Sartor, Alton Oliver

245 Background: Circulating tumor DNA (ctDNA) can be used as a prognostic biomarker in mCRPC patients, with changes in ctDNA providing insight into patient survival. In this study, we evaluate the ctDNA landscape of patients with mCRPC prior to their death. Methods: A retrospective clinical data review, 2015-2024, was conducted at Tulane Cancer Center to identify mCRPC patients who underwent ctDNA testing prior to death. All ctDNA data were obtained through a multi-gene cancer panel via the Guardant 360 assay (70-83 genes). Lethal mCRPC was defined as patients who underwent ctDNA testing ≤3 months prior to death. A matched control group (CTRL) was defined as mCRPC patients with ctDNA collection ≥2 years prior to death or most recent follow-up. Statistical analyses were performed using Pearson Chi-Square Test or Fisher Exact Test whenever appropriate. Furthermore, survival analysis was conducted using the Kaplan-Meier method. Results: There were 70 patients in lethal mCRPC group and 157 patients in CTRL group. Compared to the CTRL group, in lethal mCRPC, somatic mutations and/or amplifications in BRAF(OR=2.1549, 95% C.I. [1.1136,4.1523], p=0.0298), CCND2 (OR=3.7925, 95% C.I.[1.1937,13.3380], p=0.03326), MYC (OR=2.6332, 95%C.I. [1.4158, 4.9120], p=0.0029), PDGFRA (OR=2.5235, 95% C.I. [1.1438, 5.5793], p=0.0291), and PIK3CA (OR=2.0328, 95% C.I. [1.1098, 3.7166], p=0.02846) were significantly more frequent. Additionally, lethal mCRPC patients were more likely to have missense (OR=4.3194, 95% C.I. [1.443456,19.3338], p=0.01687) and nonsense (OR=1.9364, 95% C.I. [1.06091,3.5250], p=0.04112) mutations at the end-of-life. Patients with a higher allelic fraction (≥0.6%) of TP53 alterations had a shorter median survival (p-value= 0.034). Conclusions: ctDNA mutations and/or amplifications in BRAF, CCND2, MYC, PDGFRA, and PIK3CA were more frequently detected in lethal mCRPC compared to matched CTRLs. Additionally, mCRPC patients with a lethal phenotype were more likely to have missense and nonsense mutations compared to the CTRL group. CtDNA assessment of copy number alterations was limited to amplifications only; additionally, with this assay, distinguishing between gene level and large scale chromosomal amplification is not assessable. Though this study is limited to a single-institution with retrospective analyses of clinical testing, understanding the somatic landscape of lethal mCRPC is critical for development of new biomarkers, strategies and ultimately druggable targets.

TPS303 Background: The treatment of advanced prostate cancer (PC) is challenging, with undesirable side effects that impact patient quality of life. Radioimmunotherapy (RIT) can localize therapy to specific tumor cells in multiple organs to reduce or eliminate damage to normal tissue. The cell surface glycoprotein prostate-specific membrane antigen (PSMA) is an ideal therapeutic target as it is highly expressed by malignant prostate cells. There is a strong rationale for further investigation of the 177 Lu-labeled, chelator-conjugated antibody, 1 77 Lu-rosopatamab, as a potential first-line RIT candidate for the treatment of PC. Methods: This multinational, multicenter, prospective, randomized, open label phase 3 study will have 2 parts: a dosimetry and safety lead-in (n=30) and a randomized treatment expansion (n=490). In Part 1, patients will be divided into 3 groups (n=10 each) to receive 2 single intravenous (IV) injections of 76 millicuries (mCi) each, 14 days apart, of 177 Lu-rosopatamab with best standard of care (SoC) combinations with abiraterone, enzalutamide, or docetaxel to fully characterize biodistribution and safety profiles of 177 Lu-DOTA-rosopatamab + SoC combinations. SoC received will be determined prior to treatment with 177 Lu-rosopatamab. In Part 2, patients will be enrolled in a 2:1 ratio to receive either the