N., Kim

PURPOSE The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

TPS5118 Background: The median overall survival of patients with mCRPC remains under 2 years even with newer therapies. Xaluritamig, an XmAb 2+1 T-cell engager that targets the six-transmembrane epithelial antigen of prostate 1 (STEAP1), facilitates lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. In a first-in-human study, xaluritamig demonstrated encouraging efficacy and a manageable safety profile for patients with mCRPC refractory to standard of care therapies (Kelly WK, et al. Cancer Discov. 2024;14(1):76-89). Methods: XALute is a randomized, multicenter, open-label, phase 3 study to evaluate the efficacy and safety of xaluritamig vs cabazitaxel or second ARDT in men with mCRPC previously treated with taxane chemotherapy. Enrollment in the control arm treatments will be split evenly between cabazitaxel and second ARDT. Stratification factors include LDH ≤ or > 260 IU/L, liver metastases (Y/N), prior prostate-specific membrane antigen radioligand therapy (PSMA-RLT) (Y/N) and the intention to treat with cabazitaxel or ARDT switch. Approximately 675 patients will be enrolled. Participants will be randomly assigned in a 2:1 ratio to xaluritamig monotherapy or standard care. Participants will receive treatment until radiographic disease progression per Prostate Cancer Clinical Trials Working Group 3 (PCWG3), unacceptable toxicity, initiation of other anticancer therapy, withdrawal of consent, death, or end of study as determined by the sponsor. The primary efficacy endpoint is overall survival. The key secondary efficacy endpoint is radiographic progression-free survival per PCWG3 by blinded independent central review. Key inclusion criteria are pathological/cytological confirmation of prostate adenocarcinoma; mCRPC with at least one metastatic lesion; evidence of progressive disease; prior treatment with at least one ARDT; one taxane therapy in the mCRPC setting, and ongoing androgen deprivation with serum testosterone levels (<50 ng/dL or <1.7 nmol/L). Prior treatment with PSMA-RLT, poly ADP-ribosylation inhibitors, and immune checkpoint inhibitors are permitted. Exclusion criteria include prior STEAP1-targeted therapy, any anticancer therapy within 4 weeks prior to first dose of study treatment (not including androgen deprivation therapy), prior PSMA-RLT within 2 months of first dose of study treatment unless less than 2 cycles received, and prior radionuclide therapy (radium-223) within 2 months of first dose of study treatment To mitigate risk of cytokine release syndrome, xaluritamig will be administered with step dosing. Cabazitaxel or second ARDT will be administered according to regional prescribing information. Funded by Amgen Inc. Clinical trial information: NCT06691984 .

Abstract Introduction: 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. Methods: 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 &lt;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). Results: 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. Conclusion: 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. Citation Format: 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.

Abstract Introduction: 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). Methods: 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. Results: 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. Conclusion: 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. Citation Format: 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.

