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478 Background: Erdafitinib is FDA-approved for patients (pts) with advanced urothelial carcinoma (aUC) with FGFR2/3 mutation or fusion and progression after platinum-based chemotherapy. It is postulated that FGFR3-altered aUC may be a “cold tumor” and associated with non-T cell-inflamed phenotype and, thus, may be less responsive to ICI. We hypothesized that pts with aUC that harbor FGFR2/3 alterations would have lower response and shorter survival on ICI. Methods: We performed a retrospective cohort study of pts with aUC treated with ICI and available genomic data in 11 institutions; pts with pure non-UC, treated with combinations or on clinical trial were excluded. Outcomes (overall response rate [ORR], progression free survival [PFS] and overall survival [OS] were compared in pts with and without FGFR2/3 alterations. PFS and OS was compared using Cox proportional hazards. All analyses were performed in the overall population and also categorized by treatment line (1st line [1L] vs salvage [2+L]). Multivariable models were adjusted for an internally developed risk score for 1L and Bellmunt risk score for 2+L; p

263 Background: Prostate cancer (PCa) is characterized by considerable genetic heterogeneity, and complex genomic features may influence prognosis and treatment response. We created a database of aggressive PCa that integrates comprehensive genomic sequencing with detailed clinical outcomes to better understand the optimal use of genomic sequencing. Methods: From 4/2005-7/2021, PCa cancer patients older than 18 years of age underwent tissue collection for tumoral RNA-sequencing and tumor/normal whole exome sequencing at our institution (HUM00046018, HUM00048105, HUM00067928, SU2C). Genomic and transcriptomic sequencing data was processed using Turnkey Precision Oncology. Genetic alterations, including ETS fusions, SPOP, FOXA1 class 1, and CDK12 mutations, as well as TP53 and RB1 mutations were analyzed. Clinical data was collected from 05/2021-01/2022, and clinical associations (metastasis free survival (MFS), time to castrate resistant prostate cancer (CRPC), and overall survival (OS)) were determined. Results: Data was available for 325 men. Median follow up from diagnosis was 106 months (IQR, 90-121), median age at diagnosis was 61 (IQR, 54-67), and most (91%) presented with PCa adenocarcinoma (n=292/325). At diagnosis, 51% (n=165) had localized, 5% (n=18) had clinical node positive, and 40% (n=128) had de-novo M1 disease. At time of tissue sampling, 87% (n=283) had metastatic disease, and 59% (n=192) were castrate resistant. Established PCa driver mutations included 140 ETS fusions (49%), 26 SPOP mutations (9%), 22 FOXA1 class 1 mutations (8%), and 15 (5%) CDK12 mutations. For men with localized disease at diagnosis (n=197/325), ETS fusion was associated with improved MFS (HR: 0.55; 95% CI: 0.37-0.81), time to CRPC (HR: 0.53; 0.35-0.80), and OS (HR: 0.56; 0.35-0.89). SPOP mutations were also associated with improved prognosis in this population (n=197/325): MFS (HR: 0.45; 0.24-0.84), time to CRPC (HR: 0.36; 0.18-0.73), and OS (HR: 0.46; 0.21-0.99). TP53 mutations were identified in 38% (n=122) of all patients and were associated with worse OS from the time of biopsy after adjusting for PCa castration state and disease spread at biopsy (HR: 2.2; 1.7-2.9, p

696 Background: Hypomethylating agents (HMA) can augment the anti-tumor immune response. Guadecitabine (G) is a novel HMA shown to induce a dose-dependent decrease of global DNA and gene-specific methylation in pre-clinical models. Methods: This is phase Ib/II clinical trial of Guadecitabine (G) and Durvalumab (D) in advanced ccRCC. Phase Ib tested two doses of G, de-escalated from 60 mg/m2 to 45 mg/m2 in combination with standard dose of D. Followed by two cohorts in phase II. Cohort 1 (C1, CPI naïve) allowed up to one prior line of treatment and Cohort 2 (C2, CPI refractory) enrolled patients with up to two prior systemic therapies including at least one CPI. Primary endpoint in phase 1b was safety, primary endpoint in phase II was overall response rate (ORR) and secondary endpoint of progression free survival (PFS) and overall survival (OS) and biomarkers evaluation. Results: Fifty-seven patients were enrolled, 42 were in C1 and 15 in C2. One dose limiting toxicity (DLT) of grade 3 neutropenia was noted with G 60 mg/m2. The combination of G 45 mg/m2 on days 1-5 along with D at 1500 mg on day 8, was deemed safe and the recommended phase II dose. Asymptomatic neutropenia was the most common adverse event (AE). Other AEs included thyroid dysfunction, diarrhea, pneumonitis, myalgia, and hepatotoxicity. No treatment-related deaths were reported. The ORR for C1 and C2 were 26% and 7% respectively. The median PFS for C1 and C2 were 18.4 and 3.9 months respectively. Median OS was not reached. Flow cytometry on peripheral blood (PB) collected before treatment demonstrated myeloid-derived suppressor cells (MDSC) to be inversely associated with response, showing the highest levels in progressive disease (PD) and the lowest in partial response (PR). Responders to treatment had the highest expression of IFN γ, IL-17 and RORyt in CD8+ T cells and lower Foxp3 expression in CD4+ T cells compared to non-responders. We observed a significant increase in serum CXCL9/CXCL10 with the study combination (p 0.00003 and p 0.000005 respectively) and this increase correlated with better clinical outcome. Conclusions: The combination of D and G has an acceptable toxicity profile and promising efficacy mainly PFS in CPI naïve ccRCC patients, that is worth further investigation in larger randomized clinical trial. Clinical trial information: NCT03308396 .

229 Background: Aberrant Wnt signaling has been implicated in prostate cancer tumorigenesis, progression, and metastasis in preclinical models. While studies have identified recurrent molecular alterations in the Wnt signaling components in about 20% of aPC pts, the clinical significance of these alterations has been incompletely characterized. Methods: PROMISE is a multi-institutional, retrospective, clinical-genomic database - inclusive of aPC pts who had tissue and/or blood-based genomic testing by commercially available CLIA-certified platforms. We evaluated outcomes in pts with alterations leading to the activation of the canonical Wnt pathway, specifically activating mutations in CTNNB1 or RSPO2 or inactivating mutations in APC, RNF43, or ZNRF3 (Wnt altered), compared to those lacking such alterations (Wnt wild type). Multiple endpoints were evaluated, including the frequency of metastatic disease to different sites and co-occurring alterations. Results: 1596 pts with aPC were included with a median age of 63 years at diagnosis. Wnt pathway alterations were identified in 12.4% (198/1596). Wnt altered pts had a statistically significant increase in liver and lung metastases compared with Wnt wild type pts at diagnosis (4.5% vs 2.1%, p=0.0438; 6.1% vs 2.9%, p=0.0292), at first metastatic disease (11.6% vs 5.4%, p= 0.0015; 14.8% vs 6.6%, p