best SoC or 2 single IV injections of 76 mCi each (equivalent to a 45 mCi/m 2 dose in a standard 1.7m 2 individual) of 177 Lu-rosopatamab, given 14 days apart, plus best SoC. SoC will be determined prior to randomization, and a change in planned SoC will not be permitted. Eligible patients must have PSMA-expressing metastatic castration-resistant PC (mCRPC) that have progressed despite prior therapy with either enzalutamide or abiraterone plus prednisone, and 1 line of prior taxane therapy or have refused or are ineligible for taxanes. Patients must have adequate organ function including at least 150x10 9 /L platelets, hemoglobin 10 g/dL, and have PSMA-positive disease on 68 Ga-PSMA-11 PET/CT imaging as confirmed by a central reader. Key exclusion criteria include small cell histology, increased risk of hemorrhage or bleeding, known brain or hepatic metastases, or history of stroke, seizure, or treatment with radioisotopes within 6 months prior to randomization. The primary endpoint is radiographic progression-free survival. Key secondary endpoint is OS. Additional secondary endpoints include 5-year overall survival, tumor objective response rate, time to symptomatic skeletal event, and health-related quality of life. Clinical trial information: NCT04876651 .

TPS294 Background: Approval of [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer, previously treated with androgen receptor pathway inhibitors and taxane-based chemotherapy, was based on the results of the Phase 3 VISION study (NCT03511664). It is important to further characterize long-term safety outcomes in 177 Lu-PSMA-617–treated patients, with particular regard to potential treatment-related risks. To this end, the long-term follow-up (LTFU) safety study (NCT05803941) has been established. Findings from the LTFU study will be crucial for assessing delayed toxicities for patients with PSMA-positive metastatic prostate cancer treated with 177 Lu-PSMA-617 globally. Methods: The LTFU study is a prospective, multi-center, non-EU post-authorization safety study. Patients who received ≥1 dose of 177 Lu-PSMA-617 within one of the prospective parent studies (Table 1) are eligible. Patients may enroll in the LTFU study after fulfilling the requirements of their corresponding parent study. The primary endpoint is the number and proportion of selected adverse events (AEs), including myelosuppression, xerostomia, renal failure, xerophthalmia, and second primary malignancies (eg, myelodysplastic syndrome or acute myeloid leukemia), other serious AEs, and changes in laboratory values. The secondary endpoint is the number and proportion of deaths. Following enrollment, patients will undergo assessments at baseline, and then every 6–8 months for up to 10 years after their first dose of 177 Lu-PSMA-617 or until death. At each visit, a review of selected treatment-related AEs (xerostomia, xerophthalmia, myelosuppression), any-cause AEs (renal toxicity, new diagnoses of second primary malignancies), and treatment-related serious AEs will be conducted. Physical and laboratory assessments, as well as details on concomitant medications and interventions, including anti-cancer therapies, will be collected. Patients may receive treatment with any medical intervention. Interim analyses are planned at 2 and 5 years post-study activation. Enrollment is ongoing (n=13). Clinical trial information: NCT05803941 . Parent studies of the long-term follow-up safety study. Trial Indication Phase N (all groups) ClinicalTrials.gov ID VISION (+sub-study) Post-taxane mCRPC 3 831 (+30) NCT03511664 PSMAfore Pre-taxane mCRPC 3 469 NCT04689828 PSMAddition mHSPC 3 1144 NCT04720157 177 Lu-PSMA-617 in patients with moderately or severely impaired, or normal renal function Post-taxane mCRPC 2 20 a NCT06004661 a Planned. mCRPC, metastatic castration-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer.