16 Background: In PSMAfore (NCT04689828), [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) prolonged rPFS versus androgen receptor pathway inhibitor (ARPI) change in taxane-naive adults with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) progressing once on an ARPI. Baseline circulating tumor DNA (ctDNA) fraction was associated with rPFS at the second interim analysis (IA) of OS (ASCO 24). Here, we assessed the association of baseline and cycle 2 day 1 (C2D1) ctDNA fraction, and early ctDNA and prostate-specific antigen (PSA) dynamics, with rPFS and OS at the third IA of OS. Methods: Patients were randomized 1:1 to 177 Lu-PSMA-617 (7.4 GBq Q6W; x6) or ARPI change. Endpoints included rPFS (primary) and OS (key secondary). Plasma ctDNA fraction was analyzed at baseline and at C2D1 using an in-house custom panel. Cox regression (adjusted for 3 risk classes based on clustering of 17 baseline clinical features) and random forest (adjusted for 15 baseline clinical features) modeling were used to assess the association of ctDNA fraction and PSA with clinical outcomes at the Feb-27-2024 data cutoff. Results: Patients with plasma samples at baseline and C2D1 were included ( 177 Lu-PSMA-617, n/N = 82/234; ARPI change, n/N = 91/234). Cox regression models adjusted for clinical features in the 177 Lu-PSMA-617 arm showed that higher ctDNA fraction was associated with shorter rPFS and OS (Table). These associations were stronger for C2D1 than baseline, both when comparing individual models and within a model including both timepoints (Table). In random forest models including clinical features and C2D1 ctDNA fraction, the total area under curves were not improved by addition of baseline ctDNA fraction (rPFS, 0.87; OS, 0.86). In the overall population, fractional decreases from baseline to C2D1 in ctDNA ( p = 0.0015) and PSA ( p < 0.0001) were strongly associated with longer rPFS, and were weakly correlated with one another (correlation coefficient, 0.26). In the 177 Lu-PSMA-617 arm, fractional decrease in ctDNA ( p = 0.002) was more strongly correlated with OS than was decrease in PSA ( p = 0.12). Conclusions: This exploratory analysis suggested that C2D1 ctDNA fraction was more strongly associated than baseline ctDNA fraction with rPFS and OS. Early ctDNA fraction dynamics contributed additional information in the prediction of rPFS and OS beyond PSA dynamics alone. Clinical trial information: NCT04689828 . Cox regression models. a rPFS OS Baseline model, HR (95% CI); p 6.0 (1.6–23.0); 0.0095 12.0 (3.0–48.7); 0.00052 C-index ± SE 0.69 ± 0.04 0.75 ± 0.04 C2D1 model, HR (95% CI); p 47.7 (10.1–226.0); < 0.0001 82.7 (16.4–417.0); < 0.0001 C-index ± SE 0.72 ± 0.03 0.77 ± 0.03 Baseline + C2D1 model Baseline, HR (95% CI); p 3.1 (0.7–14.0); 0.14 2.1 (0.4–12.7); 0.41 C2D1, HR (95% CI); p 35.9 (7.2–180.0); < 0.0001 52.5 (7.6–362.0); < 0.0001 C-index ± SE 0.72 ± 0.03 0.79 ± 0.03 a HRs correspond to 1 unit change in ctDNA fraction.

121 Background: In the Phase 3 VISION trial, treatment with the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) + protocol-permitted standard of care (SoC) significantly improved median radiographic progression-free survival (rPFS; 8.7 vs 3.4 months [mo]) and overall survival (OS; 15.3 vs 11.3 mo) in patients with metastatic castration-resistant prostate cancer (mCRPC) vs SoC alone. However, it is unclear how the addition of androgen receptor pathway inhibitors (ARPIs) affected 177 Lu-PSMA-617 treatment outcomes. Here we compared the efficacy and safety of 177 Lu-PSMA-617 in patients treated with vs without concomitant ARPIs. Methods: In VISION, adult patients with PSMA-positive mCRPC previously treated with ≥1 prior ARPI and 1–2 taxane chemotherapy regimens were randomized 2:1 to receive 177 Lu-PSMA-617 (7.4 GBq Q6W, 4–6 cycles) + SoC (which included ARPIs) vs SoC alone. In this secondary analysis, we assessed baseline characteristics, OS, rPFS, prostate-specific antigen (PSA) response rate, duration of PSA response, PSA-PFS, and safety among patients in the intervention arm who were treated with vs without concomitant ARPIs. Results: In total, 289 patients were treated with concomitant ARPIs and 262 patients were not (N=551). Imbalances between the groups were observed in some baseline characteristics: patients treated with concomitant ARPIs were younger, had lower ECOG performance scores, lower mean PSA and lactate dehydrogenase levels, and fewer prior taxane chemotherapy regimens. Baseline mean standardized [ 68 Ga]Ga-PSMA-11 uptake values and mean hemoglobin levels were well-balanced. A statistically significant difference in median OS was observed in patients treated with concomitant ARPIs vs those without (17.8 vs 12.4 mo; HR, 0.72; 95% CI, 0.58–0.89; nominal P=0.001). No statistically significant between-group differences were observed for rPFS, PSA response rate, duration of PSA response or PSA-PFS. The proportion of adverse events reported was similar in patients with or without concurrent ARPI, except for the number of adverse events leading to interruption of best supportive care/SoC, which was higher in patients treated with concurrent ARPIs. Conclusions: OS was significantly different in patients treated with concomitant ARPIs vs those without, while other efficacy endpoints were not. No new safety signals were observed for 177 Lu-PSMA-617 with concomitant ARPI. These findings may be confounded by varied exposure to ARPIs, or differing patient characteristics; patients who received concomitant ARPIs may represent a more favorable treatment population than those who did not. These findings should be considered as hypothesis-generating, and a multivariate analysis has been planned to ascertain the influence of these potential biases. Clinical trial information: NCT03511664 .