TPS739 Background: The landscape for treatment of metastatic renal cell carcinoma (mRCC) has changed dramatically over the past 7 years with the approvals of tyrosine kinase inhibitors and immune-oncology (IO) agents alone or in combination for untreated mRCC. However, multiple knowledge gaps remain. While active surveillance remains an option for selected pts, prospective evidence on selection of and outcomes for pts is limited. Recent phase III trials all used a common comparator, sunitinib, so no comparative effectiveness data on the new IO-based regimens exists. There are also no routinely used predictive biomarkers in mRCC pt management. Therefore, a better understanding of the biologic determinants associated with cancer heterogeneity and clinical outcomes through blood, tumor, and radiographic based assessments is needed. Importantly, longitudinal changes in health-related quality of life (QOL) and symptom burden of patients with mRCC initiated on new IO–based regimens outside of an interventional clinical trial are poorly understood. Pt reported outcomes (PRO) are rarely captured in a systematic manner. Addressing the evidence gap for how real world pts symptomatically change with treatment combinations and sequences over time is a pressing unmet need. Methods: This is a prospective, observational cohort, phase IV study of 800 mRCC pts in the US. Pts must: be age ≥19 at informed consent; have a diagnosis of mRCC (any histology) with no prior systemic therapy for mRCC (surgery and radiation therapy, prior neoadjuvant/adjuvant therapy for non-mRCC, and pts currently not on systemic therapy and being observed are all permitted); and be able to comply with completion of PROs. Those being treated for active malignancies other than mRCC or not intending to undergo follow up care at a study site within PCORnet are excluded. Pts will undergo consent and baseline assessments, including research blood collection and processing, by the study site team. A novel aspect of this study is the use of PCORnet and Medicare data to minimize data collection burden on sites. PCORnet, the National Patient-Centered Clinical Research Network, is a network of networks that curates EHR data from multiple health systems using a common data model. This allows subsequent follow up to be centrally coordinated by the coordinating center. PRO will be collected at baseline (pre-treatment), every 3 mos for 2 yrs, and then every 6 mos until end of follow up (minimum 18 mos follow-up; maximum 36 mos follow-up). The primary objective is to determine distinct patterns of change in QOL and symptom burden of mRCC pts receiving therapy. Secondary objectives include quantifying the time to treatment discontinuation of pts, identifying patterns of clinical management in the real world setting of mRCC pts on various treatment regimens, and evaluating overall survival of mRCC pts. ClinicalTrials.gov Identifier: NCT04919122 Clinical trial information: NCT04919122 .

717 Background: There is an unmet need for biomarkers enabling therapeutic selection and prediction of clinical outcomes in kidney cancer . We evaluated the feasibility and utility of profiling of circulating tumor cells (CTCs) via multiplexed fluorescence immunocytochemistry (ICC) to identify liquid biopsy biomarkers linked to treatment response (or resistance) in advanced RCC patients. In addition, transcriptome analysis for 20802 genes from exosomal RNA is planned to evaluate novel prognostic and predictive signatures. Methods: Patients with either untreated or pretreated advanced RCC were eligible prior to starting a new systemic therapy regimen. IRB approved written informed consent was obtained. Serial blood samples were collected at baseline, and at 3, 6, 12 and 24 months. Primary endpoint of the study was to detect the proportion of patients with RCC in whom CTCs can be detected and profiled. Secondary endpoints are to correlate the profiling and changes in CTC with response and clinical outcomes. The study will meet its primary endpoint if the assay provides adequate detection and profiling for at least 12 patients. With an overall sample size of 50 the width of a 95% confidence interval for the rate of providing a therapeutic intervention is guaranteed to be less than 26%. Results: 44 evaluable patients have been enrolled; 11 females, 33 males. Median age was 64 years (range 40-85 years). 38 white patients, 2 black patients and 4 of other ethnicity have been enrolled.16 patients were untreated, 22 were pretreated and 6 were undergoing adjuvant therapy post nephrectomy. 37 patients had clear cell histology, 4 non clear cell and 3 unclassified histology. 42 of the 44 (95.5%) patients had detectable CTCs in the baseline sample. 21 on treatment samples have been collected to date, with detectable CTCs in all except one sample. 53 of 65 samples (81.5%) demonstrated detection of at least one biomarker by ICC. VEGFA expression was the most commonly detected biomarker on ICC (detected in 28 of 63 samples). Conclusions: The primary endpoint was met, and feasibility of the test was demonstrated with 95% of the baseline samples showing CTC detection and 81.5% showing biomarker expression. This blood-based, non-invasive liquid biopsy demonstrated high sensitivity for detection of cancer cells, and presents a potential opportunity for biomarker profiling to predict therapeutic efficacy of conventional RCC therapeutic agents. Correlation of longitudinal CTC with clinical outcomes will be reported. Transcriptome analysis is under evaluation for novel prognostic and predictive signatures and will be reported.

514 Background: EV is FDA-approved in pts with aUC and ≥1 prior therapy line. Data from EV-103 trial indicate robust response to first-line EV/pembrolizumab, suggesting potentially at least additive treatment effect with EV/ICI combination. Given the long half-life of ICIs, pts who start EV treatment immediately after ICI may potentially derive benefit from that therapy sequence. We hypothesized that the last systemic therapy prior to EV would impact outcomes, as pts treated with ICI immediately prior to EV would have superior outcomes relative to pts treated with chemotherapy (chemo). Methods: UNITE is a retrospective study of pts treated with EV at 16 US sites. Pt characteristics and outcomes were abstracted from EMR review at each site. Observed response was determined by investigators for evaluable pts with scans following ≥1 EV dose. Pts treated with EV monotherapy were divided into two groups based on whether they received chemo or ICI as the line of therapy immediately prior to EV, regardless of other therapy received. Chi-squared test was used to assess differences in pt characteristics and ORR while log-rank tests were used for OS and PFS measured from EV start. Results: Among 325 pts treated with EV monotherapy, 247 had chemo or ICI as immediate prior treatment, with 186 pts receiving ICI (Group A) and 61 pts receiving platinum-based chemo (Group B). In 247-pt cohort, ORR to EV was 52% and mPFS and mOS were 6 and 13 mos. Group B pts were younger, had more bone mets and higher Bellmunt risk factors, but were otherwise similar to Group A (Table). Most pts had both prior chemo and ICI in both group A (58%) and group B (84%). Group A pts had shorter time from last treatment (median 1.2 vs 3.2 mo, p

450 Background: EV, an antibody-drug conjugate (ADC) targeting Nectin-4, is used widely in treatment-refractory aUC, but limited data are available on biomarkers predictive of EV outcomes. We investigated potential biomarkers of response to EV in a pt cohort in the UNITE dataset. Methods: We included the retrospective UNITE study pts from 16 sites, with available next generation sequencing using institutional or commercial platforms, treated with EV alone outside clinical trials. Observed response (ORR) was determined by investigators for evaluable pts with scans after ≥1 dose of EV. Assessed molecular biomarkers included tumor mutation burden (TMB), PD-L1 status, somatic alterations (alts) in ≥ 10% of pts ( TERTp, TP53, ARID1A, CDKN2A, CDKN2B, FGFR3, ERBB2, CCND1, KDM6A, MTAP, PIK3CA, RB1, TSC1) and presence of ≥1 DNA damage response mutations ( ATM, BARD1, BRCA1, BRCA2, CDK12, CHEK2, PALB2, PPP2R2A, or RAD51B). ORRs were compared using Chi-squared test, while median progression-free and overall survival (mPFS, mOS) from EV start were compared with log-rank test and Cox proportional hazards in pts with and without biomarker presence. Results: A total of 170 pts had outcomes and NGS data available. Median age was 70, 133 (78%) were men, 144 (85%) Caucasian, 110 (65%) with pure urothelial histology, 118 (69%) with primary bladder tumor, and 116 (68%) had ≥ 2 lines of therapy before EV. For all pts, ORR 47%, mPFS 6 mos, mOS 12 mos. ORRs were higher in pts with ERBB2 (67% vs 44%; p = 0.05) and TSC1 (68% vs 25%; p=0.04) alts vs wild-type. Shorter mPFS was noted in pts with CDKN2A, CDKN2B, and MTAP alts, and longer mOS in pts with high TMB (table). Conclusions: This large, multi-site, retrospective cohort of pts with aUC identified several potential biomarkers associated with differential outcomes to EV. These findings, upon external validation, may help inform clinical decision making and potential therapy sequencing with available ADCs. Limitations include retrospective nature, pt selection, and confounding biases. [Table: see text]

