Corn, Paul Gettys

4515 Background: Adenocarcinomas of the urinary tract are rare malignancies with limited prospective data. Outcomes of triplet chemotherapy remain poorly defined. Methods: This was a prospective, single-arm, phase II study (NCT00082706) conducted at MD Anderson. Between 2005 and 2010, patients (pts) aged ≥18 years with ECOG 0–2 and metastatic or unresectable urachal (UA) or non-urachal adenocarcinoma (NUA) received frontline GemFLP (5-fluorouracil 200 mg/m² continuous infusion ×5 days with leucovorin 23 mg IV daily ×5; cisplatin 20 mg/m² IV daily ×5; gemcitabine 200 mg/m² IV on days 1 and 5). Best overall response (BOR) was assessed by imaging. Primary endpoints were objective response rate (ORR) and overall survival (OS); secondary endpoint was toxicity. PFS was calculated from treatment initiation and duration of response (DoR) from first CR/PR to progression or death; time-to-event endpoints were estimated by Kaplan–Meier (KM). Post hoc analyses evaluated baseline tumor markers (CEA, CA19-9, CA125, β-hCG) Treatment-related adverse events (TRAEs) were graded per CTCAE v5. Results: Forty-six pts were enrolled (28 UA, 18 NUA). Median age was 58 years; 41% were de novo metastatic, and 78% had visceral metastases. ORR was 44% (20/46). Among responders, median DoR was 8.6 months (95% CI 4.6–30.8). median PFS was 3.3 months (95% CI 2.3–8.4) and median OS (mOS) was 21.0 months (95% CI 15.9–35.3) There was no difference in PFS (p=0.39) or OS (p=0.99) between UA and NUA. Baseline CEA, CA19-9, CA125, and β-hCG were not associated with ORR or PFS. Higher baseline CA125 was associated with inferior OS (HR 1.33, 95% CI: 1.12–1.58; p =0.001) Subsequent systemic therapy was administered to 28 pts (60.9%); median number of subsequent treatment lines was 2 (range 1–5). The most common hematologic TRAEs were anemia (28.1%; grade ≥3 [G3] 12.5%), thrombocytopenia (21.9%; G3 12.5%), and neutropenia (12.5%; G3 9.4%). The most frequent non-hematologic TRAEs were dehydration (21.9%; G3: 6.2%), diarrhea (9.4%; G3 6.2%) and catheter-related thrombosis (9.4%; G3 9.4%). No grade 5 events occurred. Conclusions: In this prospective phase II study, frontline GemFLP achieved a 44% ORR with durable responses (mDoR 8.6 mo) and 21 mo mOS in advanced UA and NUA. Survival did not differ between UA and NUA subtypes. Baseline CA125 was associated with OS. Toxicity was manageable. These data provide a prospective benchmark for this rare disease. Clinical trial information: NCT00082706 . Variable UA (n=28) NUA (n=18) Characteristics Age, median [ICR] 58 [54– 62] 58 [54– 62] 67 [ 62-72] Race, n (%) White 22 (79) 11 61) Black 6 (21) 6 (33) Other 0 1 (6) Prior surgery for localized disease, n (%) 18 (64) 5 (28) Mets at baseline Any 24 (86) 7 (39) Lung 6 (21) 4 (22) Liver 3 (11) 0 Peritoneum 17 (61) 0 Bone 3 (11) 3 (17) Nodal-only mets 1 (3) 2 (10) Outcomes ORR (%) 43.5 35.7 55.6 BOR n (%) CR 4 (14) 2 (11) PR 6 (21) 8 (44) SD 11 (39) 4 (22) PD 6 (21) 3 (17) NE 1 (4) 1 (6)

