Citations

TPS891 Background: Bacillus Calmette-Guérin (BCG) is the standard first-line therapy for patients with high-risk non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) ± papillary tumors; however, patients whose disease is unresponsive to BCG therapy are unlikely to benefit from further courses of BCG. Bladder-preserving treatment options for patients with BCG-unresponsive NMIBC with CIS ± Ta/T1 include intravesical gene therapy (nadofaragene firadenovec-vncg), intravesical chemotherapy (gemcitabine and docetaxel), and immunotherapy (intravenous pembrolizumab and intravesical nogapendekin alfa inbakicept-pmln). In a pivotal phase 3 study, 53.4% of participants (55/103) with BCG-unresponsive NMIBC with CIS ± Ta/T1 achieved a complete response (CR) within 3 months of a single instillation of nadofaragene firadenovec, and of them, 45.5% (25/55) maintained a CR at 12 months. Nadofaragene firadenovec in combination with chemotherapy or immunotherapy may further improve clinical efficacy. ABLE-22 (NCT06545955) is an interventional study evaluating the safety and efficacy of nadofaragene firadenovec alone or in combination with chemotherapy (gemcitabine and docetaxel) or immunotherapy (pembrolizumab) in participants with high-risk BCG-unresponsive NMIBC. Reinduction for nonresponders once at month 3 will also be evaluated. Methods: ABLE-22 will include approximately 40 to 75 sites across the United States and Canada; however, sites in Asia, Australia, and Europe may be included. Participants (anticipated N=150) will be randomly assigned 1:1:1 to receive nadofaragene firadenovec (n=50), nadofaragene firadenovec plus gemcitabine and docetaxel (n=50), or nadofaragene firadenovec plus pembrolizumab (n=50). Adults aged ≥18 years with documented NMIBC with CIS ± Ta/T1 that is unresponsive to ≥2 courses of BCG therapy within the last 12 months are eligible to enroll. The primary endpoint is CR (defined as absence of low- and high-grade NMIBC) at months 3 or 6, as participants with persistent NMIBC (any CIS, low-grade Ta, and >3 cm or multifocal high-grade Ta) will be offered reinduction once, at month 3. Secondary endpoints include durability of CR, incidence of muscle-invasive progression, cystectomy-free survival, pathologic staging, overall survival, and safety. Durability of CR will be assessed quarterly up to and including month 24; all other secondary endpoints will be assessed up to and including month 36. Exploratory endpoints include changes in expression of potential biomarkers in blood and urine. Results from this investigational, randomized, multicenter, open-label study evaluating the safety and efficacy of nadofaragene firadenovec alone or in combination with chemotherapy or immunotherapy are expected July 2028. Clinical trial information: NCT06545955 .

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.

108 Background: PARPi are approved for the treatment of pts with mCRPC either as single agents or as a combination with an androgen receptor pathway inhibitor (ARPI) [PMID: 37442702]. In a US Food and Drug Administration (FDA) pooled analysis, the benefit from PARPi appeared greatest for pts harboring BRCA1/2 alterations [PMID: 38484203]. However, real-world uptake of PARPi in pts with mCRPC with BRCA1/2 alterations is unknown. Herein, our objective was to assess the usage of PARPi in real-world pts with mCRPC harboring BRCA1/2 alterations. Methods: A de-identified nationwide Flatiron Health electronic health record (EHR)-derived database was used to extract pt-level data. Eligibility criteria: pts with mCRPC harboring alterations in BRCA1 or BRCA2 or both and alive after 8/15/2020 (i.e., 3 months following the approval of the first PARPi, rucaparib, in mCRPC) with available treatment information. The data cutoff date was 5/31/2024. Pts were categorized into two cohorts based on the receipt of any PARPi or not. Baseline characteristics at the time of mCRPC diagnosis, including age, race-ethnicity, and insurance plan, were collected in both cohorts. Results: Of the overall cohort of 24,105 pts with metastatic prostate cancer, 443 pts had mCRPC with BRCA1/2 alterations and were eligible and included in this analysis. 227 (51.2%) received a PARPi, while 216 did not (48.8%). Among the 227 pts who received a PARPi, 166 received it as a single agent (73.1%), 40 received it in combination with an ARPI (17.6%), and 21 received it in combination with other agents (9.3%). The median age was 72 in both cohorts (IQR 65 – 79 in patients receiving a PARPi and 66 – 78 in patients who did not). Other baseline characteristics in both groups are shown (Table). Conclusions: Despite PARPi demonstrating survival improvement in pts with mCRPC with BRCA1/2 alterations, a significant proportion of pts do not receive them. Our findings highlight the need to improve education among clinicians of level 1 evidence and improve access to life-prolonging therapies in pts with mCRPC. Baseline characteristics of pts with mCRPC who received vs. did not receive a PARPi. Characteristic Subgroup Pts who received a PARPiN = 227 Pts who did not receive a PARPiN = 216 Race-ethnicity, n (%) Asian 9 (4) 1 (0.5) Black 22 (9.7) 30 (13.9) Hispanic-Latino 10 (4.4) 10 (4.6) White 149 (65.6) 124 (57.4) Other and unknown 37 (16.3) 51 (23.6) Insurance, n (%) Commercial health plan 192 (84.5) 182 (84.3) Medicare-other government programs 31 (13.7) 18 (8.3) Medicaid 1 (0.4) 3 (1.4) Others and unknown 3 (1.3) 13 (6)