LBA4500 Background: Patients (pts) who undergo resection of renal cell carcinoma (RCC) with curative intent remain at risk for disease relapse. We conducted a phase III, double-blind, placebo (PB)-controlled, intergroup study to determine the effect of adjuvant treatment with the mTOR inhibitor everolimus (EVE) on recurrence-free survival (RFS). Methods: Pts with treatment-naïve, non-metastatic, fully-resected RCC at intermediate high- (pT1 G3-4 N0 to pT3a G1-2 N0) or very high-risk (pT3a G3-4 to pT4 G-any or N+) for recurrence were randomized 1:1 to EVE 10 mg PO daily x 54 weeks or PB within 12 weeks of radical or partial nephrectomy. Randomization was stratified by risk group, histology (clear vs. non-clear cell), and performance status (0 vs. 1). RFS was the primary end point; secondary endpoints included overall survival (OS) and adverse events (AEs). The study was designed to detect an 18% reduction in the risk of RFS with EVE compared to PB, corresponding to an improvement of median RFS from 6.75 (based on E2805 ASSURE) to 8.23 years. Final analysis, using a stratified logrank test, was to occur after 804 total events or by 3/2022, whichever occurred first. Results: Between 4/2011 and 9/2016, 1545 pts were randomized to EVE (n = 775) or PB (n = 770). Overall pt characteristics included: intermediate high-/very high-risk 45%/55%; clear cell/non-clear cell 83%/17%. The DSMC recommended study continuation after each of 4 pre-specified interim analyses. 556 DFS events among 1499 eligible pts occurred by the time of final study analysis on 2/23/2022. The median follow-up was 76 months. RFS was improved with EVE vs. PB (HR 0.85, 95% CI, 0.72 – 1.00; P1-sided= 0.0246), narrowly missing the pre-specified, one-sided significance level of 0.022 which accounted for interim analyses. Median RFS was not reached; the 6-year RFS estimate was 64% for EVE and 61% for PB. RFS improvement with EVE vs. PB was observed in the very high-risk group (HR 0.79, 95% 0.65-0.97; P1-sided= 0.011) but not in the intermediate high-risk group (HR 0.99, 95% CI 0.73-1.35, P1-sided= 0.48) ( P for interaction = 0.22). With 290 deaths, OS was similar between arms (HR 0.90, 95% CI, 0.71 – 1.13; P1-sided= 0.178). Fewer pts completed all 54 weeks of study treatment in the EVE group (45% v 69%). In the EVE group, 37% withdrew due to AEs (vs 5% in PB). Grade 3-4 AEs occurred in 46% of pts treated with EVE and 11% with PB. The most common grade 3-4 AEs were mucositis (14% v 0%), hypertriglyceridemia (11% vs. 2%), and hyperglycemia (5% vs. 0%). Conclusions: Adjuvant EVE improved RFS in RCC pts after nephrectomy, but the nominal significance level was narrowly missed. The RFS improvement was seen despite a high rate of early treatment discontinuation. A 21% improvement in RFS with EVE was observed in pts with very high-risk disease, a group for whom adjuvant therapy may be most relevant. Clinical trial information: NCT01120249.

TPS5113 Background: Molecular imaging (i.e. PSMA directed agents) identifies metastatic prostate cancer at an earlier disease state than conventional imaging resulting in a new clinical entity within metastatic hormone-sensitive prostate cancer (mHSPC): molecular positive HSPC (mpHSPC). Historically, patients in this category with prior local therapy would have been classified as having a biochemical recurrence only, and observation was routine. Approaches to mpHSPC include observation or the use of focal and/or systemic therapies. Focal radiation for mpHSPC may delay the need for systemic therapy, yet many patients require further focal or systemic treatment. Androgen deprivation therapy (ADT) with abiraterone (abi) benefits men with high-risk localized disease and standard mHSPC. mpHSPC hypothetically resides somewhere between these two disease states. Finally, the inhibition of poly(ADP-ribose) polymerase (PARP) with olaparib plus abi shows promise in metastatic castration resistant prostate, suggesting this approach may be worthy of testing in earlier disease states. Methods: FAALCON is a single-site, phase 2 clinical trial testing olaparib with abi, ADT and radiation therapy in oligometastatic mpHSPC. Oligometastatic mpHSPC is defined as up to 5 radiation treatment sites (5 cm maximum size each) and must encompass all visible disease on the molecular scan. Patients must have had their prostate previously treated. The primary endpoint is the percentage of patients without treatment failure 24 months from study start. Treatment failure is defined as one of the following: new or progressive metastases on CT/MRI, new lesions on bone scan without alternate explanation, clinical progression, or a PSA doubling time under 6 months with an absolute final PSA over 1.5 ng/mL. Additional radiation therapy is deemed progression. Select secondary endpoints include time to any subsequent therapy, and percentage of patients with undetectable PSA with a recovered testosterone at multiple timepoints. Correlative work will analyze quality of life and prior prostatic tissue. ADT and abi (1000 mg daily) are given for 6 months, and radiation is completed by day 40. Olaparib (300 mg PO twice daily) is started 2 weeks after radiation completes and continues for the remaining ̃5 months. After therapy completion, patients are monitored by PSA q3 months with imaging based on predetermined PSA cutoffs. Molecular imaging (PSMA-PET) may be offered on study. Historical disease control at 24 months is estimated at 40% from prior molecular guided radiation studies and intermittent ADT. With 80% power and a one-sided 5% type-I error, we can detect a hazard ratio of 0.5 (80% control rate) at 24 months with 26 patients. To account for dropout, 29 patients will be accrued. Clinical trial information: NCT04748042.

4545 Background: Despite recent advances in the treatment of clear cell RCC, there is a paucity of data to guide management of nccRCC due to the heterogeneity and rarity of these tumors. The clinical activity of combination therapies (including IO-IO, IO-VEGF, VEGF-mTOR) in subtypes of advanced nccRCC is unknown. Methods: In this multicenter retrospective analysis, we evaluated the efficacy of combination systemic therapies in patients with nccRCC. Eligible patients included those with nccRCC as determined by local genitourinary pathology review and receipt of one of three combination regimens during any line treatment (IO-IO, IO-VEGF, mTOR-VEGF). The primary endpoint was objective response rate (ORR) assessed by investigator review. Secondary endpoints were progression- free survival (PFS), disease control rate (DCR), and overall survival (OS). Results: Among 128 included patients, median age was 57 years; 66% were male and 65% white. Histologies included papillary (37%), unclassified (33%), chromophobe (16%), translocation (9%), and other (5 %). Among all patients, 69% had prior nephrectomy; 80% were IMDC intermediate/poor risk; 20% had sarcomatoid and/or rhabdoid differentiation, 27% and 29% had liver and bone metastasis respectively and 63% received combination treatment as first line. Comparison of outcomes based on treatment regimen, line of treatment and subtype is shown in the table. Median PFS and OS were longer with IO/IO and IO/VEGF compared to VEGF/ mTOR at 8.5, 9.5 and 3.7 months and 24.4, 18.2 and 15.4 months respectively. Conclusions: Antitumor activity was observed with novel combinations in nccRCC in both frontline and later line setting. Optimal management of nccRCC remains an unmet need and prospective data is warranted to guide treatment selection for this population. [Table: see text]