309 Background: Standard of care (SOC) treatment options for HR-PCa include RT with long-term androgen deprivation (LT-ADT) or RP with selective use of post-operative RT +/- androgen deprivation therapy (ADT). The optimal treatment approach has been assessed in retrospective population-based and multi-center comparisons, which have yielded mixed results with substantial bias. Therefore, we conducted an emulated randomized comparison of RT vs RP in HR-PCa leveraging patients enrolled in RCTs. Methods: We searched Medline for RCTs in HR-PCa with a SOC arm of an RT- or RP-based regimen. Inclusion required similar experimental treatment and contemporaneous enrollment in the same country to reduce bias. This identified 2 trials, NRG/RTOG 0521 (RT+LT-ADT +/- 6 cycles docetaxel [doce]), and CALGB 90203 (RP +/- neoadjuvant 6 cycles doce and ADT). Due to inherent difference in the biochemical recurrence criteria after RT vs RP, we chose inverse probability of treatment weighted (IPTW) cumulative incidence of distant metastasis (DM) as the primary endpoint, considering deaths as competing events. Death after DM was measured to create a harmonized metric of deaths likely attributed to PCa. To assess potential residual selection bias, death without DM to capture non-cancer associated deaths was analyzed. Results: Overall, 1290 patients (RT n=557, RP n=733) were included, with similar median follow-up of 6.4 years. Prior to IPTW, RP patients were significantly younger with lower baseline PSA compared to RT patients. Adjuvant (18%) and salvage therapy (44%) was used in RP cohort. Cumulative incidence of DM was significantly lower in patients who underwent RT compared to RP (8-year DM: 16% vs 23%; p=0.01; subdistribution hazard ratio [sHR] 0.48 [95%CI 0.34-0.69], p<0.001). 8-year rates of death after DM were 10% vs 8% (p=0.72) in the RP and RT patients, respectively. RT patients had significantly greater risk of death without DM (HR 2.09 [1.01-4.34], p=0.048) with early differences measured. On a cross-arm comparison, 8-year cumulative incidence of DM when comparing SOC RT+LT-ADT group versus the doce+ADT+RP group was 18% vs 21%, respectively (sHR 0.75 [0.45-1.24], p=0.26). Conclusions: HR-PCa patients enrolled on RCTs had significantly lower incidence of DM with an RT-based strategy compared to an RP-based approach. Longer follow-up is needed to assess deaths attributed to PCa. Despite the strengths of the comparison (use of cooperative group RCT data, contemporaneous enrollment in the same country, patients fit enough for chemotherapy, and IPTW adjustments) there appears to be residual unmeasured bias, as expected, based on greater early deaths without DM in the RT arm. Utilization of post-operative radiotherapy and ADT+Doce may mitigate differences between RP and SOC RT+LT-ADT.

114 Background: Oncologists have traditionally relied upon serial assessments of PSA and periodic imaging (i.e., every 2 to 3 cycles) to monitor treatment response. Early identification of disease progression allows for faster transitions to alternative therapies that might be more effective. In this study, we evaluated the utility of post-treatment SPECT/CT for earlier detection of treatment failure in patients receiving Lutetium-177–PSMA-617 (LuPSMA). Methods: We queried an IRB-approved registry including all patients starting LuPSMA at Mayo Clinic, MN, in the interval of March 2022 to March 2023. Those receiving fewer than 2 cycles of treatment and missing SPECT/CT data were excluded. We reviewed clinical notes to document the date and reason(s) for treatment discontinuation. The assembled cohort consists of patients stopping LuPSMA for progressive disease ([PD], categorized as biochemical, radiographic, or both). Results of the prior SPECT/CT imaging reports were reviewed. At our institution SPECT/CT images are typically acquired on the day after each infusion. Metrics collected from the radiology reports included: new foci of PSMA localization since the prior PSMA PET or SPECT/CT, suspicion for new non-PSMA avid disease, and a visual determination of PSMA-avid tumor volume. Results: A total of 256 patients received an initial cycle of LuPSMA. SPECT/CT imaging data for at least 2 consecutive treatment cycles was available for 68 patients who developed PD after a median (IQR) of 3 (2-4) cycles. There were 55 