Gupta, Sumati

ImportancePatients with metastatic castration–resistant prostate cancer (mCRPC) harboring BRCA1/2 alterations are eligible to receive poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as single agents or in combination with an androgen receptor pathway inhibitor after these agents showed survival improvement in their landmark clinical trials. However, data are limited regarding the uptake of PARP inhibitors in these patients.ObjectiveTo investigate the use of PARP inhibitors in patients with mCRPC harboring BRCA1/2 alterations.Design, Setting, and ParticipantsThis retrospective cohort study used the deidentified Flatiron-Health electronic health record–derived database of US community and academic practices to extract patient-level data. The data cutoff date was May 31, 2024. Patients with mCRPC with evidence of harboring BRCA1/2 alterations and alive after August 15, 2020 (ie, 3 months after the approval of the first PARP inhibitor, rucaparib, in mCRPC) were included. Statistical analysis was performed from September 2024 to May 2025.ExposuresAge, race and ethnicity, insurance status, and practice type at the time of mCRPC diagnosis.Main Outcomes and MeasuresThe receipt of PARP inhibitors. Multivariable logistic regression was conducted to assess the association between the exposures and the main outcome.ResultsOf 24 105 patients with metastatic prostate cancer, 443 male patients (median [IQR] age, 72 [65-79] years) had mCRPC with BRCA1/2 alterations and were eligible and included in our analysis. Of these patients, 227 (51.2%) received a PARP inhibitor, whereas 216 (48.8%) did not. Compared with patients covered by a commercial health plan, those covered by Medicare were significantly more likely to receive a PARP inhibitor (odds ratio, 1.91; 95% CI, 1.02-3.66; P = .047). The odds of receiving a PARP inhibitor were not significantly higher in patients treated in community practice compared with those treated in academic centers (odds ratio, 1.64; 95% CI, 1.00-2.70; P = .05).Conclusions and RelevanceThis retrospective cohort study of patients with mCRPC and evidence of BRCA1/2 alterations found that approximately half of patients did not receive PARP inhibitors despite evidence of survival improvement in this population. These findings highlight the need to increase awareness of the survival data and access to life-prolonging therapies in patients with mCRPC.

5076 Background: C and Lu are both life-prolonging therapies for pts with mCRPC after progression on androgen receptor pathway inhibitor (ARPI) and docetaxel (D). Herein, our objective was to assess the comparative effectiveness of C vs. Lu in pts with mCRPC with prior progression on D and ARPI in real-world pts in the USA. Methods: A de-identified nationwide Flatiron Health electronic health record (EHR)-derived database was used to extract pt-level data. Eligibility: pts with mCRPC who progressed on D and ARPI and received for the first-time single-agent C or Lu. Pts who received alternative Lu or C in a later line of therapy (LOT) were excluded. Endpoints: real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS). These were summarized via Kaplan-Meier survival estimates with a 95% confidence interval (CI) and compared in the context of propensity score (PS) matching weighted analysis using the Cox proportional hazard model. PS model included the following covariates: age, race-ethnicity, socioeconomic status, treatment year, Gleason score, ECOG performance status, log2PSA, alkaline phosphatase, hemoglobin, creatinine, LOT, insurance, and practice type. All the covariates achieved balance after PS matching weighting. Results: Among 24,105 pts with metastatic prostate cancer in the dataset, 1,445 met the eligibility criteria and were included (1,227 treated with C, 218 treated with Lu). In C cohort: median age was 73 (IQR 67 – 78), 66.9% had Gleason score ≥ 8, and median LOT was 4 (IQR 3-4). In Lu cohort: median age was 75 (IQR 67.25 – 80), 68.1% had Gleason score ≥ 8, and median LOT was 4 (IQR 3-5). In PS matching weighting analysis, there was evidence that pts receiving Lu had a significantly improved rwTTNT (median 8.3 months [mo], 95% CI 6.3 – 9.8) compared to those receiving C (median 4.7 mo, 95% CI 4.2 – 5.4) (HR 0.49, 95% CI 0.37 – 0.63, p < 0.001), which persisted after adjusting for covariates (HR 0.43, 95% CI 0.32 – 0.57, p < 0.001). Additionally, there was evidence that rwOS was longer in pts receiving Lu (median 10.3, 95% CI 8.9 – 12.8) compared to those receiving C (median 8.8 mo, 95% CI 6.6 – 10.8) (HR 0.69, 95% CI 0.51 – 0.92, p = 0.01). This improvement in rwOS with Lu compared to C persisted after adjusting for covariates (HR 0.61, 95% CI 0.44 – 0.84, p < 0.001). Conclusions: This is the largest real-world data to date assessing the comparative effectiveness of Lu vs. C, and it showed significantly longer rwTTNT and rwOS with Lu compared to C in pts with mCRPC pretreated with ARPI and D. Limitations: retrospective nature, selection bias, missingness, lack of randomization, etc. and residual confounding in real-world datasets. Upon external validation, these findings could guide treatment selection in the clinic and design of clinical trials.