5013 Background: Black men have been underrepresented in large-scale molecular prostate cancer (PC) surveys, despite having higher PC incidence and mortality. Since molecular profiling to guide the use of targeted agents is increasingly important in mCRPC, we compared precision medicine data and utilization in a cohort of black and white men with mCRPC. Methods: The PROMISE precision medicine database is an academic collaboration to compile clinical and genomic data from men with PC. All patients have had germline and/or somatic genetic testing performed. Eligibility criteria for this analysis included a diagnosis of mCRPC with available race and biomarker data. The primary outcome was the proportion of non-Hispanic black (NHB) and non-Hispanic white (NHW) men with actionable molecular data, defined as the presence of mismatch repair deficiency (MMRd/MSI-H), homologous recombination repair deficiency (HRRd), tumor mutational burden (TMB) ≥ 10 mut/MB, or AR-V7. Secondary outcomes included the proportion of NHB and NHW men with other alterations, the type and timing of genomic testing performed, and the use of targeted therapy. Results: A total of 962 mCRPC patients (21.2% NHB; 78.8% NHW) met inclusion criteria of 1619 in the overall database. Median age (NHB/NHW) was 61/63; 77.5/68.8% had Gleason 8-10; 52.5/56.7% presented with de novo metastatic disease (33.8/29.9% LN, 36.2/32.2% bone and 8.3/6.1% viscera). The median time from diagnosis to first molecular result was 56.3 mo for NHB v 58.7 mo for NHW (p = 0.45). Use of blood-based molecular testing was more common in NHB men (48.7% v 36.4%, p < 0.001). Overall, 32.8% of NHB men harbored actionable molecular data compared to 30.3% of NHW men (Table). MMRd/MSI-H was more common in NHB men (9.1 v 4.9%, p = 0.04). Other than PTEN (12.7/23.8% NHB/NHW, p = 0.0001), no significant differences were seen in the 15 most frequently mutated genes, including TP53, AR, CDK12, RB1, and PIK3CA. Tumor suppressor co-mutations (PTEN/TP53/RB1) were found in 13.1% of NHB and 18.0% NHW (p = 0.13). Delivery of targeted therapy was reported in 19.6% of NHB and 23.7% of NHW men (p = 0.25) after a median of 2 CRPC lines. Median OS from development of mCRPC was 41.5 mo (95% CI, 34.7-51.3) and 44.7 mo (95% CI, 41.1-51.5) for NHB and NHW men, respectively (p = 0.14). Conclusions: In a real-world mCRPC molecular profiling cohort, we found similar overall rates of actionable molecular alterations in NHB and NHW men, but higher rates of MMRd/MSI-H and lower frequency of PTEN alterations in NHB men. We did not find differences in delivery of targeted therapy. [Table: see text]

5024 Background: The OSPREY clinical trial was a phase 2/3 prospective study of prostate specific membrane antigen (PSMA) PET/CT using piflufolastat F 18. Piflufolastat F 18 (aka 18F-DCFPyL or PyL) is a novel PSMA-targeting radiopharmaceutical approved for imaging of PCa pts both at initial staging and for disease recurrence. Here we describe SUV results by biopsy status, baseline PSA levels, and Gleason score (GS). Methods: Piflufolastat F 18-PET/CT was evaluated in men with NCCN high-risk PCa scheduled to undergo radical prostatectomy with pelvic lymphadenectomy (RP-PLND) (Cohort A) and men with radiologically suspected recurrent/metastatic PCa (Cohort B). A single IV dose of 9 mCi (333 MBq) of piflufolastat F 18 was administered followed by PET/CT acquisition 1-2 hours later. Piflufolastat F 18 uptake in various lesion locations as defined by maximum and peak SUV (SUVmax, SUVpeak) were determined by three blinded, independent central readers for each tissue (e.g., bone, lymph nodes (LN), soft tissue). To measure SUVs, the reader placed a volume of interest (VOI) on each identified lesion. SUVmax was defined as the maximum single-voxel SUV within the VOI. SUVpeak within the VOI was defined as the average SUV within a fixed-sized VOI (1 cm diameter sphere), representing the cluster with the highest average SUV. Results: 345 men underwent piflufolastat F 18-PET/CT. Cohort B (n = 93evaluable) SUVmax and SUVpeak were significantly higher for biopsy positive (+)(one biopsy lesion/pt) when compared to biopsy negative (-) lesions from bone and LN. SUVpeak for biopsied bone and LN (Cohort B) appeared to increase with rising baseline PSA. In high-risk PCa pts, SUVpeak for prostate (Cohort A; n = 252 evaluable) increased with baseline PSA and were highest for GS 9-10 (Table). Conclusions: Piflufolastat F 18-PET/CT uptake was significantly higher in biopsy + lesions and increased with baseline PSA. Prostate SUVpeak was highest for GS 9-10. Clinical trial information: NCT02981368. [Table: see text]

519 Background: Pembro is a 1L treatment for cisplatin-ineligible pts with UC. This post hoc landmark analysis evaluated clinical outcomes by response at 9 wk to 1L pembro monotherapy in pts with advanced/unresectable or metastatic UC from the single-arm phase 2 KEYNOTE-052 (NCT02335424) and the randomized phase 3 KEYNOTE-361 (NCT02853305) trials. Methods: Cisplatin-ineligible pts with advanced UC were enrolled in KEYNOTE-052 and received pembro (200 mg Q3W for ≤2 y). Platinum-eligible pts with advanced UC who had not previously received systemic chemotherapy (chemo) were enrolled in KEYNOTE-361 and randomly assigned 1:1:1 to receive pembro (200 mg Q3W for ≤2 y), pembro + chemo (1000 mg/m2 gemcitabine on d1 and d8 + cisplatin [70 mg/m2] or carboplatin [AUC 5] on d1 of each 3-wk cycle), or chemo. The primary analysis group included pembro monotherapy–treated pts; the sensitivity analysis group included pembro monotherapy–treated pts from KEYNOTE-052 and the choice of carboplatin subpopulation of pembro monotherapy–treated pts from KEYNOTE-361. Landmark analyses of OS by pts with CR, PR, SD, or PD per RECIST v1.1 by BICR at first imaging assessment (wk 9) were pooled for the ITT populations. Duration of CR/PR/SD and OS were estimated using the Kaplan-Meier method. Data cutoffs were Sep 26, 2020 (KEYNOTE-052) and Apr 29, 2020 (KEYNOTE-361). Results: The primary analysis group included 681 pembro-treated pts (KEYNOTE-052, N = 374; KEYNOTE-361, N = 307); the sensitivity analysis group included 544 pembro-treated pts (KEYNOTE-052, N = 374; KEYNOTE-361, N = 170). Median time from randomization to cutoff was 51.9 mo (range, 22.0-65.3) and 53.7 mo (range, 22.0-65.3) for the primary and sensitivity analysis groups, respectively. Twenty-five pts (4.6%) had CR and 135 (24.6%) had PR (primary group); 17 pts (3.9%) had CR and 105 (24.1%) had PR (sensitivity group). Median DOR was 25.9 mo for pts with CR/PR at wk 9; pts with CR/PR or SD at wk 9 had longer OS than pts with PD at wk 9 (Table). Conclusions: In this post hoc analysis, pts with advanced UC in KEYNOTE-052 and KEYNOTE-361 with CR/PR at wk 9 had better clinical outcomes with pembro monotherapy than pts with SD or PD; 1L pembro monotherapy continues to show efficacy in advanced UC. Clinical trial information: NCT02335424 and NCT02853305. [Table: see text]