PURPOSE We tested the hypothesis that adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy improves progression-free survival (PFS) among patients with oligometastatic disease. METHODS EXTEND was a multicenter randomized phase II trial. Patients with 1-5 metastases were randomly assigned to MDT + SOC versus SOC in one of the six baskets (breast, pancreas, kidney, two prostate baskets, and an other basket) with basket-specific stratification and powering. PFS, the primary end point, was prespecified in the per-protocol set within each basket, across all baskets, and across all baskets excluding the prostate baskets. Exploratory end points included circulating tumor DNA (ctDNA) and immune profiling. RESULTS From 2018 through 2023, 521 patients were screened, 350 were randomly assigned, and 334 were analyzed per protocol (MDT + SOC, n = 166; SOC, n = 168). Radiotherapy was used as MDT for 98% of metastases (370/379). Overall, after a median follow-up of 53 months, PFS was improved with MDT + SOC (hazard ratio [HR], 0.54 [95% CI, 0.41 to 0.72], P < .001). Similarly, PFS was improved when excluding the prostate baskets (HR, 0.60 [95% CI, 0.40 to 0.89]). Within each basket, PFS superiority was identified for the pancreas, prostate, and other baskets, whereas the breast and kidney baskets were inconclusive. At enrollment, detectable ctDNA correlated with shorter PFS and survival; by contrast, ctDNA clearance 3 months postenrollment correlated with improved survival. MDT + SOC-induced systemic immune activation was most pronounced among baskets demonstrating PFS superiority. CONCLUSION The phase II EXTEND trial supports the addition of MDT to SOC for oligometastatic disease. Histology-specific efficacy signals were identified for phase III testing. Translational insights suggest the potential for optimizing the definition of oligometastasis using ctDNA and point to systemic immune responses as a possible mechanism of benefit from MDT.

140 Background: In the phase II EXTEND iADT omPC basket, MDT+iADT improved progression-free survival (PFS) vs iADT. Here we present the primary results of the EXTEND cADT omPC basket. We further report a pre-specified combined analysis with updated results from the iADT basket and examine the effects of MDT on immunity. Methods: Patients with 1 to 5 omPC metastases were randomized 1:1 to MDT+cADT vs cADT (NCT03599765). MDT consisted of definitive local therapy. cADT consisted of ADT +/- second-generation anti-androgens. The primary endpoint was per-protocol PFS, defined by biochemical criteria (Prostate Cancer Working Group 3), radiologic measures (RECIST v1.1), clinical progression, or death. 87 patients were needed to show superiority at a one-sided P of 0.10 by log-rank test. CDR3 regions in rearranged T cell receptor (TCR) β-chains from pre- and post-enrollment peripheral blood were sequenced with immunoSEQ (Adaptive Biotech). TCR repertoire modulation was defined as having TCR expansion plus contraction using a false-discovery-corrected betabinomial model. TCR sequencing from the ORIOLE trial (NCT02680587) was assessed for external validation. Results: From 2018 to 2022, 87 randomized patients were treated per protocol (MDT+cADT: 45; cADT: 42). 39% had castrate resistant omPC. MDT was definitive radiotherapy in all cases. With median follow-up of 31 mo, median PFS was 47 mo after MDT+cADT vs 22 mo after cADT (HR 0.50; 95% CI 0.23 to 1.08; one-sided P = 0.036). In the combined analysis (N=174) with median follow-up of 42 mo, MDT+ADT improved PFS (HR 0.45; 95% CI 0.30 to 0.69; P < 0.001), radiologic PFS (HR 0.63; 95% CI 0.40 to 0.97; P = 0.038), and castration-resistance free-survival (HR 0.40; 95% CI 0.19 to 0.82; P = 0.013). MDT+ADT had higher odds of TCR repertoire modulation vs ADT (55% vs 15%, P < 0.001). This finding was validated in the ORIOLE trial (MDT: 57% vs observation: 19%, P = 0.03). Among the subset of patients with extreme responses, random forest modeling of 37 clinical/immune variables identified TCR repertoire modulation as the variable with highest importance; further, MDT+ADT induced TCR repertoire modulation in all patients with favorable responses (i.e. PFS > 4 years) and none with unfavorable responses (i.e. PFS < 1 year). Among all patients randomized to MDT+ADT, TCR repertoire modulation was associated with longer PFS (HR 0.21; 95% CI 0.06 to 0.76; P = 0.02). Conclusions: MDT+cADT met the PFS primary endpoint of the phase II EXTEND trial, warranting phase III testing. From the combined analysis, MDT+ADT may also improve longer term outcomes including radiologic PFS and castration-resistance-free survival. Improved outcomes may result from MDT-induced immunomodulation, with implications for future trial design. Clinical trial information: NCT03599765 .