patients (81%) with both biochemical and radiographic evidence of PD, 7 (10%) with biochemical only progression, and 6 (9%) with radiographic only progression. The most used imaging modality for response assessment was PSMA PET/CT (n=46, 67%), followed by conventional imaging (n=9, 13%), and choline PET/CT (n=5, 7%). The median time between most recent post-therapy SPECT/CT and determination of PD was 39 days. The prior SPECT/CT had detected new foci of PSMA avid disease in 12 (18%) cases and new non-PSMA avid disease in 5 (7%) cases. Two patients had both new PSMA-avid and non-PSMA avid lesions. The most common sites of new PSMA-avid disease on SPECT/CT were bone (n=10) and liver (n=2). A total of 20 (29%) patients had visually increased tumor volume on SPECT/CT, 9 (45%) of which had no new lesions. In total, 24 of 68 patients (35%) had early detection of treatment futility detected by SPECT/CT. At a median (IQR) follow-up time of 8 (6.4-12) mo, the median OS [95% CI] was similar for patients with PD detected on SPECT/CT (7.8 [6.6 – 9] mo) compared to those without clear evidence of PD on SPECT/CT(8.4 [6.4-10.3] mo, p=0.885). Conclusions: Post-treatment SPECT/CT imaging may complement traditional forms of response assessment and provide an earlier warning of treatment failure through identification of new PSMA-avid lesions, non-PSMA avid disease, and increased tumor volume.

112 Background: We now have more than a decade of experience using Androgen Receptor Pathway Inhibitors (ARPIs) across various disease states of prostate cancer, and the safety of their combination with Lutetium-177–PSMA-617 has been demonstrated in VISION and other large randomized clinical trials. However, real-world data on treatment patterns and outcomes involving combination therapies with 177 Lu-PSMA-617 remain limited. Methods: For this analysis, we utilized the Mayo Clinic Rochester radiopharmaceutical database, a prospectively maintained retrospective database containing all patients who received 177 Lu-PSMA-617 at our institution. We focused on patients who started treatment from March 2022 to March 2023. Patients receiving an ARPI (abiraterone acetate, enzalutamide, apalutamide, or darolutamide) during the course of 177 Lu-PSMA-617 treatment were identified, inclusive of patients who continued using an ARPI prescribed as a prior line of treatment and those who started (i.e., switched) to a new ARPI. Baseline clinicopathologic and imaging characteristics were abstracted and compared using the Mann-Whitney U and Chi-square tests. Best PSA response during treatment was reported as a percent decline from baseline. Survival was calculated from the date of the first cycle of 177 Lu-PSMA-617. PSA50 response and overall survival (OS) outcomes for the two groups (concurrent use of ARPI vs. 177 Lu-PSMA-617 alone) were compared using the Chi-square test and Kaplan-Meier method, respectively. A multivariate Cox regression analysis was performed, including established prognostic factors. Results: An ARPI was prescribed to 106 of the 256 patients (41.4%) starting 177 Lu-PSMA-617 in the interval of March 2022 to March 2023. With regards to baseline characteristics, those receiving an ARPI concurrently with 177 Lu-PSMA-617 had a lower PSA (3.4 vs 29.7 ng/mL, p < 0.001) and a lower frequency of bone (77.4% vs. 87.4%, p = 0.035) and visceral metastases (18.9 vs 34%, p = 0.008) at start of treatment. Median follow-up for the overall cohort (IQR) was 19.1 months (8.7 – 23.6). Patients receiving an ARPI plus 177 Lu-PSMA-617, as compared to 177 Lu-PSMA-617 alone, were more likely to complete all 6 planned doses of treatment (63.2% vs. 48.7%, p < 0.001), though the PSA50 response rate was similar (49.1% vs 47.3%, p = 0.786). Median OS [95% CI] for the overall cohort was 21.3 [16.7 – 25.9] months and significantly longer for those receiving ARPI with 177 Lu-PSMA-617 (NR [NE – NE]) as compared to 177 Lu-PSMA-617 alone (15.3 mo [11.6 – 19.1], p < 0.001). However, on multivariate analysis including known prognostic variables, use of ARPI was not independently associated with improved survival (HR = 1.03 [CI: 0.68 to 1.55], p = 0.891). Conclusions: Patients receiving an ARPI with 177 Lu-PSMA-617 were more likely to complete all 6 cycles of treatment, but no clear differences in survival were observed on multivariate analysis.