103 Background: Prostate cancer with CDK12 inactivation represents a distinct subtype in mCRPC, tumors are characterized by excessive tandem duplications, genomic instability, gene fusion-caused putative neoantigens and increased tumor T cell infiltration. Retrospective experiences with ICI in CDK12 inactivation CRPC pts reported PSA and radiographic responses. We conducted a prospective multi-site clinical trial of ipilimumab and nivolumab in CDK12 inactivation or mutated cancers. Herein, we report our findings in the completed cohort A of men with mCPRC. Methods: Eligible pts had mCRPC (ongoing androgen deprivation therapy with serum testosterone £ 50 ng/dL) and putative CDK12 inactivation of function aberrations on any commercial or institutional CLIA/CAP approved next generation sequencing assay. Archival tumor tissue was requested for correlative biomarker analysis. Pts received nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV q3 weeks for up to 4 cycles, followed by maintenance nivolumab at 480 mg IV q4 weeks until disease progression, intolerable toxicity, or consent withdrawal. The primary endpoint was PSA response, defined as a greater than or equal to 50% decline in PSA from baseline. Secondary endpoints included safety/toxicity, secondary efficacy measures including QoL and overall survival. Exploratory objectives included baseline tumor whole exome analysis and changes in circulating immune profiles with therapy. Results: As of data cut-off in Aug 2021, 28 mCRPC pts enrolled in Cohort A; median ECOG PS was 1 (0-2 range), 22/28 had Gleason 8-10 cancer, mean baseline PSA at study entry was 231 ng/dL, all pts had received ≥1 prior oral androgen signaling inhibitor and ≥1 cytotoxic chemotherapy. Unconfirmed PSA ≥30% decline was seen in 6/28 pts (21.4%) and PSA ≥50% decline in 4/28 pts (14.2%). Grade ≥3 possible/probable/definite adverse events were noted in 7/28 (25%) and SAEs in 10/28 pts (35.7%). Six pts (21.4%) experienced a rapid PSA increase by ≥ 10-fold over baseline. Conclusions: Combination immunotherapy was reasonably tolerated in this heavily pre-treated population and was associated with unconfirmed PSA responses in a subset of pts. Ongoing correlative analyses could explain responses mechanistically. Enrollment in Cohort B of non-prostate cancers and Cohort C of nivolumab monotherapy in prostate cancer are still ongoing. Clinical trial information: NCT03570619.

35 Background: The OSPREY clinical trial was a phase 2/3 prospective study of prostate specific membrane antigen (PSMA) PET/CT using piflufolastat F 18. Piflufolastat F 18 (aka 18F-DCFPyL or PyL) is a novel PSMA-targeting radiopharmaceutical approved for imaging of PCa pts both at initial staging and for disease recurrence. Here we describe SUV results by biopsy status, baseline PSA levels, and Gleason score (GS). Methods: Piflufolastat F 18 -PET/CT was evaluated in men with NCCN high-risk PCa scheduled to undergo radical prostatectomy with pelvic lymphadenectomy (RP-PLND) (Cohort A) and men with radiologically suspected recurrent/metastatic PCa (Cohort B). A single IV dose of 9 mCi (333 MBq) of piflufolastat F 18 was administered followed by PET/CT acquisition 1-2 hours later. Piflufolastat F 18 uptake in various lesion locations as defined by maximum and peak SUV (SUVmax, SUVpeak) were determined by three blinded, independent central readers for each tissue (e.g., bone, lymph nodes (LN), soft tissue). To measure SUVs, the reader placed a volume of interest (VOI) on each identified lesion. SUVmax was defined as the maximum single-voxel SUV within the VOI. SUVpeak within the VOI was defined as the average SUV within a fixed-sized VOI (1 cm diameter sphere), representing the cluster with the highest average SUV. Results: 345 men underwent piflufolastat F 18-PET/CT. Cohort B (n = 93 evaluable) SUVmax and SUVpeak were significantly higher for biopsy positive (+) (one biopsy lesion/pt) when compared to biopsy negative (-) lesions from bone and LN. SUVpeak for biopsied bone and LN (Cohort B) appeared to increase with rising baseline PSA. In high-risk PCa pts, SUVpeak for prostate (Cohort A; n = 252 evaluable) increased with baseline PSA and were highest for GS 9-10 (Table). Conclusions: Piflufolastat F 18-PET/CT uptake was significantly higher in biopsy + lesions and increased with baseline PSA. Prostate SUVpeak was highest for GS 9-10. Clinical trial information: NCT02981368. [Table: see text]

129 Background: Pathogenic HRR gene mutations may confer sensitivity to PARP inhibitors (PARPi) and/or platinum chemotherapy (chemo). While pts harboring mutations in BRCA1/2 appear to benefit from these DNA damaging therapeutics, outcomes data for those with non- BRCA1/2 mutations are less robust. We evaluated outcomes in men with HRR gene-mutated PC who received treatment with PARPi and/or platinum-based chemo stratified by type of HRR alteration. Methods: Retrospective data from the PROMISE Consortium was utilized (PMID: 34363009). PC pts with pathogenic HRR mutations who received PARPi and/or platinum-based chemo were included. Differences in PSA progression-free survival (PFS), clinical/radiographic PFS (rPFS), and overall survival (OS) between those with BRCA1/ 2 mutations (Cohort A) and those with mutations in HRR genes that do not directly interact with the BRCA complex (Cohort B: ATM, CDK12, CHEK1, CHEK2, FANCL) were evaluated. We also evaluated outcomes in pts with HRR gene mutations known to interact with the BRCA complex aside from BRCA1/2 (Cohort C: RAD51B/C/D, RAD54L2, BARD1, GEN1, PALB2, FANCA, BRIP1). Results: Of 361 pts identified with HRR gene alterations, 89 received PARPi and 70 received platinum-based chemo. Prior therapy and metastatic disease sites were similar between cohorts. PSA PFS, rPFS, and OS were significantly improved in Cohort A vs. Cohort B with PARPi but not platinum-based chemo (Table). Sample size in cohort C was too small to allow for statistical comparison, although PSA PFS, PFS and OS were reasonably long. Conclusions: PC pts with BRCA1/2 mutations had improved outcomes to PARPi compared to those with mutations in HRR genes not directly interacting with the BRCA complex. Platinum-based chemo appeared effective regardless of which HRR gene was affected. [Table: see text]

536 Background: This trial evaluated COXEN, a gene expression model, as a predictive biomarker in muscle-invasive bladder cancer (BC) patients randomized to Gemcitabine-Cisplatin (GC) or dose-dense Methotrexate-Vinblastine-Adriamycin/doxorubicin-Cisplatin (ddMVAC). Primary results correlating COXEN with pathologic response at surgery have been reported. This secondary analysis includes progression-free (PFS) and overall survival (OS). Methods: Eligibility included Stage cT2-T4a N0 M0, urothelial BC (mixed histology allowed), ≥ 5 mm of viable tumor, cisplatin eligible, with plan for cystectomy. 237 patients were randomized between ddMVAC, given every 14 days for 4 cycles, and GC, given every 21 days for 4 cycles. Cox regression was used to evaluate COXEN score or treatment arm association with PFS and OS, adjusting for stratification factors (stage and PS). Results: 167 patients were included in the primary COXEN analysis all having either at least 3 cycles of chemo and surgery within 100 days of last chemo or having progressed while receiving chemo. The COXEN scores were not significantly prognostic for OS or PFS in their respective arms; the COXEN GC score was a significant predictor for OS in pooled arms. OS and PFS data are shown for both scores in the table. In the intent to treat analysis (n=227), there was no significant difference in OS or PFS for ddMVAC versus GC (for OS, HR =0.87, 95% CI 0.54-1.40), p = 0.57); for PFS (HR= 0.76 95% CI 0.58-1.01, p = 0.055). Association of path response with OS will be presented. Conclusions: The COXEN GC score may be prognostic of survival in those receiving platinum-based neoadjuvant treatment. The randomized, prospective design provides estimates of OS and PFS for GC and ddMVAC that appear comparable, but this phase II trial is underpowered for definitive comparisons. The prospective data and correlative samples from S1314 will allow for further assessment of COXEN and other RNA and DNA based predictive and prognostic biomarkers. Clinical trial information: NCT02177695. [Table: see text]