TPS888 Background: There is currently no Food and Drug Administration (FDA)-approved treatment for intermediate-risk non–muscle-invasive bladder cancer (IR NMIBC), defined by the AUA as recurrence of low-grade (LG) Ta within 1 year, solitary LG Ta >3 cm, multifocal LG Ta, high-grade (HG) Ta (≤3 cm), and/or LG T1. Nadofaragene firadenovec-vncg is the first FDA-approved intravesical nonreplicating gene therapy for the treatment of adult patients with high-risk Bacillus Calmette Guérin (BCG)-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumors. In a nonrandomized, multicenter, open-label, repeat-dose, phase 3 study, 53.4% of participants (55/103) with CIS ± HG Ta/T1 achieved complete response 3 months after the first instillation. Nadofaragene firadenovec was well tolerated, with no grade 4/5 study drug-related AEs. Because maintenance treatment with nadofaragene firadenovec following tumor resection may improve clinical outcomes in patients with IR NMIBC, the ABLE-32 open-label randomized study is being conducted to evaluate the efficacy of nadofaragene firadenovec administered every 3 months versus observation in participants with IR NMIBC. Methods: This phase 3 study includes approximately 100 global sites with 454 anticipated participants. Adults diagnosed with new or recurrent IR NMIBC and having undergone transurethral resection of bladder tumor within 60 days prior to randomization are eligible. Participants will be randomly assigned 1:1 to receive nadofaragene firadenovec or continue observation. The nadofaragene firadenovec group will receive quarterly doses unless disease recurs or progresses. The observation group will be followed quarterly and may receive nadofaragene firadenovec if IR NMIBC recurs within 24 months. All participants will be evaluated for recurrence and progression using cytology, cystoscopy, and for-cause biopsy for up to 5 years. The primary endpoint is recurrence-free survival (RFS), from randomization to first documented recurrence, progression, or death. Secondary endpoints include RFS at 12 and 24 months and safety. Exploratory endpoints include effect on potential biomarkers and health-related quality of life. Final results are expected in 2031. Clinical trial information: NCT06510374 .

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.

175 Background: 177 Lu-PSMA-617, a PSMA-directed radionuclide therapy, is an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). This retrospective study evaluates clinical outcomes of 177 Lu-PSMA-617 in low volume (LV) and high volume (HV) mCRPC, classified using the CHAARTED criteria. Methods: We conducted a retrospective review of the Mayo Clinic Prostate Cancer Registry, including mCRPC patients treated with 177 Lu-PSMA-617 at Mayo Clinic Rochester, MN, from August 2017 to August 2024. Patients were categorized based on CHAARTED criteria, which define high-volume disease by the presence of visceral metastases and/or four or more bone metastases, with at least one outside the vertebral column and pelvis. PSA-response rate (PSA-RR), overall survival (OS), PSA-progression-free survival (PSA-PFS), and radiographic progression-free survival (rPFS) were analyzed using Kaplan-Meier curves with log-rank tests, as well as uni- and multivariate Cox regression. Results: Of the 264 patients treated with 177 Lu-PSMA-617, 83 were classified as LV (median follow-up: 17.1 months) and 177 as HV (median follow-up: 13.7 months). LV patients had lower serum PSA levels (P < 0.0001), higher hemoglobin levels (P < 0.0001), and a longer time from diagnosis to treatment initiation (10.3 years vs. 7.2 years, P = 0.04). In the HV group, 92% had bone metastases, 60% had lymph node involvement, 54% had both, and 35% had visceral metastases. In the LV group, 64% had bone metastases, 84% had lymph node involvement, 25% had both, and none had visceral metastases. Median OS was 14.4 months for HV patients and 17.6 months for LV patients (P < 0.0001). Median PSA-PFS was 11.4 months for HV patients and 13 months for LV patients. Median rPFS was 9.1 months for HV patients and 10.6 months for LV patients. PSA-RR significantly differed between groups (P < 0.0001). In the HV group, 20% achieved CR (PSA < 0.2 ng/mL), 29% had PR (PSA decreased by ≥50%), 16% experienced SD, and 35% had PD (PSA increased ≥25% from nadir). In contrast, the LV group had 51% achieving CR, 10% achieving PR, 18% with SD, and 11% with PD. Conclusions: Lower disease volume in mCRPC is strongly associated with improved outcomes following 177 Lu-PSMA-617 therapy. These findings suggest that tumor burden is a key predictor of response to PSMA radioligand therapy.