136 Background: The ECOG performance status (PS) is a critical measure for evaluating functional capacity and determining clinical trial eligibility in patients with advanced prostate cancer. We aim to assess the capability of large language models (LLMs) to accurately infer ECOG PS from unstructured oncology notes. Methods: This retrospective study included patients with metastatic castration-resistant prostate cancer (mCRPC) receiving Lutetium-177–PSMA-617 ( 177 Lu) at the Mayo Clinic (2022-2023). Baseline ECOG PS scores were manually curated by a trained clinician from clinical notes recorded within four weeks prior to 177 Lu initiation. Structured zero-shot prompts were then used to prompt GPT-4 to infer ECOG PS scores from unstructured oncology notes. Total dataset was randomly sampled to prompt development (20%) and held-out test set (80%). Three experimental setups were employed to assess model performance: (i) utilizing unmasked clinical notes, (ii) clinical notes with only numerical ECOG PS scores masked while retaining narrative descriptive/assessment by oncologist of ECOG score, and (iii) clinical notes with both numerical scores and narrative ECOG descriptors masked. Final performance was assessed using evaluation metrics (precision, recall, F1 score) on the held-out test set. Results: A total of 240 patients (n: 50 prompt development; n: 190 test set) were included in the analysis. The median age was 70 (IQR: 66-76); a majority of patients were White (n: 229; 95%) and non-Hispanic (n: 233; 97%). The most prevalent ECOG PS score was 0 (n: 140; 58%), followed by 1 (n: 88; 37%), and 2 (n: 12; 5%). The performance was numerically higher when using unmasked notes (weighted average precision: 0.89; recall: 0.89; F1: 0.89), compared to using notes with masked scores only (weighted average precision: 0.76; recall: 0.79; F1: 0.75) and notes with both scores and narrative masked (weighted average precision: 0.57; recall: 0.53; F1: 0.48). Metrics by each ECOG PS score is outlined (Table). Conclusions: Large language models demonstrate significant potential in precisely extracting ECOG performance status from unstructured oncology notes, offering valuable support for treatment decision-making and clinical trial enrollment. However, model performance declines as reliance on implicit reporting within clinical notes increases. Future efforts focusing on prediction of ECOG using a series of notes over time will be the next step. ECOG Unmasked oncology notes ECOG Score masked only ECOG Score + ECOG narrative marked Precision Recall F1 Score Precision Recall F1 Score Precision Recall F1 Score 0 0.89 0.92 0.91 0.75 0.93 0.83 0.59 0.74 0.66 1 0.88 0.86 0.87 0.76 0.74 0.75 0.19 0.47 0.27 2 1.00 0.82 0.90 0.78 0.33 0.47 0.78 0.16 0.26

132 Background: Distant metastasis at the time of prostate cancer (PCa) diagnosis is associated with increased morbidity and mortality. This study aimed to assess the impact of sociodemographic characteristics on distant metastasis at the time of PCa diagnosis. Methods: The Surveillance Epidemiology and End Results (SEER) database (2000-2021), including PCa patients from 17 registries, was queried. Patients with late-stage diagnosis (LSD) were defined as those who were initially diagnosed with stage IV disease, indicating distant metastasis. Sociodemographic predictors included race, ethnicity, age, marital status, residential status, and median household income. Multicollinearity was assessed using variance inflation factors (VIF). Univariable logistic regression was performed to identify significant predictors of LSD, which were further analyzed in multivariable logistic regression using a maximum likelihood estimation approach. Odds ratios with 95% confidence intervals (CI) were computed with a p-value of <0.05 indicating a statistically significant association. Results: Of the 1,089,736 PCa patients diagnosed, 64,983 (6%) had an LSD. The majority were white (80%), non-Hispanic/Latino (HL) (91%), aged ≥65 years (60%), married (75%), residents in metropolitan areas (88%), and had an annual house income of ≥$70,000 (70%). Multivariable logistic regression identified Black (OR: 1.24; 95%CI: 1.22-1.27), Asian or Pacific Islander (1.35; 1.30-1.40), and American Indian/Alaska