521 Background: First-line treatment with pembrolizumab (pembro) monotherapy has shown durable clinical activity in selected patients (pts) with advanced/unresectable or metastatic urothelial carcinoma (UC). In a pooled population of pts with advanced UC from the single-arm phase 2 KEYNOTE-052 (NCT02335424) and the randomized, open-label, phase 3 KEYNOTE-361 (NCT02853305) studies, this exploratory analysis evaluated the relationship between baseline characteristics and clinical outcomes of first-line pembro monotherapy. Methods: Cisplatin-ineligible pts with advanced UC were enrolled in KEYNOTE-052 and chemotherapy-naive pts with advanced UC were enrolled in KEYNOTE-361. For analysis of predictive factors for ORR and OS in pembro-treated pts, the purposeful selection method was used to build the multivariable logistic regression model (ORR) and multivariable Cox model (OS), beginning with a univariable analysis of each independent variable. Any variable in the univariate model with P < 0.10 was a candidate for the multivariate model. The stepwise selection method was used to select the variables in the final model. Significance of the final model was set at P < 0.05. Data cutoff dates were September 26, 2020 (KEYNOTE-052) and April 29, 2020 (KEYNOTE-361). Results: This pooled analysis included 681 pts treated with pembro monotherapy (KEYNOTE-052, N = 374; KEYNOTE-361, N = 307 [170 were cisplatin ineligible]). Median follow-up was 51.9 mo (range, 22.0-65.3). ORR was 29.4% (95% CI, 26.0-32.9; 69 CRs, 131 PRs), and median DOR was 33.2 mo (range, 1.4+ to 60.7+). Median OS was 12.5 mo (95% CI, 11.0-14.6). By multivariate analysis, independent factors significantly associated with higher ORR were PD-L1 status (combined positive score [CPS] ≥10 vs CPS < 10; odds ratio [OR], 1.90 [95% CI, 1.33-2.71]; P = 0.0004), site of metastasis (lymph node only vs visceral disease; OR, 1.66 [95% CI, 1.06-2.59]; P = 0.0265), liver involvement (absent vs present; OR, 1.75 [95% CI, 1.06-2.89]; P = 0.0294), and baseline hemoglobin level ≥10 vs < 10 g/dL; OR, 2.17 [95% CI, 1.09-4.31]; P = 0.0276). Multivariate analysis of OS is displayed in the Table. Conclusions: This exploratory multivariate analysis identified numerous factors, including PD-L1–positive status (CPS ≥10), lymph node only metastasis, and lower ECOG PS score, associated with improved clinical outcomes in pts with advanced UC treated with first-line pembro monotherapy. Clinical trial information: NCT02335424 and NCT02853305. [Table: see text]

TPS213 Background: Alterations in the cell cycle signaling pathway are common in mCRPC and may contribute to resistance to AR-targeted therapies. Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) have revolutionized the therapeutic landscape in ER+ breast cancer and have demonstrated robust anti-tumor activity in multiple pre-clinical mCRPC models such as enzalutamide-resistant cell lines, including those with the androgen-receptor splice variant 7 (AR-V7). Pre-clinical synergy has also been seen in multiple studies of CDK4/6i and anti-programmed death 1 (PD-1) or PD-ligand-1 (PD-L1). Additionally, loss of function alterations of CDK12, found in 5-7% of mCRPC, may confer vulnerability to anti-PD-L1 agents. Methods: This multi-center study will enroll 54 unselected mCRPC patients (pts), randomized 1:1 to abema (arm A) or abema + atezo (arm B); and 21 pts with known loss of function mutations in CDK12 (arm C) treated with atezo (n = 5) or abema + atezo (n = 16). All pts will undergo on-treatment (6-week) tumor biopsy. Treatment will be continued until disease progression and crossover is prohibited. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-1, biopsy-proven prostate adenocarcinoma, progressive metastatic disease per Prostate Cancer Working Group 3 (PCWG3), progression/intolerance to ≥ 1 novel antiandrogen in hormone-sensitive or CRPC setting, ineligible for docetaxel/cabazitaxel (progression within 12 months of taxane, pt refusal, investigator discretion), no uncontrolled comorbidity or history of pneumonitis/ILD. Arms A & B will use two stage design for co-primary endpoints of progression-free survival at 6 months using PCWG3 (6m-PFS) and objective response rate (ORR). If ≥ 1/12 pts meet either co-primary endpoint, 2nd stage will open to enroll 15 more pts in that arm. Treatment will be deemed to have meaningful clinical activity (MCA) if ≥ 6/27 meet 6m-PFS or ≥ 5/27 have an ORR. This will provide 86% power for 6m-PFS (34% vs. 12%) and 85% power for ORR (30% vs. 10%) at a one-sided α = 0.08. For MCA in arm C, 16 patients treated with abema+atezo will provide 80-85% power for 6m-PFS (34% vs. 12%) at a one-sided α = 0.05 using a one-sample log-rank test. Primary safety endpoint is the incidence of dose-limiting toxicities in pts receiving abema+atezo. Key secondary endpoints are clinical benefit rate (ORR + stable disease), duration of response and overall survival in arms A and B, and safety events in all arms. Primary exploratory endpoint is comparison of tumoral FoxP3+/CD8+ ratio in pts treated with abema vs. abema + atezo. Additional exploratory endpoints will evaluate association between response and genomic alterations identified from tissue or circulating tumor-derived exosomes. Enrollment began in July 2021 and projected enrollment goal is 3 years (NCT04751929). Clinical trial information: NCT04751929.

308 Background: The combination of immuno-oncology agents (IO) ipilimumab and nivolumab (IPI-NIVO) and combinations of IO with vascular endothelial growth factor targeted therapies (IOVE) have demonstrated efficacy in clinical trials for the first-line treatment of mRCC. This study seeks to establish real-world clinical benchmarks based on the International mRCC Database Consortium (IMDC) criteria using vascular endothelial growth factor targeted therapy (VEGF-TT) treated patients for context. Methods: The IMDC database (IMDConline.com) was used to identify patients with mRCC who received first-line IPI-NIVO, IOVE (axitinib/pembrolizumab, lenvatinib/pembrolizumab, cabozantinib/nivolumab, or axitinib/avelumab) and VEGF-TT (sunitinib or pazopanib) from 2002-2021. The primary endpoint was overall survival (OS) and was calculated from time of initiation of first-line therapy to death or last follow up. Log-rank tests were conducted to compare favorable, intermediate, and poor risk OS outcomes within treatment groups. Overall response rates (ORR) and complete response (CR) rates were calculated based on physician assessment of best clinical response. Results: In total, 692 patients received IPI-NIVO, 244 received IOVE, and 7152 received VEGF-TT. Baseline characteristics for IPI-NIVO, IOVE, and VEGF-TT, respectively, were as follows: median age (interquartile range) 63 (56-69), 64 (57-70), and 63 (56-70); male 72%, 74%, and 72% (p=0.74); non-clear cell histology 15%, 10%, and 13% (p=0.15); sarcomatoid features 24%, 15%, and 13% (p