AbstractBackground[177Lu]Lu–PSMA‐617 (177Lu‐PSMA‐617) plus protocol‐permitted standard of care (SOC) prolonged overall survival (OS) and radiographic progression‐free survival (rPFS) versus SOC in patients with prostate‐specific membrane antigen (PSMA)–positive metastatic castration‐resistant prostate cancer (mCRPC) in the phase 3 VISION study, in addition to beneficial effects on symptomatic skeletal events (SSEs) and health‐related quality of life (HRQOL).MethodsPost hoc analyses used the full analysis set from the VISION study (N = 831) overall and by randomized treatment arm (177Lu‐PSMA‐617 plus SOC, n = 551; SOC, n = 280). Correlations were determined between OS and rPFS and between rPFS or OS and time to SSE or to worsening HRQOL (Functional Assessment of Cancer Therapy–Prostate [FACT‐P] and 5‐level EQ‐5D [EQ‐5D‐5L]). Correlation analyses used an iterative multiple imputation copula‐based approach (correlation coefficients [rho] of <0.3 were defined as weak, ≥0.3 and <0.5 as mild, ≥0.5 and <0.7 as moderate, and ≥0.7 as strong).ResultsIn the overall population, rPFS correlated strongly with OS (rho, ≥0.7). Correlations between rPFS or OS and time to SSE without death were weak or mild. Time to worsening in the FACT‐P total score and emotional and physical well‐being domains correlated mildly or moderately with rPFS and moderately with OS. Correlation coefficients for time‐to‐worsening EQ‐5D‐5L scores were mild to moderate for both rPFS and OS. Correlation coefficients were similar between treatment arms.ConclusionsIn this analysis of the VISION study, rPFS correlated strongly with OS but not with time to SSE or worsening HRQOL. These findings require further investigation.

5008 Background: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) versus androgen receptor pathway inhibitor (ARPI) change in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC) in PSMAfore (NCT04689828). In this exploratory analysis, associations between baseline circulating tumor DNA (ctDNA) and outcomes were assessed. Methods: Patients were randomized 1:1 to 177Lu-PSMA-617 (7.4 GBq Q6W; 6 cycles) or ARPI change (abiraterone/enzalutamide). Patients known to have actionable mutations (e.g. BRCA) were excluded. The primary endpoint was rPFS. Baseline plasma ctDNA was analyzed using a customized 585-gene sequencing assay. ctDNA fraction was assessed in all samples passing quality control. Alterations in key prostate cancer drivers (prevalent in >10% participants) were assessed in samples with ctDNA fraction >1%. Univariate Cox regression (reference: ARPI change) was used to assess association of ctDNA fraction or alterations with rPFS, prostate-specific antigen response (≥50% decline; PSA50) and RECIST response (RR) at the June 21, 2023 data cutoff. Results: Of 360 samples from 468 patients, 255 passed quality control and 156 had ctDNA fraction >1% (median 5.85%; range 0–85). Detection of ctDNA alterations was comparable between arms and with published data. Median rPFS was shorter for patients with ctDNA fraction > versus ≤1% (HR 2.753; 95% CI 1.957–3.872; p<0.0001) (Table); ctDNA fraction >1% was also associated with worse RR and PSA50 response. Median rPFS was shorter for patients with detected versus undetected AR(HR 1.954; 95% CI 1.333–2.865; p<0.001), TP53(1.655; 1.13–2.426; p<0.01) and PTEN(1.62; 1.018–2.578; p<0.05) alterations. Median rPFS was longer with 177Lu-PSMA-617 versus ARPI change in patients with detected AR, TP53, PTEN(Table) , PI3K pathway and DNA repair pathway alterations. There was no significant association between ctDNA alterations and PSA50 or RR. Conclusions: ctDNA fraction >1% and AR, TP53and PTENalterations were associated with worse outcomes in PSMAfore regardless of treatment. Nonetheless, patients with these negative prognostic biomarkers did better with 177Lu-PSMA-617 than with ARPI change. Clinical trial information: NCT04689828 . [Table: see text]