727 Background: Despite the availability of targeted therapies like erdafitinib for pts with aUC with susceptible genomic alterations, the rate of NGS testing remains low at 32% in the United States (Hage Chehade...Swami, JAMA Network Open, 2024). Furthermore, limited data exist regarding the timing of NGS testing in relation to the time of death. Herein, we sought to assess the rates of NGS testing at the end of life in pts with aUC in a real-world patient population. Methods: A de-identified nationwide Flatiron Health electronic health record (EHR)-derived database was used to extract patient-level data. Inclusion criteria: pts who received NGS testing (blood/tissue) and who had a date of death recorded. The analytic cohort included pts diagnosed with aUC between 1/1/2011 and 11/14/2022 who received first NGS testing results between 5/3/2012 and 12/21/2022. The time difference between each pt’s first NGS result delivered and death was calculated, and thereafter, pts were categorized into 3 categories: pts receiving results > 3 months (mo) before death, within 3 mo of death, or after death. The frequency and percentages of the 3 categories were reported, as well as by year of death. The percentages in each category were compared between 2019 (year of erdafitinib approval) and 2022 (last year in dataset) to evaluate changes in NGS testing trend. Results: Among 12,157 pts with aUC in the dataset, 1,637 had both a recorded date of death and underwent NGS testing, and were eligible and included in final analysis. The median age was 72 (IQR 66 – 79). The majority were male (73%), White non-Hispanic (76%), and treated in community practice (86%). 68.2% received NGS results > 3 mo before death (n = 1,117), 28.3% received results within 3 mo of death (n = 464), and 3.4% of NGS results were reported after death (n = 56). In pts who died in 2019 versus 2022, the percentage of pts receiving NGS results > 3 mo before death increased from 61% to 75%, while the percentage of pts receiving results within 3 months decreased from 33% to 22%, and the percentage of NGS results reported after death declined from 5.2 to 2.7%. Baseline characteristics (including race-ethnicity, insurance plan, practice type [academic vs. community]) in these categories will be presented at the meeting. Conclusions: Our findings suggest that a sizeable number of pts with aUC (∼ 32%) received their first NGS testing results towards the end of life, highlighting the need to integrate genomic testing earlier during the course of the disease to optimize benefit with targeted therapies. These results could inform clinical practice and therapeutic decisions in the clinic. CHC, YJ: Equal contribution; US, NA: Senior authors.

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)

104 Background: Androgen deprivation therapy (ADT) intensification [ADT + androgen receptor-pathway inhibitor (ARPIs) +/- docetaxel] has been shown to improve survival outcomes in pts with mHSPC and is recommended as standard of care by all major guidelines. However, prior studies have shown underutilization of ADT intensification [PMID: 39191549]. There are limited updated and large-scale studies on the use of ADT intensification, beyond January 2023. In this study, we aimed to assess the treatment patterns of ADT intensification in real-world pts with mHSPC in the US, including data on those treated since January 2023. Methods: This retrospective study utilized the nationwide Flatiron Health Electronic Health Record (EHR) derived de-identified database. Eligibility: Pts diagnosed with mHSPC and availability of treatment information (ADT and/or line of therapy in mHSPC). The data cut-off date was 5/31/2024. Treatment patterns were summarized using frequency and percentages. All analysis was done using R version 4.2.3. Results: Among 24,105 pts with metastatic prostate cancer in the database, a total of 14,084 were eligible and included. The median age at metastatic diagnosis was 72 years (IQR 65 – 79), and 60% were White non-Hispanic. In the overall cohort (1/1/2013–5/15/2024), 56.8% received ADT monotherapy, and 37.7% received ADT intensification. Table summarizes the treatment patterns by year, highlightinga consistent increase in adoption of intensified ADT regimens, and a decline in use of ADT monotherapy. Notably, since January 2023, 76.8% pts with mHSPC received ADT intensification while only 17.3% of pts received ADT monotherapy. Conclusions: To our knowledge, this is the first and largest study to evaluate the current use of ADT intensification. These data indicate a notable improvement in the adoption of level 1 evidence (ADT intensification) in the treatment of pts with mHSPC. These encouraging data emphasize the benefits of continued efforts to promote guideline-concordant care and provide the current treatment landscape to design clinical trials. Treatment patterns by year in pts with mHSPC. Treatment 2013–2017n = 5,263(%) 2018n = 1,313 (%) 2019n = 1,407(%) 2020n = 1,353(%) 2021n = 1,483(%) 2022n = 1,556(%) 2023n = 1,459(%) 2024n = 250(%) ADT monotherapy 4,095 (77.8) 856 (65.2) 819 (58.2) 664 (49) 698 (47.1) 569 (36.6) 291 (20) 5 (2) ADT + ARPI 155 (2.9) 238 (18) 354 (25.1) 452 (33) 555 (37.4) 695 (44.7) 842 (58) 154 (61.6) ADT + Docetaxel 709 (13.5) 156 (12) 175 (12.4) 156 (12) 134 (9.0) 117 (7.5) 78 (5.3) 19 (7.6) Triplet(ADT + ARPI + Docetaxel) 6 (0.1) 2 (0.2) 1 (0.1) 2 (0.1) 9 (0.6) 82 (5.2) 166 (11.1) 53 (21.2) Other therapies 298 (5.7) 61 (4.6) 58 (4.1) 79 (5.8) 87 (5.9) 93 (6) 82 (5.6) 19 (7.6)