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.

155 Background: Primary results from the randomized, multicenter, open-label, phase 3 TRITON3 (NCT02975934) study of rucaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi) in patients with chemotherapy-naive mCRPC and BRCA1/2 (BRCA) vs the control arm of physician’s choice of DTX or ARPI (abiraterone acetate [ABI] or enzalutamide [ENZ]) demonstrated that rucaparib significantly improved radiographic progression-free survival (rPFS, primary efficacy endpoint) vs physician’s choice. Here, we report final OS and safety results from TRITON3. Methods: Patients with disease progression after 1 prior second-generation ARPI in any setting were randomized 2:1 to rucaparib 600 mg BID or physician’s choice of DTX, ABI, or ENZ (control). OS was a key secondary endpoint tested initially in the BRCA subgroup, followed by the intent-to-treat (ITT) population in an ordered step-down multiple-comparisons procedure. Crossover from placebo to rucaparib was allowed after radiographic progression was confirmed by independent radiology review. Results: As of March 1, 2024 (final analysis data cutoff),patients with BRCA (N = 302) and ATM (N = 103) alterations were randomized (ITT, N = 405). After an overall median follow-up of 44.0 months, median OS in the BRCA subgroup in the rucaparib arm was 23.2 months vs 21.2 months for the physician’s choice control arm (HR, 0.91 [95% CI, 0.68–1.20]; P = 0.5044; Table). Hierarchical testing did not continue due to lack of statistical significance. No OS benefit was observed in the ITT population or ATM subgroup (Table). Median duration of treatment in rucaparib and physician’s choice arms was 8.3 and 5.1 months, respectively. The most frequent any-grade treatment emergent adverse event (TEAE) in the rucaparib (n = 270) and physician’s choice (n = 130) arms was asthenia/fatigue (61.5% and 63.1%, respectively). The most frequent grade ≥3 TEAE was anemia (23.7%) with rucaparib, and asthenia/fatigue (9.2%) with physician’s choice. Of the 135 patients in the physician’s choice arm, 77 patients had radiographic progression and 70 crossed over to rucaparib. Conclusions: Rucaparib remains the only PARPi to show improved rPFS vs a DTX-containing control arm and has a similar OS even when most patients cross over to rucaparib. Safety was consistent with prior reports. These data support rucaparib as a treatment option for patients with BRCA-mutated mCRPC. Clinical trial information: NCT02975934 . Median OS at final analysis. Group Rucaparib, n Physician's choice, n Rucaparib, months Physician's choice, months HR (95% CI) a BRCA 201 101 23.2 21.2 0.91 (0.68–1.20) ITT 270 135 22.8 21.7 0.99 (0.78–1.26) ATM 69 34 18.4 22.1 1.21 (0.77–1.90) a Calculated by stratified Cox proportional hazard model.

