Though most deaths from prostate cancer occur in older men, screening guidelines recommend against screening prostate-specific antigen (PSA) for this group. We aimed to determine if total or free PSA level in men age 65-80 years predicts long-term risk of fatal prostate cancer over 39 years of follow-up We leveraged a nested case-control study within the Physicians’ Health Study, a randomized primary prevention trial among US male physicians initiated in 1982. Among men with a blood sample at enrollment, there were 37 fatal prostate cancer cases that occurred during follow-up, age-matched to 148 controls (within 2 years). Total and free PSA levels were measured in pre-diagnostic blood samples. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals (CI) for the association between baseline total PSA and fatal prostate cancer. We estimated Area Under the Curve (AUC) to evaluate predictive ability of total and free PSA. We also estimated the cumulative incidence of fatal prostate cancer by baseline PSA category. Median (interquartile range) PSA at blood draw was 1.7 ng/mL (0.9-3.2) among controls, and median follow-up from blood draw to end of study was 19 years. The cumulative risk of fatal prostate cancer at 30 years was 0.9% for PSA <1.5 ng/mL, 7.9% for PSA ≥1.5 ng/mL, 8.9% for PSA ≥3 ng/mL, and 14.8% for PSA ≥5 ng/mL. Relative to those with total PSA <1.5 ng/mL, the odds ratios for fatal prostate cancer were 9.7 (95% CI 2.8, 33.0) for those with total PSA ≥1.5 ng/mL, 12.1 (95% CI 3.3, 44.2) for PSA ≥3 ng/mL, and 26.0 (95% CI 6.4, 105.1) for PSA ≥5 ng/mL. Adding the free/total PSA ratio to total PSA in men with total PSA ≥2 ng/mL improved prediction for fatal prostate cancer, with the AUC rising from 0.71 (95% CI 0.59, 0.83) to 0.82 (95% CI 0.73, 0.91). Restricting to those who survived at least 10 years after blood draw, the cumulative risk of fatal prostate cancer at 30 years remained higher for those with elevated baseline PSA: 1.1% for PSA <1.5 ng/mL, 7.1% for PSA ≥1.5 ng/mL, 7.0% for PSA ≥3 ng/mL, and 12.0% for PSA ≥5 ng/mL. A baseline PSA in older men age 65 to 80 predicts long-term risk of fatal prostate cancer across decades-long follow-up. The ratio of free to total PSA improved prediction in men with PSA ≥2 ng/mL and should be considered for reflex testing. These findings suggest healthy older men with PSA ≥3 ng/mL and an estimated life expectancy of at least 10 more years remain at increased risk for fatal prostate cancer and should consider shared decision-making about ongoing PSA monitoring. Hannah E. Guard, Kendrik Yim, Kathryn M. Wilson, Sigrid V. Carlsson, Lorelei A. Mucci, Travis Gerke, Mark A. Preston. Baseline prostate-specific antigen levels in men aged 65 to 80 and fatal prostate cancer: Implications for risk-stratified screening among older men [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr PR031.

The time dependence in the performance of prognostic factors for cancer survival is typically incompletely understood, including in prostate cancer. We applied a "cumulative/dynamic" time-varying area under the curve (tAUC) for cumulative incidence of lethal prostate cancer (metastases/cancer-specific death). In two prospective prostate cancer patient cohorts followed for lethal outcomes after radical prostatectomy, genitourinary pathologists undertook a histopathologic review of tumor specimens to assign Gleason grade groups 1-5, a known strong short-term prognostic factor. Among 1490 patients, 144 lethal events occurred during 35 years of follow-up (median, 18). The 10-year risk of lethal disease was 2% (95% CI, 1-3) for grade group 2 and 21% (95% CI, 16-28) for grade group 5 cancers. By 25 years, risks were 5% (95% CI, 3-8) and 32% (95% CI, 26-41), respectively. Prediction accuracy was strongest over the first 10 years (tAUC 0.83 [95% CI, 0.79-0.86]) but remained informative for 25 years (tAUC 0.76 [95% CI, 0.70-0.81]), including among long-term metastasis-free survivors. Risk-based AUCs instead of hazard-based "incident/dynamic" AUCs allowed for interpretable characterization of prognostic accuracy over well-defined time periods. Lethal progression of high-grade prostate cancer occurred predominantly early, while that of lower grade tumors accumulated over decades after surgery.