The NCCN Guidelines for Older Adult Oncology address specific issues related to the management of cancer in older adults, including screening and comprehensive geriatric assessment (CGA), assessing the risks and benefits of treatment, preventing or decreasing complications from therapy, and managing patients deemed to be at high risk for treatment-related toxicity. CGA is a multidisciplinary, in-depth evaluation that assesses the objective health of the older adult while evaluating multiple domains, which may affect cancer prognosis and treatment choices. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines providing specific practical framework for the use of CGA when evaluating older adults with cancer.

Objectives To evaluate outcomes of patients achieving a post‐treatment pathological stage of <ypT2N0 at radical cystectomy (RC) following neoadjuvant chemotherapy (NAC) for muscle‐invasive bladder cancer (MIBC) to identify an optimal definition of pathological response. Patients and Methods Patients from 10 international centres who underwent NAC for cT2–4aN0–1 MIBC and achieved <ypT2N0 disease at RC were included. The primary outcome was time to recurrence, either local or distant. Kaplan–Meier and Cox proportional hazards regression were used to evaluate associations between clinicopathological variables and outcomes. Results A total of 625 patients were included. The median age was 66 years and 80% were male. Gemcitabine and cisplatin (GC, 56%) and methotrexate, vinblastine, doxorubicin and cisplatin (MVAC)/dose‐dense (dd)MVAC (32%) were the most common NAC regimens. ypT0, pure ypTis, ypTa ±ypTis and ypT1 ± ypTis were attained in 58.1%, 20.0%, 7.6% and 14.2% of patients, respectively. The cumulative incidence of recurrence at 5 years was 9%, 16%, 29% and 30%, respectively. Pathological stage was prognostic for recurrence, with ypTa ± Tis (hazard ratio [HR] 3.20, 95% confidence interval [CI] 1.40–7.30) and ypT1 ± Tis disease (HR 4.03, 95% CI 2.13–7.63) associated with a significantly higher recurrence risk. Pure ypTis (HR 1.66, 95% CI 0.82–3.38) and the type of NAC regimen (ddMVAC: HR 1.59, 95% CI 0.55–4.56; MVAC: HR 1.18, 9%% CI 0.25–5.54; reference: GC) were not associated with recurrence. Conclusion We propose that optimal pathological response after NAC be defined as attainment of ypT0N0/ypTisN0 at RC. Patients with ypTaN0 or ypT1N0 disease (with or without Tis) at RC displayed a significantly higher risk of recurrence and may be candidates for trials investigating adjuvant therapy.

5043 Background: Pathologic complete response (pCR) after NAC for MIBC is strongly correlated with long-term overall survival. However, there are sparse data on the risk of recurrence based on depth of pathologic response (pT0, pTa, pTis, pT1), and the differential impact of clinicopathologic factors and NAC regimen on recurrence. Methods: Baseline data on all pts with cT2-4N0-1 MIBC receiving NAC and who achieved < ypT2N0 disease at radical cystectomy (RC) from 9 international centers were obtained. The key outcome was time to recurrence (TTR) – defined as the time to any recurrence in the urinary tract or regional/distant metastasis, with death (in the absence of recurrence) considered a competing risk. Cox regression analysis was used to analyze the impact of clinical factors on recurrence. Results: A total of 506 pts were available. Median age was 66 years (range 33-86) and 78% (n = 396) were male; median follow-up after RC was 2.6 years. The majority of patients had pure urothelial histology (n = 371, 73%), and baseline stage was cT2N0 (n = 368, 73%), cT3-4N0 (n = 95, 19%) and TanyN1 (n = 43, 9%). NAC regimens were gemcitabine-cisplatin (GC, n = 296, 59%), dose-dense methotrexate-vinblastine-doxorubicin-cisplatin (ddMVAC, n = 141, 28%), split-dose GC (n = 29, 6%), MVAC (n = 29, 6%) and non-cisplatin based regimens (n = 11, 2%). At RC, 304 patients (60%) had ypT0N0 disease, 32 (6%) had ypTaN0, 107 (21%) had ypTisN0 and 63 (13%) had ypT1N0. Overall, 43 patients (8%) recurred with a median TTR of 56 weeks (range 7-251); 5-year freedom from recurrence was 87% (95% CI 83-91). The majority (n = 38) recurred outside the urinary tract. On multivariable analysis, ypTa (HR = 3.36 [1.24-9.11]) and ypT1 (HR = 2.88 [1.33-6.22], p = 0.013) disease at RC were predictors of shorter TTR, while female sex was associated with longer TTR (HR = 0.52 [0.27-0.98], p = 0.043). The type of NAC was not predictive of TTR (GC vs. other, HR = 1.49 [0.75-2.97], p = 0.26). Conclusions: To our knowledge, this is the largest study to quantify the risk of recurrence in pts achieving pathologic response after NAC and RC for MIBC. 8% of patients undergoing NAC and achieving < ypT2N0 at RC recurred. Residual ypTa and ypT1 disease conferred a significantly higher risk of recurrence, while ypTis did not; female sex was associated with a lower risk of recurrence. Importantly, the type of cisplatin-based NAC regimen used was not an independent predictor of recurrence.