75 Background: The Rx landscape of pts with mCRPC has recently evolved with the approval of lutetium-177-PSMA-617 (Lu-177) and poly(ADP) ribose polymerase inhibitors (PARPi) either as single agents or as combinations with an androgen receptor pathway inhibitor (ARPI) [PMID: 37442702]. However, real-world data on the uptake of these agents are lacking. Herein, we sought to assess the Rx patterns and attrition rates of pts with mCRPC in the era of newly approved therapies. Methods: The de-identified nationwide Flatiron Health Electronic-Health Record (EHR)-derived database was used to extract pt-level data. Eligibility criteria: diagnosis of mCRPC and Rx line (L) information. The data cut-off date was 5/31/2024. Rx patterns in each line of therapies were summarized using frequency and percentages. All analysis was done using R version 4.2.3. Results: Of the overall cohort of 24,105 pts with metastatic prostate cancer, 12,333 pts diagnosed with mCRPC between 1/1/2013 and 5/9/2024 met the eligibility criteria and were included. Rx trends are summarized (Table). Of pts receiving 1L Rx, 61% of pts received 2L therapy, and 35% received 3L therapy. Androgen receptor pathway inhibitor (ARPI) was the most common Rx in the 1L setting (73.7%), followed by taxane (10%) and sipuleucel-T (3.8%). In 2L, ARPI was again the most frequent Rx (46.8%), followed by taxane (23.6%). In 3L, taxane became the most frequent Rx (35.4%), followed by ARPI (26.2%) and radium-223 (4.9%). Rx trends per year will be presented in the meeting. Conclusions: In the current era,a high proportion of pts with mCRPC receiving 1L Rx do not receive a subsequent line of Rx (39% of pts do not receive 2L, and 65% do not receive 3L Rx). ARPIs and taxanes remain the most frequently used Rx options in most L of therapy. These findings highlight the need for better tolerated Rx, therapies with a novel mechanism of action, and improved access to care for our pts. Rx trends per year will be presented in the meeting. Rx patterns in pts with mCRPC. Rx 1L, n (%)N = 12,333 2L, n (%)N = 7475 3L, n (%)N = 4316 4L, n (%)N = 2339 5L, n (%)N = 1225 ARPI 9085 (73.7) 3503 (46.8) 1130 (26.2) 356 (15.2) 157 (12.8) PARPi-based therapies 93 (0.8) 185 (2.5) 142 (3.3) 98 (4.2) 47 (3.9) Platinum-based therapy 127 (1) 216 (2.9) 198 (4.6) 148 (6.3) 130 (10.6) Lu-177-based therapies 50 (0.4) 109 (1.5) 169 (3.9) 143 (6.3) 103 (8.4) Radium-223 183 (1.5) 241 (3.2) 213 (4.9) 125 (5.3) 79 (6.4) Sipuleucel-T 474 (3.8) 94 (1.3) 53 (1.2) 18 (0.8) 8 (0.7) Taxane 1240 (10) 1763 (23.6) 1526 (35.4) 935 (40) 393 (32) Pembrolizumab 24 (0.2) 41 (0.5) 36 (0.8) 27 (1.2) 29 (2.4) Other*/not-applicable** 665 (5.4)/392 (3.2) 1000 (13.4)/323 (4.3) 602 (14)/247 (5.7) 320 (13.7)/169 (7.2) 162 (13.3)/117 (9.5) *Includes drugs approved for mCRPC in combination with unapproved agents or clinical trial drugs. **Includes agents not approved for prostate cancer.

61 Background: 177 Lu-PSMA-617 was approved in March 2022 for patients with mCRPC pretreated with an androgen receptor pathway inhibitor (ARPI) and a taxane. There are limited data on the effectiveness of treatments post- 177 Lu-PSMA-617. The aim of this study was to describe prostate-specific antigen (PSA) responses among patients with mCRPC receiving a guideline-recommended therapy as the next therapy after 177 Lu-PSMA-617 treatment. Methods: This retrospective, observational study used real-world data from the PRECISION data platform, a proprietary dataset developed by Novartis, comprised of patient-level electronic health record and claims data that represent the US advanced prostate cancer population in the community, academic, urology, and medical oncology settings. Patients with mCRPC who received any guideline-recommended therapy at least 14 days after treatment with 177 Lu-PSMA-617 between March 23, 2022 and July 31, 2024 were included. Guideline-recommended therapies included abiraterone, enzalutamide, darolutamide, apalutamide, cabazitaxel, docetaxel, pembrolizumab, sipuleucel-T, niraparib, olaparib, talazoparib, rucaparib, and radium-223. Patients’ PSA values while on 177 Lu-PSMA-617 treatment were compared with their PSA values during the subsequent therapy course. Proportions of patients achieving reductions in PSA levels ≥50% (PSA50) and ≥80% (PSA80) were estimated. All analyses were descriptive. Results: A total of 152 patients receiving any subsequent guideline-recommended therapy after 177 Lu-PSMA-617 were identified. Mean age was 72.1 years. Most patients received an ARPI (n=93, 61.2%) – abiraterone (n=38), enzalutamide (n=37), darolutamide (n=10), or apalutamide (n=8) – as their subsequent therapy. Of patients who received a taxane (n=42, 27.6%), 24 received cabazitaxel and 18 received docetaxel. Median time to initiation of subsequent therapy was 206 days (interquartile range [IQR] 101–301 days) from 177 Lu-PSMA-617 initiation and 44 days (IQR 17–119 days) from 177 Lu-PSMA-617 discontinuation. Overall, among patients with sufficient information for PSA evaluation (n=30), 46.7% achieved PSA50 and 40.0% PSA80 post- 177 Lu-PSMA-617. Among patients receiving an ARPI, PSA50 was observed in 11/18 (61.1%) and PSA80 in 10/18 (55.6%). Among patients receiving a taxane, PSA50 and PSA80 were seen in 3/12 (25.0%) and 2/12 (16.7%), respectively. Conclusions: In this real-world analysis, the majority of patients who received guideline-recommended therapies after 177 Lu-PSMA-617 achieved at least a PSA50 response, suggesting that 177 Lu-PSMA-617 treatment does not preclude response to other subsequent therapies.