Most people who die from prostate cancer are older than 75 years. However, prostate cancer diagnosed at younger ages is often more aggressive. While epidemiologic studies have examined the association between age and survival in patients with prostate cancer overall, the clinical drivers of this relationship in patients with advanced disease remain unclear. We leveraged the International Registry of Men with Advanced Prostate Cancer (IRONMAN, NCT03151629) to (1) quantify the association between age and overall survival and (2) explore whether this association is explained by treatments. We included 3, 734 patients enrolled from 15 countries with new diagnoses of metastatic hormone sensitive (mHSPC, N=2, 642) or castration resistant prostate cancer (CRPC, N=1, 092). Age at enrollment was categorized as <55, 55-59, 60-64 (reference), 65-69, 70-74, 75-79, 80-84, 85+ years. We computed age-specific death rates (95% confidence intervals [CIs]) by disease state (mHSPC, CRPC) at enrollment. To explore whether this relationship was explained by treatment, we fitted disease state-stratified Cox models and sequentially adjusted for (1) de novo metastatic status and country, and (2) baseline treatment (androgen deprivation therapy [ADT] alone, ADT + androgen receptor pathway inhibitors [ARPI], ADT + chemotherapy, ADT + ARPI + chemotherapy, other). Over 5.5 years of follow-up (median: 3.2 years, IQR: 1.7, 4.8), 995 patients died from any cause. Younger patients were more likely to have de novo metastatic disease. Among those with mHSPC at enrollment, the age-specific death rates per 1, 000 person-years followed a J-shaped pattern: 80 (95% CI: 54, 117) in patients under 55 years, 58 (46, 74) in patients aged 60-64, 102 (78, 133) in patients aged 80-84, and 172 (125, 236) in patients aged 85 and older. The death rates among those with CRPC followed a similar pattern, albeit rates were higher in magnitude: 212 (95% CI: 140, 323) in patients under 55 years, 153 (115, 202) in patients aged 60-64, 200 (155, 258) in patients aged 80-84, and 204 (142, 291) in patients aged 85 and older. After adjusting for disease state, country, and the timing of diagnosis of metastases, death rates were substantially higher for ages 75-79 (HR 1.4; 95% CI 1.1, 1.7), 80-84 years (HR 1.6; 95% CI 1.2, 2.1), and 85 years and older (HR 2.0; 95% CI: 1.5, 2.7) compared to ages 60-64 years. Patients aged under 55 years had 1.4-fold higher death rates (95% CI: 1.0, 1.9) compared to those 60-64 years. After additionally adjusting for baseline treatment, overall survival remained worse for the older patients and the youngest age group with hazard ratios remaining meaningfully unchanged. Age at enrollment is associated with overall survival in people with advanced prostate cancer enrolled in IRONMAN in a J-shaped pattern. This relationship is not explained by differences in baseline treatment. Hannah E. Guard, Michelle O. Sodipo, Colleen B. McGrath, Anna Siefkas, Lauren E. Howard, Konrad H. Stopsack, Christopher M. Sauer, Robert Dreicer, Emilio Esteban, Hassan M. Dogo, Ademola Popoola, Charles Waihenya, Anders Bjartell, Kim N. Chi, Sebastien Hotte, Richard Cathomas, Deborah Enting, Scott Tagawa, Michael Ong, Michael Kolinsky, Vincent Khoo, Joaquin Mateo, Chidiebere N. Ogo, Rana R. McKay, Stefanie Fischer, Heather H. Cheng, Russell Szmulewitz, Young E. Whang, Anand Sharma, Frédéric Pouliot, Simon Crabb, Monica S. Chatwal, Miguel A. Climent, Raymond McDermott, Ian D. Davis, Camille Ragin, Folakemi T. Odedina, Simon Anderson, Simone Badal, Natalie Greaves, Karen A. Autio, Laurel Cannon, Alyssa Chan-Cuzydlo, Marie Grant, Travis Gerke, Hannah D. McManus, Philip W. Kantoff, Daniel J. George, Lorelei A. Mucci, IRONMAN investigator team. Disentangling the association between age and overall survival in an international cohort of patients with advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4935.