317 Background: Metastatic renal cell carcinoma (mRCC) with pancreatic metastases (PM) is characterised by heightened angiogenesis, which is associated with improved outcomes with vascular endothelial growth factor (VEGF) inhibitors. We aimed to compare the efficacy of first-line (1L) ipilimumab/nivolumab (IOIO) vs. anti-PD(L)1/anti-VEGF (IOVE) vs. VEGF monotherapy (VE) in mRCC patients with and without PM. Methods: We performed a retrospective analysis of patients with and without PM, using the IMDC. Sites of metastases were captured at initiation of 1L. Patients with PM could also have metastases at other sites. We studied overall survival (OS) from start of 1L therapy using Cox regression, adjusted for IMDC risk groups. Kaplan Meier survival curves were generated. Results: 543/7,634 (7%) patients had PM. Patients with PM in the overall population had improved OS compared to those without, 56 vs 25.6 months respectively (HR 0.63, 95% CI 0.55-0.73, p

540 Background: The 3-arm, open-label, phase 3 KEYNOTE-361 study (NCT02853305) evaluated first-line pembro ± chemo vs chemo in advanced UC regardless of PD-L1 status. The trial did not meet its primary end points of superior PFS and OS with pembro + chemo vs chemo and thus analysis of pembro monotherapy (mono) vs chemo was exploratory. We explored the association of TMB status and PD-L1 combined positive score (CPS) with clinical outcomes in KEYNOTE-361. Methods: In pts with TMB and/or PD-L1 data, the association between TMB (via whole exome sequencing) and PD-L1 (via PD-L1 IHC 22C3 pharmDx) and clinical outcomes (ORR, PFS, and OS) was evaluated. In each treatment arm, the hypotheses regarding the associations were evaluated using logistic regression (ORR) and Cox proportional hazards regression (PFS; OS), and 1-sided (pembro; pembro + chemo) and 2-sided (chemo) P values were calculated; significance was prespecified at α = 0.05 without multiplicity adjustment. Clinical utility was assessed using prespecified cutoffs of 175 mut/exome (TMB) and CPS 10 (PD-L1). Clinical data cutoff was April 29, 2020. Results: 820/993 pts (82.6%) had evaluable TMB data (pembro, 252; pembro + chemo, 282; chemo, 286). TMB (log10) was significantly positively associated with ORR, PFS, and OS for pembro ( P < 0.001, < 0.001, and 0.007, respectively) and PFS and OS for pembro + chemo ( P= 0.007 and 0.010, respectively). The area under the receiver operating characteristics (AUROC) curve (95% CI) for discriminating response was 0.64 (0.56-0.71) for pembro, 0.53 (0.46-0.60) for pembro + chemo, and 0.52 (0.45-0.59) for chemo. Efficacy by TMB cutoff is reported in the Table. All 993 pts had PD-L1 data (pembro, 302; pembro + chemo, 349; chemo, 342). PD-L1 was significantly positively associated with PFS for pembro ( P= 0.006) and ORR for pembro + chemo ( P= 0.042) but not chemo. Efficacy by PD-L1 CPS is reported in the Table. Conclusions: Strong associations were observed between TMB and all 3 clinical outcomes (ORR, PFS, and OS) with pembro mono in the first-line setting and a reduced association was observed between TMB and clinical outcomes with pembro + chemo. No consistent associations were observed between PD-L1 and clinical outcomes with pembro mono or pembro + chemo. Clinical trial information: NCT02853305. [Table: see text]

138 Background: AR alterations such as ligand binding domain mutations and amplification evolve under the selective pressure of testosterone suppression and AR targeted agents (ARTA) such as abiraterone or enzalutamide, but their relevance to ARTA treatment outcomes remain unclear. Methods: PROMISE is a multi-institutional retrospective clinical-genomic database inclusive of aPC pts who had tissue and/or blood based genomic testing by commercially available CLIA-certified platforms. We analyzed men who received second generation ARTA and stratified patients according to genomic testing timing (pre-/post-ARTA), castration resistance, type of AR alteration, and PSA decline ≥50% on first ARTA. Time to progression (TTP) from first ARTA initiation was estimated using the Kaplan-Meier method and differences between subgroups defined by AR alteration status were assessed using the log-rank test. Results: 854 pts who received ARTA and had tissue-based (n = 600) or blood-based (n = 335) genomic testing were included. Median age was 62 (range, 33-93). Pre- and post-ARTA genomic testing was available in 387 and 467 pts, respectively. AR alterations were identified in 16% (61/387) of pre-ARTA and 48% (226/467) of post-ARTA pts with AR amplifications in 10% (38/387) and 35% (161/467) of the pts, respectively. 15/52 pts who had pre- and post-ARTA testing developed a new AR alteration. In pre-ARTA cohort; castration status, median TTP, and PSA response for 1st ARTA according to alteration status are summarized in the table. In the post-ARTA group, the most common AR mutations were L702H (53%), followed by T878A (33%); whereas, in the pre-ARTA group, the H875Y (26%) mutation was most common. AR mutations in post-ARTA group were seen at similar rates regardless of prior docetaxel exposure (14.3% vs 18.0%, p = 0.46) and following first abiraterone vs enzalutamide/apalutamide exposure (48.6% vs 48.3%, p = 1.0). Conclusions: AR mutations, unlike amplifications, were associated with shorter TTP on abiraterone. Genomic testing should be considered before second line ARTA.[Table: see text]

530 Background: Localized muscle-invasive bladder cancer (MIBC) exhibits heterogeneous molecular features and outcomes, with a 5-year mortality rate of approximately 30%. Immune checkpoint blockade (ICB) has the potential to improve oncological outcomes but molecular tools are needed to identify those most likely to benefit. Here, we integrate transcriptomically derived tumor immune microenvironment (TIME) data with molecular subtypes to create a novel integrative classifier with prognostic and therapeutic implications. Methods: RNAseq data from patients with localized muscle-invasive bladder cancer (MIBC) from the Cancer Genome Atlas BLCA (TCGA-BLCA) project was utilized (n = 187). CIBERSORT was used for immune cell deconvolution, and unsupervised hierarchical clustering divided the cohort based on similar immune profiles. Consensus molecular clustering information for the cohort was obtained from Kamoun et al. Overall survival (OS) of each cluster were analyzed. The tumor immune dysfunction and exclusion (TIDE) tool, which uses a genomic signature validated on immunotherapy treated melanoma patients to model tumor immune evasion, was then used to predict response to ICB. Results: In the TCGA-BLCA cohort, there were two distinct clusters enriched with macrophages, CL1-M0Hi (n = 18) and CL5-M2Hi (n = 35). Compared to the rest of the cohort, these two macrophage enriched clusters combined exhibited a decreased OS (33.1 mo vs. NR, p = 0.01). TIDE tool predicted ICB response was lowest in CL1 (6/18, 33%; p = 0.09), CL5 (12/35, 34%; p = 0.02), and the Ba/Sq molecular cluster (16/57, 28%; p = 1.3x10-5). Patients designated as CL1 or CL5 by immune clustering and Ba/Sq by molecular consensus were combined into a subgroup (n = 20). Compared to the rest of the cohort, this Ba/Sq_MacrophageHi subgroup had a higher body mass index (31.0 vs. 25.8 BMI, p = 0.0004), more whites (95% vs. 64%, p = 0.03), and had a higher stage (80% Stage III/IV vs. 20% Stage I/II, p = 0.05). The Ba/Sq_MacrophageHi cluster demonstrated higher PD-L1 expression (mean Z score 0.15 vs. -0.09; p = 0.008), there was a higher degree of T cell exclusion (mean Z score 0.16 vs. -0.06; p = 0.003) and cancer-associated fibroblasts (mean Z score 0.03 vs. -0.02; p = 3.4x10-5). Overall, the predicted response to ICB by TIDE in the Ba/Sq_MacrophageHi was lower (OR 0.15, 0.03-0.55 p = 0.002) and OS was significantly shorter (median 16.7 mos vs. 54.9 mo, p = 0.04). Conclusions: We demonstrated the prognostic significance of the Basal/Squamous subtype with macrophage enrichment in patients with localized MIBC. Pending further prospective validation, this sub-population may be less amenable to ICB treatment.