Abstract Background: This is an update of the safety and efficacy of durvalumab monotherapy in pts with locally advanced/metastatic urothelial carcinoma (UC) from an ongoing, phase 1/2 open-label study (NCT01693562). Methods: Pts received 10 mg/kg every 2 weeks up to 12 months or until unacceptable toxicity, progression, or starting another anticancer therapy. Pts were stratified by tumor PD-L1 expression (Ventana PD-L1 [SP263] Assay [PD-L1 cutoff: ≥25% of tumor cells and/or immune cells with membrane staining]) and treatment line. Results: As of the data cutoff (16Oct2017), 201 UC pts with Stage IV disease received treatment, with a median follow-up of 16.9 months (range, 0.4-37.7). Across treatment lines, objective response rate (ORR) by blinded independent central review was 17.4% (95% CI, 12.4, 23.4) in all pts; 27.5% in the PD-L1 ≥25% group vs 5.8% in the PD-L1 &lt;25% group. The responses have been durable regardless of PD-L1 status, with the median duration of response not yet reached in the PD-L1 ≥25% group and 12.2 months in the PD-L1 &lt;25% group. Responses lasted ≥12 mo in 62.9% of responders (max 25.7+ mo). Overall, median OS was 10.5 months (95% CI, 6.9, 15.7); 19.8 months in the PD-L1 ≥25% group vs 4.8 months in the PD-L1 &lt;25% group (Table). Pts previously treated with platinum based chemotherapy also reported similar durable responses. At least one treatment-related AE was reported in 120 pts (59.7%), including fatigue (39 [19.4%]), decreased appetite and rash (18 [9.0%] each), and diarrhea (16 [8.0%]). Grade 3/4 treatment-related AEs occurred in 19 (9.5%) pts; 6 (3.0%) treatment discontinuations and 2 (1.0%) deaths were attributed to treatment-related AEs. Conclusions: With extended follow-up, durvalumab continues to show durable clinical activity in UC pts, especially in the PD-L1 ≥25% group with an acceptable toxicity profile. PD-L1 ≥25%PD-L1 &lt;25%PD-L1 unknownTotalAll UCn=102n=86n=13N=201Confirmed ORR, %27.55.815.417.4(95% CI)(19.1, 37.2)(1.9, 13.0)(1.9, 45.4)(12.4, 23.4)CR, %7.83.57.76.0PR, %19.62.37.711.4Median DoR, monthsNR12.2NRNR(min, max)(2.7, 25.7+)(8.6, 21.7+)(14.5+, 14.6+)(2.7, 25.7+)Median PFS, months (95% CI)1.9 (1.4, 2.7)1.4 (1.3, 1.5)2.8 (1.4, NE)1.5 (1.4, 1.8)6-month PFS rate, %28.68.625.220.412-month PFS rate, %22.37.125.216.2Median OS, months (95% CI)19.8 (9.3, NE)19.8 (9.3, NE)4.8 (3.3, 8.1)NR (4.9, NE)10.5 (6.9, 15.7)6-month OS rate, %67.645.869.258.912-month OS rate, %57.629.561.546.6 Citation Format: Peter O'Donnell, Christophe Massard, Bhumsuk Keam, Sang-We Kim, Terry Friedlander, Myung-Ju Ahn, Michael Ong, Michael Gordon, Marcus Butler, Scott Antonia, Gerardo Colon-Otero, Martin Gutierrez, Sumati Gupta, Alexander Spira, Alexandra Drakaki, Michele Maio, Feng Xiao, Natasha Angra, Shaad Abdullah, Thomas Powles. Updated efficacy and safety profile of durvalumab monotherapy in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT031.