was 70 years, and 1,336 deaths were recorded over 5.5 years.

Researchers observed a J-shaped relationship between age and mortality. Among patients with mHSPC, mortality rates were higher at both ends of the age spectrum: in men aged 55 or younger and in those aged 80 or older. A similar pattern emerged in CRPC, although mortality rates were approximately two to three times higher.

Importantly, the association persisted after adjusting for several potential explanations, including metastatic disease at initial diagnosis, PSA levels, first-line treatments, cardiovascular risk factors, smoking, and self-reported frailty. Both overall survival and prostate cancer-specific survival were worse in the youngest and oldest age groups.

The researchers also explored whether biological aging might help explain these differences. In a small exploratory analysis involving 20 patients with mHSPC, they examined DNA methylation patterns to estimate biological age and investigated clonal hematopoiesis, a condition involving the expansion of blood cell populations carrying acquired mutations.

Patients showing accelerated epigenetic aging had a mortality rate of 144 deaths per 1,000 person-years, compared with 55 among those without accelerated aging. Similarly, patients with high-risk clonal hematopoiesis had a mortality rate of 199 per 1,000 person-years, compared with 82 in those without it.

These preliminary observations suggest that biological aging markers could potentially provide prognostic information beyond chronological age. However, the biomarker analysis involved only 20 patients, including just three with high-risk clonal hematopoiesis, making the findings highly exploratory.

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