Native (1.70; 1.53-1.89) to have higher odds of LSD compared to White patients (Table). In addition, HL ethnicity compared to non-HL (OR: 1.45; 95% CI: 1.42-1.49), age ≥65 compared to <65 (1.68; 1.65-1.71), unmarried status compared to married (1.88; 1.85-1.91), residency in non-metropolitan areas compared to metropolitan (1.10; 1.07-1.12), and household income <$70,000 compared to ≥$70,000 (1.03; 1.01-1.05) had a significant association with LSD. Conclusions: Older, non-White (Black, Asian/Pacific Islander, American Indian/Alaska Native), Hispanic/Latino, unmarried men, residents of non-metropolitan areas, or those with lower annual household incomes have higher odds of late-stage diagnosis. Interventions targeting early detection in these at-risk groups may improve prostate cancer outcomes in the US. Variable Odds Ratio (95% CI) p-value Race (Black vs White) 1.24 (1.22-1.27) <0.01 Race (Asian or Pacific Islander vs White) 1.35 (1.31-1.40) <0.01 Race (American Indian/Alaska Native vs White) 1.70 (1.53-1.89) <0.01 Ethnicity (Hispanic/Latino vs non-/Hispanic/Latino) 1.45 (1.42-1.49) <0.01 Age (≥65 vs <65) 1.68 (1.65-1.71) <0.01 Marital status (unmarried vs married) 1.88 (1.85-1.91) <0.01 Residence status (non-metropolitan vs metropolitan) 1.10 (1.07-1.12) <0.01 Household income (<$70,000 vs ≥$70,000) 1.03 (1.01-1.05) <0.01

341 Background: Specialist clinicians (oncologists, urologists, radiation oncologists) read through free text reports of prostate MRI and biopsy reports to risk stratify patients during initial consultation of localized PCa. This laborious and time-consuming process is repeated for each day during the clinic. Herein, we propose a hybrid stratification framework utilizing a combination of large language model (LLM) and rule-based programming to automate this process. Methods: This retrospective study included patients with localized PCa (2004-2024) presenting to care at Mayo Clinic with at least one positive prostate biopsy and MRI report available. The state-of-the-art LLM – GPT4 – was utilized using a structured zeroshot prompt to extract relevant phenotypic variables (clinical T stage, Gleason patterns, grade group, extent of specimen/cores involved, prostate size/volume) from unstructured MRI and biopsy reports. Using a rule-based algorithm, the extracted variables and PSA at PCa diagnosis were used to categorize each patient into one of the six NCCN risk categories (very low [VL], low [L], favorable intermediate [FInt], unfavorable intermediate [UFInt], high risk (HR), very high risk [VHR]). Prompts were iteratively developed using ~5% of the total dataset and validated on ~10% of the dataset. Final performance was assessed against a held-out expert annotated test dataset using evaluation metrics (accuracy, F1-score, precision, recall). Additionally, manual annotation was conducted by two independent novice reviewers to compare machine annotated and novice-human annotated risk categorization. Results: A total of 397 patients were included in the evaluation. The median age at diagnosis was 64.8 (IQR: 59.7-68.5); majority of the men were White (n: 366; 92%) and non-Hispanic (n: 371; 94%). The most prevalent risk category was UFint (n: 151; 38%) followed by FInt (n: 80; 20.2%), HR (n: 76; 19.1%), VHR (n: 64; 16.1%), L (21: 5.3%), and VL (n: 5; 1.3%). Novice reviewers achieved an accuracy of 79%, precision of 80%, recall of 82% and a F1-score of 0.81. The hybrid stratification framework using GPT4 achieved an accuracy of 89%, precision of 89%, recall of 88% and a F1-score of 0.88. Among 43 errors by GPT4 risk stratification, majority of the errors were due to miscategorization of clinical T-stage (n: 21; 49%) followed by erroneous number of positive cores (n: 13; 30%). However, additional evaluation showed that GPT4 achieved numerically higher performance (accuracy: 90%; precision: 91%; recall: 90%; F1: 0.90) compared to novice reviewers (accuracy: 77%; precision: 89%; recall: 77%; F1: 0.82) for ascertaining clinical T-stage. Conclusions: Large language models exhibited superior performance than novice clinicians for risk stratification in patients with localized PCa. As the next step, we intend to validate our framework for automated risk classification in a prospective manner.