32 Background: Conventional imaging and bone scintigraphy are suboptimal modalities for identifying PCa. PSMA-based imaging is highly promising for PCa detection. 18F-DCFPyL is a novel PSMA-targeted radiopharmaceutical for positron emission tomography (PET) that may be useful in staging of PCa. The diagnostic performance, detection rate, and potential impact of 18F-DCFPyL on staging of pts with high- risk PCa have been previously reported. Here we report on the impact of 18F-DCFPyL on staging of pts with PCa recurrence or metastases on conventional imaging. Methods: 18F-DCFPyL-PET/CT was evaluated in 117 men with radiologic evidence of local recurrence or metastatic disease on baseline anatomical imaging (CT, MRI) or whole-body bone scintigraphy and in whom at least one lesion was deemed amenable to biopsy. A single dose of 9 mCi (333 MBq) of 18F-DCFPyL was administered via intravenous injection, followed by PET/CT acquisition 1 to 2 hours thereafter. Based on TNM staging: prostatic (T), pelvic LN (N), extra-pelvic LN (M1a), bone (M1b) and other visceral organs/soft tissue (M1c), 18F-DCFPyL-PET/CT detection rates including lesion counts were systematically analyzed. Three central, blinded, and independent readers evaluated the 18F-DCFPyL scans. Results: In this study, 82 (70%) patients had baseline radiographic M1 stage disease (14 patients with M1a, 50 patients with M1b, 18 patients with M1c) and 33 (28%) patients were M0 stage at baseline by central conventional imaging review; two patients were unevaluable. 18F-DCFPyL-PET/CT up-staged 58% (19/33) of pts from M0 to M1, of whom 91% (10/11) who underwent an extra-pelvic biopsy were confirmed to have M1 disease by pathology, including 9 patients with M1b and 1 patient with M1a. Of the patients who were staged M1 at baseline, 18F-DCFPyL-PET/CT upstaged 16% (10/64; M1a to M1b or M1c: n = 4; M1b to M1c: n = 6) of pts to a higher M1 sub-stage and down-staged 22% (18/82) to M0. Conclusions: 18F-DCFPyL-PET/CT identified M1 disease in the majority of patients examined who otherwise had locoregional disease. These data suggest that 18F-DCFPyL-PET/CT may be a useful tool in properly staging men with both metastatic and nonmetastatic relapsed disease, which could lead to superior treatment paradigms than currently exist using conventional imaging. Clinical trial information: NCT02981368.

191 Background: Translational studies have shown that CDK12 mutations may delineate an immunoresponsive subgroup of PC, characterized by high neoantigen burden. Given that these mutations may define a clinically relevant PC subgroup, we sought to describe outcomes to both standard drugs and PD1 inhibitors. Methods: Clinical data from consecutive patients with CDK12 mutations were retrospectively collected from 7 centers. Multiple clinical grade sequencing assays were used to assess for CDK12 alterations. Descriptive statistics included PSA50 (≥50% decline in PSA from baseline) and clinical/radiographic progression-free survival (PFS). Results: Of 56 CDK12-mutated PC patients, 27 (48%) had biallelic CDK12 alterations. At diagnosis, 46 (82%) had Gleason grade group 4-5 disease, 52% had T3-T4 disease and 15 (27%) had M1 disease. Median follow up was 8.2 yrs (95% CI: 5.6-11.1) and 53 (95%) developed metastatic disease. Median overall survival (OS) from metastasis was 3.9 years (95% CI: 3.2-5.8). Nineteen patients received an anti-PD1 therapy. PSA50 responses to PD1 blockade were infrequent and overall PFS was short (Table); however, the estimated 9-month PFS was 23%. PFS was higher in chemotherapy naïve patients who received anti-PD1 therapy (P=0.004). Outcomes were similar in monoallelic vs. biallelic CDK12-mutated patients. Conclusions: CDK12-mutations define an aggressive PC subgroup, with a high rate of metastatic disease and short OS. Immune checkpoint inhibitors may be effective in a minority of these patients and exploratory analysis supports using anti-PD1 drugs early.[Table: see text]

1014 Background: TAPUR is a phase II basket study evaluating the anti-tumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. P is an immune checkpoint inhibitor and HTMB is an emerging predictive biomarker for checkpoint inhibitor therapy. Results in a cohort of MBC pts with HTMB treated with P are reported. Methods: Eligible pts had advanced cancer, no standard treatment options, ECOG PS 0-1, measurable disease and acceptable organ function. Genomic testing was performed using commercially available tests selected by sites. Pts matched to P had HTMB defined as ≥9 mutations/megabase (Muts/Mb) by a FoundationOne test (n=20) or approved by the TAPUR Molecular Tumor Board for other tests (n=8). A Simon two-stage design was used to test a null rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16 weeks (wks) (SD16+)), an additional 18 pts are enrolled. If ≥7 of 28 pts have DC, the drug is considered worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-eight female MBC pts were enrolled from October 2016 to July 2018. Pts received P at 2 mg/kg (n=8) or 200 mg (n=20) IV over 30 minutes, every 3 wks. HTMB ranged from 9 to 37 Muts/Mb. Demographics and outcomes are summarized in Table (N=28). No relationship was observed between #Muts/Mb and PFS or OS. Two grade 3 AEs (weight loss and hypoalbuminemia) and 1 grade 2 SAE (urinary tract infection) were reported as at least possibly related to P. Conclusions: P demonstrated anti-tumor activity in heavily pre-treated MBC pts with HTMB . Additional study of P is warranted in MBC pts with HTMB. Clinical trial information: NCT02693535. [Table: see text]

TPS496 Background: There are currently no standard treatment options for patients with mUC that has progressed on or after platinum (cisplatin/carboplatin)–based chemotherapy (PBC) and/or immune checkpoint inhibitors (ICIs), emphasizing the need for new therapies. Analysis of The Cancer Genome Atlas bladder cancer dataset suggests that approximately 60% of bladder cancer tumors have homologous recombination deficiency (HRD), as defined by high genomic loss of heterozygosity (LOH) or a deleterious mutation in a homologous recombination pathway gene. The poly(ADP-ribose) polymerase inhibitor (PARPi) rucaparib has demonstrated activity in tumors with HRD and in homologous recombination proficient tumors in the recurrent ovarian cancer setting. The ATLAS (NCT03397394) trial will evaluate the efficacy and safety of rucaparib in patients with locally advanced/unresectable UC or mUC treated with 1–2 prior anticancer treatments. Methods: Eligible patients must have measurable disease per RECIST v1.1, adequate organ function, and radiographic progression after 1–2 prior regimens (eg, PBC and/or ICI). Confirmation of HRD status before enrollment is not required, but fresh tumor tissue or recently obtained archival tissue is mandatory for HRD profiling. Prior PARPi treatment is exclusionary. All patients will receive oral rucaparib 600 mg BID until disease progression or other reason for discontinuation. The coprimary endpoints are confirmed objective response rate (investigator-assessed per RECIST v1.1) in the intent-to-treat and HRD-positive (signature based on tumor genomic LOH) populations. Secondary endpoints include response duration, progression-free survival, overall survival, safety, and pharmacokinetics. Exploratory endpoints include evaluation of molecular biomarkers associated with response and resistance to rucaparib, including changes in plasma and tumor samples, and circulating tumor DNA. Patients are being enrolled in 6 countries (France, Germany, Italy, Spain, UK, and USA), with a target enrollment of 200 patients. The study has > 90% power to reject the null hypothesis (P = 0.10) at a 5% significance level if the true response rate for rucaparib is 20%. Clinical trial information: NCT03397394.