259 Introduction: RA-223 prolongs OS in BM-CRPC pts but predictive markers are lacking. We hypothesized that molecular profiling of plasma-derived extracellular vesicles (EVs) from BM-CRPC pts treated with RA-223 would predict efficacy and inform development of combinations. Methods: Paired baseline (BL) and end of treatment (EoT) blood samples were collected from 25 pts treated with RA-223. Pts were stratified by median OS into 3 groups: 1) 6.3 months (range 3.3-8.5, n=5 pts, UnFav OS), 2) 18.2 months (range 12.6-19.4, n=7 pts, Middle OS) and 3) 27.6 months (range 23.1-33.8, n=13 pts, Fav OS). EVs were isolated from plasma and analyzed for specific proteins and RNA transcripts. Marker profiles by domain and analytic method were determined in pts from the stratified OS groups. Results: At EoT, there is enrichment of RNA transcripts and proteins involved in regulating immune responses, DNA Damage Response (DDR) and bone metabolism (Table). By benchmarking molecular signatures in pts with UnFav Os and Fav OS, we could analyze the molecular profiles of pts in the Middle OS group and stratify them to UnFav OS or Fav OS groups. Conclusion: Plasma-based molecular markers are predictive for RA-223 efficacy. An association between OS and immune and DDR profiles in men with BM-CRPC may indicate mechanism of action and identify subsets most likely to benefit. These preliminary results provide rationale for combination therapy with RA-223 and immune-checkpoint blockade or PARP inhibition. Clinical trial information: NCT02135484. [Table: see text]

169 Background: Cabozantinib (Cabo), a tyrosine kinase inhibitor of c-Met and VEGFR2, modulates the tumor microenvironment in a therapeutically favorable manner. We combined Cabo with androgen deprivation therapy (ADT) in patients (pts) with androgen-dependent metastatic prostate cancer (PCa) (NCT01630590). Methods: Pts received Cabo (starting dose 60 mg PO daily) and ADT with a GnRH analogue. Pts could receive up to 3 months of ADT prior to initiating Cabo. Bone scan (BS) and CT scans were performed every 12 weeks (wks). Efficacy endpoints included response in markers, BS and RECIST, and time to castrate-resistant progression defined by radiographic progression, clinical progression, or receipt of additional anti-cancer therapy. Results: From 01/27/2014 to 01/12/2016, 62 pts were enrolled: 94% (58/62) with bone metastasis, 56% (35/62) with measurable disease, 15% (9/62) with visceral involvement and 26% (16/62) with prior treatment of their primary tumor. 79% (49/62) of pts have high volume disease defined by > 4 bone lesions and/or involvement of viscera. Median time from start of ADT to start of Cabo was 3.4 wks. Improvements in BS were observed in 81% (44/54) of evaluable pts including complete responses (CR) in 15% (8/54). In evaluable pts with measurable disease, best response was stable disease in 9% (3/33), PR in 61% (20/33) and CR in 30% (10/33). Reductions in PSA > 90%, bone specific alkaline phosphatase > 50% and urine N-telopeptides > 50% occurred in 83% (50/60), 87% (34/39), 86% (19/22) of evaluable pts, respectively. With a median follow up of 21.4 months (mo), median PFS is 15.6 mo. Median duration of Cabo treatment is 13 mo. Most common toxicities are Grade 3 hypertension (16%), pulmonary embolus (6%), diarrhea (4%), fatigue (3%), nausea (3%), and deep venous thrombosis (3%) with no Grade 4 events. Cabo dose reductions to 40 and 20 mg occurred in 68% and 18% of pts, respectively, with discontinuations due to toxicity in 10% of pts. Conclusions: Cabo plus ADT has potent clinical activity in pts with high volume androgen-dependent PCa including improvements BS and reduction in markers of bone stromal function. Studies are underway to identify biomarkers predictive of best response. Clinical trial information: NCT01630590.