5003 Background: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged radiographic progression-free survival vs change of androgen receptor pathway inhibitor (ARPI) in taxane-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) in PSMAfore (NCT04689828). We now present health-related quality of life (HRQoL) and pain outcomes at second interim analysis. Methods: Eligible patients had mCRPC, were candidates for change of ARPI after progression on one prior ARPI, and had ≥1 PSMA-positive and no exclusionary PSMA-negative metastatic lesions by [68Ga]Ga-PSMA-11 PET/CT. Ineligible patients were candidates for PARP inhibition or had received prior systemic radiotherapy, immunotherapy or chemotherapy. Patients were randomized 1:1 to open-label 177Lu-PSMA-617 (7.4 GBq/6 weeks; 6 cycles) or ARPI change (abiraterone/enzalutamide). Patients with confirmed radiographic progression on ARPI change could cross over to 177Lu-PSMA-617. Secondary endpoints included time to worsening (TTW) in self-reported HRQoL (FACT-P, EQ-5D-5L) and pain (BPI-SF), defined as a composite of score worsening (prespecified thresholds), clinical progression (including new anti-cancer treatment) or death. Post hoc analyses of TTW in FACT-P and BPI-SF excluded clinical progression and death. The study was not powered for these endpoints and type I error was not controlled. Results: We randomized 468 patients (234/arm) with a median age of 72 years (range, 43–94). Median duration of exposure was 8.4 months for 177Lu-PSMA-617 and 6.5 months for ARPI change. 177Lu-PSMA-617 delayed TTW in FACT-P, EQ-5D-5L and BPI-SF scales and subscales vs ARPI change (Table). Results were similar in non-composite analyses. Incidence of grade ≥3 adverse events (AEs), serious AEs and AEs leading to discontinuation for 177Lu-PSMA-617 and ARPI change were 34% vs 44%, 20% vs 28% and 5.7% vs 5.2%, respectively. Conclusions: 177Lu-PSMA-617 delayed TTW in self-reported pain and HRQoL vs change of ARPI in taxane-naïve patients with PSMA-positive mCRPC. Clinical trial information: NCT04689828 . [Table: see text]

PURPOSE To describe a newly established international registry recruiting diverse patients with advanced prostate cancer across academic and community practices to address unmet needs in this population. PATIENTS AND METHODS Initiated in 2017, IRONMAN (International Registry for Men with Advanced Prostate Cancer) is a prospective cohort of patients with advanced prostate cancer. The study will enroll 5,000 patients with metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (CRPC), recruited from Australia, the Bahamas, Barbados, Brazil, Canada, Ireland, Jamaica, Kenya, Nigeria, Norway, South Africa, Spain, Sweden, Switzerland, the United Kingdom, and the United States. The study is collecting datatypes to study variation in care and treatment of advanced prostate cancer across countries and across academic, community-based, and government practices with a focus on clinical outcomes, patient-reported outcomes, epidemiologic data, biologic subtypes, and clinician questionnaires. RESULTS Through July 2022, 2,682 eligible patients were enrolled in 11 of 12 active countries. Sixty-six percent of patients have mHSPC, and 34% have CRPC. On the basis of self-report, 11% of patients are Black and 9% are Hispanic. Five Veterans Affairs Medical Centers are enrolling patients. Globally, 23% of patients report being veterans of military service. CONCLUSION To our knowledge, this is the first international cohort of people newly diagnosed with advanced prostate cancer designed to describe variations in patient management, experiences, and outcomes. IRONMAN aims to identify optimal treatment sequences to improve survival, understand patient-reported outcomes, and explore novel biomarkers to understand treatment resistance mechanisms. Insights from IRONMAN will inform and guide future clinical management of people with mHSPC and CRPC. This cohort study will provide real-world evidence to facilitate a better understanding of the survivorship of people with advanced prostate cancer.