The standard of care for metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with the expanded approval of androgen receptor pathway inhibitors (ARPIs) alongside androgen deprivation therapy (ADT). ADT alone has been shown to affect cognitive function. However, the cognitive impact of distinct treatment combinations remains unclear. We investigated the association between first-line systemic treatments and the trajectory of subjective cognitive function among mHSPC survivors in the International Registry for Men with Advanced Prostate Cancer (IRONMAN). This analysis included 2435 newly diagnosed mHSPC patients enrolled across 15 countries between July 2017 and August 2024. Treatments were reported by site personnel and physicians. For this analysis, we focused on first-line systemic treatment and classified treatment groups at enrollment as ADT monotherapy (referent), ADT + ARPIs, or ADT + chemotherapy. Subjective cognitive function was assessed via the EORTC QLQ-C30 Cognitive Function subscale, with patient-reported scores (range 0-100) collected at enrollment and every 3 months for up to 5 years; higher scores reflect better cognitive function. Associations were estimated using linear mixed effects models with clustering by study site and country to examine differences at enrollment and across trajectories of subjective cognitive function by first-line treatment, adjusting for demographic and clinical factors. Median age at enrollment was 70 years, with a median follow-up of 1.7 years. 724 (30%) participants were treated with ADT monotherapy, 1317 (54%) with ADT + ARPIs, and 394 (16%) with ADT + chemotherapy. Mean cognitive function scores at enrollment were 85.4 (Standard Deviation [SD] 19.5) for participants treated with ADT monotherapy, 86.7 (SD 17.3) for ADT + ARPIs, and 86.7 (SD 18.0) for ADT + chemotherapy. Cognitive function scores decreased by -0.60 points (95% Confidence Interval [CI] -0.72, -0.48) per year among those treated with ADT monotherapy, with similar rates observed for those treated with ADT + chemotherapy. Participants treated with ADT + ARPIs had a slower decline in cognitive function, with scores decreasing by -0.36 points (95% CI -0.60, -0.08) per year. In this international cohort of mHSPC survivors, subjective cognitive function scores were generally high at enrollment but declined over time. There was no evidence of worse cognitive function in those treated with ADT + ARPIs nor ADT + chemotherapy over time compared to ADT monotherapy. Cognitive functioning is a key component of survivorship, and defining cognitive trajectories associated with first-line treatment can inform supportive interventions, patient treatment decision-making, and clinical guidelines. Michelle O. Sodipo, Alicia K. Morgans, Erica T. Warner, Emily M. Rencsok, Lauren E. Howard, Colleen B. McGrath, Anna Siefkas, Konrad H. Stopsack, Christopher Sauer, Robert Drecier, Emilio Esteban, Hassan M. Dogo, Ademola Popoola, Charles Waihenya, Anders Bjartell, Kim Chi, Sebastien Hotte, Richard Cathomas, Deborah Enting, Scott Tagawa, Michael Ong, David Lorente, Elisabeth Heath, Rana McKay, Stefanie Fischer, Heather H. Cheng, Young E. Whang, Frederic Pouliot, Simon Crabb, Monica Chatwal, Miguel A. Climent, Raymond McDermott, Ian D. Davis, Camille Ragin, Folakemi Odedina, Natalie Greaves, Simone Badal, Simon Anderson, Sharon Harrison, Karen Autio, Laurel Cannon, Marie Grant, Alyssa Chan-Cuzydlo, Travis Gerke, Hannah D. McManus, Philip W. Kantoff, Daniel George, Sebastien Haneuse, Lorelei A. Mucci, on behalf of the IRONMAN Registry. First-line therapies and subjective cognitive function trajectories among international metastatic hormone-sensitive prostate cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3630.

Supplemental Figure 2. Outcomes for primary and exploratory arms.

Abstract Bone pain is a well-known quality-of-life detriment for individuals with prostate cancer and is associated with survival. This study expands previous work into racial differences in multiple patient-reported dimensions of pain and the association between baseline and longitudinal pain and mortality. This is a prospective cohort study of individuals with newly diagnosed advanced prostate cancer enrolled in the International Registry for Men with Advanced Prostate Cancer (IRONMAN) from 2017 to 2023 at U.S. sites. Differences in four pain scores at study enrollment by race were investigated. Cox proportional hazards models and joint longitudinal survival models were fit for each of the scale scores to estimate HRs and 95% confidence intervals (CI) for the association with all-cause mortality. The cohort included 879 individuals (20% self-identifying as Black) enrolled at 38 U.S. sites. Black participants had worse pain at baseline compared with White participants, most notably a higher average pain rating (mean 3.1 vs. 2.2 on a 10-point scale). For each pain scale, higher pain was associated with higher mortality after adjusting for measures of disease burden, particularly for severe bone pain compared with no pain (HR, 2.47; 95% CI: 1.44–4.22). The association between pain and all-cause mortality was stronger for participants with castration-resistant prostate cancer compared with those with metastatic hormone-sensitive prostate cancer and was similar among Black and White participants. Overall, Black participants reported worse pain than White participants, and more severe pain was associated with higher mortality independent of clinical covariates for all pain scales. Significance: Black participants with advanced prostate cancer reported worse pain than White participants, and more pain was associated with worse survival. More holistic clinical assessments of pain in this population are needed to determine the factors upon which to intervene to improve quality of life and survivorship, particularly for Black individuals.

Selection of study participants exclusion flowchart

Supplemental Table 4. Patient Demographics.

Kaplan–Meier curves for overall survival by pain categories at study enrollment, IRONMAN Registry 2017–2023. A, Kaplan–Meier curve for the EORTC pain scale. B, Kaplan–Meier curve for the average pain scale. C, Kaplan–Meier curve for the worst pain scale. D, Kaplan–Meier curve for the bone pain scale.

Supplemental Table 2. SAEs per arm.

Kaplan-Meier survival curve by disease state at study enrollment

Baseline worst pain scale Cox model results from sensitivity analysis for missing indicator values during MICE procedure

Further information guiding the choice of methods and a glossary of technical terms

Supplemental Figure 1. PFS for primary arms.

Supplemental Table 1. Treatment Modifications.

Longitudinal observation status of questionnaires and reasons for being off-study throughout follow-up

Kaplan-Meier survival curve by self-reported race

Correlation coefficients between baseline pain scale scores

Cohort demographic and clinical characteristics by self-reported race (N = 879), 2017–2023