184 Background: We update evidence on mHSPC when new evidence becomes available (PMID: 36862387). ARANOTE trial prompted us to assess the comparative efficacy of darolutamide (DARO) with other ARPi agents in mHSPC using the living network meta-analysis (LNMA). Methods: This LNMA is conducted using the living interactive evidence (LIvE) synthesis framework. Phase III trials assessing systemic treatments in mHSPC are included. Mixed treatment comparisons were made using a frequentist network meta-analysis. P-scores were computed to assess relative treatment rankings with higher values indicating potentially better efficacy. Results: This report of LNMA includes a total 11 trials (12628 patients; 12 unique treatment options) as of October 1 st , 2024. Overall results were consistent with prior updates. Analysis limited to the ARPi trials showed that inhigh volume, abiraterone acetate (AAP)+androgen deprivation therapy (ADT) (HR: 0.46; 95% CI: 0.40-0.53; rank 1), apalutamide (APA)+ADT (0.53; 0.41-0.68; rank 3), DARO+ADT (0.60; 0.44-0.81; rank 4) and enzalutamide (E)+ADT (0.48; 0.41-0.56; rank 2) significantly improved radiographic progression-free survival (rPFS) compared to ADT alone. No statistically significant differences were observed with DARO+ADT compared to AAP+ADT (1.30; 0.94-1.82), APA+ADT (1.14; 0.77-1.67) and E+ADT (1.24; 0.89-1.79). Inlow volume, AAP+ADT (0.48; 0.37-0.63; rank 4), APA+ADT (0.36; 0.22-0.58; rank 3), DARO+ADT (0.30; 0.15-0.60; rank 1) and E+ADT (0.32; 0.25-0.41; rank 2) significantly improved rPFS compared to ADT. E+ADT significantly improved rPFS compared to AAP+ADT (0.67; 0.47-0.96) in low volume. No statistically significant differences were observed with DARO+ADT compared to AAP+ADT (0.62; 0.30-1.30), APA+ADT (0.83; 0.36-1.92) and E+ADT (0.93; 0.45-1.94). In synchronous disease, AAP+ADT (0.58; 0.51-0.67; rank 4), APA+ADT (0.49; 0.39-0.62; rank 2), DARO+ADT (0.59; 0.44-0.79; rank 3) and E+ADT (0.42; 0.36-0.50; rank 1) significantly improved rPFS compared to ADT. E+ADT significantly improved rPFS compared to AAP+ADT (0.73; 0.59-0.89) in synchronous disease. In metachronous disease, DARO+ADT (0.34; 0.17-0.67; rank 1), APA+ADT (0.41; 0.22-0.77; rank 2) and E+ADT (0.44; 0.35-0.57; rank 3) significantly improved rPFS compared to ADT. No statistically significant differences were observed with DARO+ADT compared to APA+ADT (0.83; 0.33-2.08) and E+ADT (0.76; 0.37-1.57) in metachronous disease. The results were consistent for overall survival. Conclusions: Current evidence suggests no significant differences for darolutamide as compared to other ARPi agents. Enzalutamide may be preferred over AAP in low-volume or synchronous disease. Given similar efficacy, choice of ARPi requires careful consideration of patient-specific factors including cost, accessibility and toxicity.